Insights Into Effects of Natural Bioactive Components on Inflammatory Diseases in Respiratory Tract

ABSTRACT

The increasing prevalence of inflammatory diseases in the respiratory tract worldwide has raised concerns, and due to its high prevalence and poor prognosis, it remains a clinical focus and research hotspot. These inflammatory diseases include airway inflammation, asthma, bacterial antigens‐induced tonsil epithelial inflammation, chronic obstructive pulmonary disease (COPD), cystic fibrosis (CF), COVID‐19, acute lung injury, and lung cancer. This review summarizes the relevant molecular mechanisms of inflammatory diseases in the respiratory tract and the progress of natural bioactive components in inflammatory diseases in the respiratory tract. The natural bioactive components have good therapeutic or intervention effects on inflammatory airway diseases in vitro, in vivo, and in clinical trials. The information on inflammatory diseases in the respiratory tract and natural bioactive ingredients in anti‐inflammatory diseases were collected from famous literature databases such as Web of Science, PubMed, and Google Scholar, with keywords including bioactive components, inflammatory diseases, respiratory tract, and so forth. The bioactive phytochemicals, such as curcumin, ginsenoside, safranal, melatonin, could improve inflammatory diseases through the regulation of PI3K/Akt, NF‐κB, NRF2/HO‐1, MAPK, cAMP‐PKA, and MEK/ERK Signaling pathways. Further high‐quality studies are still needed to firmly establish the clinical efficacy of bioactive ingredients. This review provides new insight for future research on functional food or drug‐lead compound development on natural products improving inflammatory diseases in the respiratory tract.

Abbreviations

6MWT

6‐min walk test

AEC

absolute eosinophil count

Akt

protein kinase B

ALI

acute lung injury

AMPK

adenosine monophosphate‐activated protein kinase

α‐SMA

α‐smooth muscle actin

Bad

Bcl‐xL/Bcl‐2 asociated death promoter

Bax

Bcl‐2 Associated X

Bcl‐2

B‐cell lymphoma‐2

Bcl‐xL

B‐cell lymphoma‐extra large

BHK

Baby hamster kidney

BSS

Bronchitis Severity Score

cAMP

cyclic adenosine monophosphate

CAT

catalase

CD4+

cluster of differentiation 4+

CD40

cluster of differentiation 40

CF

cystic fibrosis

CFTR

cystic fibrosis conductance regulator gene

CL

chlorine

COPD

chronic obstructive pulmonary disease

COX‐2

cyclooxygenase 2

CS

cigarette smoke

DCs

dendritic cells

DNA

deoxyribonucleic Acid

ER

endoplasmic reticulum

ERK

extracellular signal regulated kinases

ERK1/2

extracellular regulated protein kinase 1/2

FcεRI

type I high‐affinity IgE receptors

FEV1

forced expiratory volume in 1 s

FoxO3

fork‐head box O3

FRT

flp recombination target

FVC

forced vital capacity

GCLM

glutamate‐cysteine ligase modifier subunit

GPX

enhanced glutathione peroxidase

GSH

glutathione

GSK3β

glycogen synthase kinase 3β

HO‐1

haem oxygenase 1

HPFs

human pulmonary fibroblasts

IFN

interferon

IFN‐γ

interferon‐gamma

IgE

immunoglobulin E

IGF

insulin like growth factor

IgG

immunoglobulin G

IgM

iommunoglobulin M

IL

interleukin

IL‐10

interleukin‐10

IL‐13

interleukin‐13

IL‐17

interleukin‐17

IL‐1β

interleukin‐1 beta

IL‐33

interleukin‐33

IL‐4

interleukin‐4

IL‐5

interleukin‐5

IL‐6

interleukin‐6

IL‐8

interleukin‐8

iNOS

inducible nitric oxide synthase

IRE1α

inositol‐requiring enzyme 1α

JNK

C‐Jun N‐terminal kinase

LDLC

low‐density lipoprotein cholesterol

LTC4

leukotriene C4

MAPK

mitogen‐activated protein kinase

MDA

malondialdehyde

Melatonin

N‐acetyl‐5‐methoxytryptamine

MMP1

matrix metalloproteinase‐1

MMP9

matrix metalloproteinase‐9

mMRC

modified medical research council

mRNA

messenger RNA

mTOR

mammalian target of rapamycin

Na

sodium

NF‐κB

nuclear factor‐kappa B

NLRP3

NOD‐, LRR‐ and pyrin domain‐containing protein 3

NOE

extracts of nasturtium officinale

Nrf2

nuclear‐factor‐E2‐related factor‐2

OligoG

alginate oligosaccharide

OVA

ovalbumin

PAI‐1

plasminogen activator inhibitor‐1

p‐AKT

phosphorylated protein kinase B

PCO

protein carbony

PEF

peak expiratory flow

p‐ERK1/2

phosphorylated extracellular regulated protein kinase 1/2

PFT

pulmonary function test

PGD2

prostaglandin D2

PI3K

phosphoinositide 3 kinase

p‐IKK

phosphorylated inhibitor of kappa B kinase

p‐JNK

phosphorylated c‐Jun N‐terminal kinase

PKA

protein kinase A

PSA

passive systemic anaphylaxis

PUMA

P53 upregulated modulator of apoptosis

Resveratrol

3,4′,5‐trihydroxystilbene

ROS

reactive oxygen species

SIRT1

sirtuin 1

SOD

superoxide dismutase

T3SS

type 3 secretion system

TGF‐β1

transforming growth factor beta 1

Th1

T helper 1

Th17

T helper 17

Th2

T helper 2

TLRs

toll‐Like receptors

TNF‐α

tumor necrosis factor α

TNF‐β

tumor necrosis factor β

TSLP

thymic stromal lymphopoietin

WBC

white blood cell

1. Introduction

Worldwide, chronic obstructive pulmonary disease (COPD), asthma, and cystic fibrosis (CF) are the leading causes of disease and death, which impose a heavy burden on healthcare systems, economies, and societies in many countries (Kumar et al. 2024). These diseases, including airway inflammation, asthma, bacterial antigens‐induced tonsil epithelial inflammation, chronic obstructive pulmonary disease (COPD), cystic fibrosis (CF), COVID‐19, acute lung injury, and lung cancer, are closely related to the occurrence and development of inflammation. The occurrence of inflammatory diseases in respiratory tract is due to abnormal development of enzymes and prostaglandins associated with airway oxidative stress, bronchial smooth muscle hypertrophy, and proliferation, hyperresponsiveness, and mucin hypersecretion (Dua et al. 2019; Mehta et al. 2019). Furthermore, these diseases in respiratory tract are all related to inflammatory mechanisms involving inflammatory cells such as macrophages, lymphocytes, neutrophils, and eosinophils (Rahman et al. 2022). The coordination of multiple inflammatory mediators is a typical feature of these inflammations in respiratory tract (Prasher et al. 2020), including histamine, tumor necrosis factors (TNF‐α), interleukins, IL‐1β, IL‐4, IL‐5, IL‐6, prostaglandins, leukotrienes, and nitric oxides (Santana et al. 2016). Therefore, studying the therapeutic effects and molecular mechanisms of potential intervention strategies for inflammatory diseases in respiratory tract has become a multidisciplinary research hotspot.

Since ancient times, people have used natural products from natural sources to treat inflammation and related diseases. Modern scientists also use vegetables and fruits from natural sources as a treasure trove for future treatment of inflammation because bioactive ingredients obtained from natural sources have no or low side effects (Zhu, Du, and Xu 2018). Specifically, the ethanol extract of Zataria multiflora and ginsenoside from Panax ginseng have been shown to have the improving effect in treating COPD in the in vivo and in vitro studies, respectively (Boskabady and Gholami Mhtaj 2014). Furthermore, Curcumin has been found in animal experiments to improve COPD by regulating the NF‐κB signaling pathway, and the randomized, double‐blind, and placebo‐controlled clinical trials have also demonstrated that Curcumin can improve the inflammatory status and respiratory indicators of COPD patients (Yuan et al. 2018; Zare'i et al. 2024). The ethanol extract of Nasturtium officinale and the water extract of Agaricus blazei have also been shown to have curing effect in treating asthma in vitro and in vivo experiments (Shakerinasab et al. 2024). In addition, more bioactive ingredients from natural sources can potentially improve inflammatory diseases in respiratory tract, and their therapeutic mechanisms will be discussed in detail in this review.

This study represented a systematic review conducted in alignment with the PRISMA criteria. The research method of this review is to search for all published original literature as of March 2024 through well‐known academic databases such as Web of Science, PubMed, and Google Scholar, and so forth. The primary literature screening method is to investigate whether there are various combinations of the following keywords in the title and abstract: natural product, bioactive components, airway inflammation, asthma, bacterial antigens‐induced tonsil epithelial inflammation, chronic obstructive pulmonary disease, cystic fibrosis, COVID 19, acute lung injury, and lung cancer. The detail is illustrated in a PRISMA flow chart of the study selection process (Figure 1). Therefore, this study aims to (1) systematically collect and organize research literature on the anti‐inflammatory effect of natural product bioactive ingredients in respiratory tract from well‐known academic databases, and (2) systematically summarize the underlying molecular mechanisms by which natural ingredients play an anti‐inflammatory role in respiratory diseases. This review concludes relevant in vivo, in vitro studies, and clinical trials, indicating that natural product bioactive components exert anti‐inflammatory effects in respiratory tract through the different molecular mechanisms (Figure 2), and provides new insight for the functional food development based on the bioactive components from natural products improving the inflammatory diseases in the respiratory tract.

FIGURE 1.

Flowchart of literature selection.

FIGURE 2.

The natural bioactive components improving the inflammatory diseases in respiratory tract including airway inflammation, asthma, bacterial antigens‐induced tonsil epithelial inflammation, chronic obstructive pulmonary disease (COPD), cystic fibrosis (CF), COVID‐19, acute lung injury, and lung cancer.

2. The Natural Bioactive Components With Anti‐Inflammatory Effect in Respiratory Tract

The active components from natural sources have biological activities to improve various inflammatory diseases in respiratory tract, including airway inflammation, asthma, tonsil epithelial inflammation, COPD, cystic fibrosis, COVID 19, acute lung injury, and lung cancer (Table 1). These components include polyphenols, flavonoids, amine hormones, monoterpene phenols, terpenes, diterpenoids, triterpenoid saponins, and lignans. Specifically, natural components that can improve airway inflammation contain resveratrol (Donnelly et al. 2004) and quercetin from Vitis vinifera (Donnelly et al. 2004; Hohmann et al. 2019; Schafer et al. 2017), and melanin from milk (Kim et al. 2012). The bioactive ingredients from foods that ameliorate asthma include safranal in Crocus sativus , isoflavone in Glycine max , carvacrol in Origanum hirtum, water extract of Agaricus blazei, and ethanol extract of Nasturtium officinale . Moreover, the Tualang honey from Apis dorsata (Devasvaran et al. 2019) and bovine lactoferrin can improve the bacterial antigens‐induced inflammation in tonsil epithelial (Ajello et al. 2002). The phytochemicals for treating COPD are ginsenoside from Panax ginseng (Xu et al. 2020), curcumin from Curcuma longa (Yuan et al. 2018), and ethanol extract of Zataria multiflora (Boskabady and Gholami Mhtaj 2014; Ghorani et al. 2022). What's more, the bioactive compounds for improving Cystic fibrosis include curcumin from Curcuma longa (Dragomir et al. 2004; Egan et al. 2004; Quispe et al. 2022), oridonin from Rabdosia rubiscons (Luan et al. 2015; Yang et al. 2019), (−)‐epicatechin‐3‐gallate from Rhodiola kirilowii (Chen et al. 2015a), and alginate oligosaccharide from Laminaria hyperborea (Fischer et al. 2022). Andrographolide from Andrographis paniculata (J. Cui et al. 2020), glycyrrhizin from Glycyrrhiza glabra (Ameri et al. 2023; van de Sand et al. 2021), and many extract of natural product including Punica granatum (Yousefi et al. 2023), Rhus verniciflua (Kim et al. 2018), Rhus coriaria (Forouzanfar et al. 2022; Salikhov et al. 2023), Liriope platyphylla (Won et al. 2022), Nigella damascena (Koshak et al. 2021), Anthemis hyaline (Ulasli et al. 2014), Citrus sinensis (Ulasli et al. 2014), and Nigella Sativa (Ulasli et al. 2014) can improve the COVID‐19. Some phytochemicals from nature product can relieve symptoms of the acute lung injury including the oridonin from Rabdosia rubescens (Luan et al. 2015; Yang et al. 2019), schisandrin from Schisandra chinensis (Sun et al. 2018), paclitaxel from Taxus brevifolia (Y.‐M. Wang et al. 2019), luteolin from Lonicera japonica (Lee et al. 2010), and hydroxysafflor yellow A from Carthamus tinctorius L. (Wang et al. 2013), Cinnamaldehyde from Cinnamomum cassia (Wu et al. 2017), glycyrrhetinic acid from Glycyrrhiza uralensis Fisch (Tang et al. 2015), platycodin D from Platycodon grandiflorum (Zhao et al. 2015), crocin from Crocus sativus (Chen et al. 2015b), and water extract of Trichosanthes kirilowii Maxim fruits (Ni et al. 2015) are bioactive components that have an alleviating effect on lung cancer. These bioactive phytochemicals achieve the anti‐inflammatory effect in different respiratory tract diseases.

TABLE 1.

The natural bioactive components with anti‐inflammation effect in respiratory tract.

Bioactive components	Source	Structure	Classification	Anti‐inflammation effect	References
Resveratrol	Vitis vinifera		Polyphenols	Air way	(Donnelly et al. 2004)
Quercetin	Vitis vinifera		Flavonoid	Air way	(Donnelly et al. 2004; Hohmann et al. 2019; Schafer et al. 2017)
Melatonin	Milk		Amine hormones	Air way	(Kim et al. 2012)
Safranal	Crocus sativus		Terpene aldehyde	Asthma	(Lertnimitphun et al. 2021)
Ethanol extract	Nasturtium officinale	—	—	Asthma	(Shakerinasab et al. 2024)
Genistein, daidzein, daidzin	Glycine max		Flavonoid	Asthma	(Bao et al. 2011)
Carvacrol	Origanum hirtum		Monoterpene phenol	Asthma	(Ezz‐Eldin, Aboseif, and Khalaf 2020)
Water extract	Agaricus blazei	—	—	Asthma	(Takimoto et al. 2008)
Tualang honey	Apis dorsata	—	—	Bacterial antigens‐induced inflammation in tonsil epithelial	(Devasvaran et al. 2019)
Bovine lactoferrin	Bovine	—	Antimicrobial peptides	Bacterial antigens‐induced inflammation in tonsil epithelial	(Ajello et al. 2002)
Ethanol extract	Zataria multiflora	—	—	COPD	(Boskabady and Gholami Mhtaj 2014)
Ginsenoside	Panax ginseng		Triterpene saponins	COPD	(Xu et al. 2020)
Curcumin	Curcuma longa		Polyphenols	COPD, Cystic fibrosis	(Dragomir et al. 2004; Egan et al. 2004; Quispe et al. 2022; Yuan et al. 2018; Zare'i et al. 2024)
Alginate oligosaccharide	Laminaria hyperborea	—	—	Cystic fibrosis	(Fischer et al. 2022)
(−)‐epicatechin‐3‐gallate	Rhodiola kirilowii (Regel)		Flavonoid	Cystic fibrosis	(Chen et al. 2015a)
Pomegranate juice	Punica granatum	—	—	COVID‐19	(Yousefi et al. 2023)
Water extract	Rhus verniciflua	—	—	COVID‐19	(Kim et al. 2018)
Sumac juice	Rhus coriaria	—	—	COVID‐19	(Forouzanfar et al. 2022)
Ethanol extract	Rhus coriaria	—	—	COVID‐19	(Salikhov et al. 2023)
Liriope platyphylla extract capsule	Liriope platyphylla	—	—	COVID‐19	(Won et al. 2022)
Andrographolide	Andrographis paniculata		Diterpenes	COVID‐19	(Cui et al. 2020; Songvut et al. 2023)
Glycyrrhizin	Glycyrrhiza glabra		Triterpene saponins	COVID‐19	(Ameri et al. 2023; van de Sand et al. 2021)
Nigella sativa oil	Nigella damascena	—	—	COVID‐19	(Koshak et al. 2021)
Ethanol extract	Anthemis hyalina	—	—	COVID‐19	(Ulasli et al. 2014)
Ethanol extract	Citrus sinensis	—	—	COVID‐19	(Ulasli et al. 2014)
Ethanol extract	Nigella Sativa	—	—	COVID‐19	(Ulasli et al. 2014)
Oridonin	Rabdosia rubescens		Polyphenols	Acute Lung Injury	(Luan et al. 2015; Yang et al. 2019)
N‐butanol extract	Tamarix nilotica	—	—	Acute Lung Injury	(Assiri et al. 2023)
Schisandrin	Schisandra chinensis		Lignans	Acute Lung Injury	(Sun et al. 2018)
Paclitaxel	Taxus brevifolia		Diterpenes	Acute Lung Injury	(Wang et al. 2019)
Ethanol extract	Fritillaria hupehensis	—	—	Acute Lung Injury	(Xiang et al. 2022)
Luteolin	Lonicera japonica		Flavonoid	Acute Lung Injury	(Lee et al. 2010)
Hydroxysafflor yellow A	Carthamus tinctorius L.		Flavonoid	Acute Lung Injury	(Wang et al. 2013)
Naringenin	Citrus fruits		Flavonoid	Lung cancer	(Lu et al. 2020)
Cinnamaldehyde	Cinnamomum cassia		Cinnamaldehyde	Lung cancer	(Wu et al. 2017)
Glycyrrhetinic acid	Glycyrrhiza uralensis Fisch		Triterpenoid saponins	Lung cancer	(Tang et al. 2015)
Platycodin D	Platycodon grandiflorum		Triterpenoid saponins	Lung cancer	(Zhao et al. 2015)
Crocin	Crocus sativus		Polyphenols	Lung cancer	(Chen et al. 2015b)
Water extract	Trichosanthes kirilowii Maxim	—	—	Lung cancer	(Ni et al. 2015)

3. Anti‐Inflammatory Effect of Bioactive Components in Respiratory Tract

The bioactive components extracted from plants improve inflammatory diseases in the respiratory tract, and some have been clinically tested (Table 2). Specifically, the improvement effect of various bioactive components on inflammatory diseases in the respiratory tract is achieved through different signaling pathways and mechanisms (Figure 2). Therefore, this review is classified and summarized based on treating different inflammatory diseases in the respiratory tract using natural ingredients, including COPD, asthma, CF, airway inflammation, and lung cancer. This review can provide target screening guidance and a theoretical basis for research on improving anti‐inflammatory effect of bioactive phytochemicals in various respiratory tract diseases.

TABLE 2.

The molecular mechanism of the natural bioactive components with anti‐inflammation effect in respiratory tract.

Bioactive components	Source	Research model	Disease	mRNA	Protein	Signaling pathway	Other Mechanism	References
Resveratrol	Vitis vinifera L.	A549 cell line	Inflammation in air way	6Btkluc (reporter of NF‐κB) ↓, IL‐1β ↓	IL‐8 ↓	NF‐κB signaling pathway ↓	—	(Donnelly et al. 2004)
Quercetin	Vitis vinifera L.	Normal lung (NL) fibroblasts, bleomycin‐induced pulmonary fibrosis in aged C57BL/6 mice	Inflammation in air way	6Btkluc (reporter of NF‐κB) ↓, IL‐1β ↓, Caveolin‐1 ↑	IL‐8 ↓, Caveolin‐1 ↑, p‐AKT ↓	NF‐κB signaling pathway ↓, PI3K/Akt signaling pathway ↓	—	(Donnelly et al. 2004; Hohmann et al. 2019; Schafer et al. 2017)
Melatonin	Milk	Human pulmonary fibroblasts	Inflammation in air way	IL‐8 ↓	iNOS ↓, IL‐1β↓, IL‐6 ↓, IL‐8 ↓, p‐ERK42/44 ↓, p‐AKT ↓	ERK1/2 signaling pathway ↓, PI3K/Akt signaling pathway ↓	—	(Kim et al. 2012)
Safranal	Crocus sativus	Bone marrow‐derived mast cells; Ovalbumin (OVA)‐induced female BALB/c mice model	Asthma	Cxcl10 ↓	IL‐4 ↓, IL‐5 ↓, IL‐6 ↓, IL‐13 ↓, IFN‐γ ↑, TNF‐α ↓, p‐p38 ↓, p‐ERK ↓, p‐IKKK ↓, p‐JNK ↓	NF‐κB signaling pathway ↓, MAPK signaling pathway ↓	Mast cell Activation, PSA reaction	(Lertnimitphun et al. 2021)
		Clinical Trial (n = 128)	Asthma				Clinical symptom and severity alleviation; Systolic and diastolic blood pressure, triglyceride and low‐density lipoprotein cholesterol (LDLC) ↓	(Zilaee et al. 2019)
Ethanol extract	Nasturtium officinale	Male Wistar rats	Asthma	TNF‐α ↓, TNF‐β ↓, IL‐1β ↓, α‐SMA ↓	TNF‐α ↓	/	Oxidative Stress ↓, FRAP ↓, GPX activity ↑, Pathological change ↓	(Shakerinasab et al. 2024)
		Clinical Trial (n = 60)	Asthma		IgE ↓, IL‐1 ↑, TNF‐α ↓, α‐SMA ↓	/	Total Oxidative stress ↓, FRAP ↑, SOD ↓, CAT ↓, PCO ↓, NO metabolite ↓, TSH ↓, MDA ↓	(Shakerinasab et al. 2024)
Soy isoflavone	Glycine max	Female specific‐pathogen‐free ICR mice	Asthma	Eotaxin ↓, IL‐4 ↓, IL‐5↓, matrix matallo proteinase (MMP)‐9 ↓, IFN‐γ ↑, tissue inhibitor of matrix matallo proteinase (TIMP)‐1 ↑	IFN‐γ ↑, IL‐4 ↓	/	Oxidative stress ↓ MPO ↓ SOD ↑ Pathological change ↓	(Bao et al. 2011)
		Clinical Trial (n = 386)	Asthma	—	—	—	Exacerbation alleviation in the asthmatic subject with high plasminogen activator inhibitor‐1 (PAI‐1) producing genotype	(Cho et al. 2019)
Carvacrol	Origanum hirtum	Adult male Wistar albino rats	Asthma		Surfactant protein D ↓, AEC ↓, TNF‐α ↓, IFN‐γ ↓, IL‐4 ↓, IL‐5 ↓, IL‐13 ↓, iNOS ↓, MDA ↓	—	Oxidative stress ↓, SOD ↑, GSH ↑	(Ezz‐Eldin, Aboseif, and Khalaf 2020)
		Clinical Trial (n = 33)	Asthma	—	IFN‐γ ↓, IL‐4 ↓, IL‐10 (serum) ↓	—	Respiratory symptom alleviation, pulmonary function test (PFT) ↑, oxidative stress ↓	(Ghorani et al. 2021)
Water extract	Agaricus blazei	Female BALB/c mice	Asthma	IFN‐γ‐inducing protein 10 (IP‐10) ↑	IL‐5 ↓ (BALF)	/	Total cell number↓ IgG1 and IgE response↑ Activation of T cells Th1/Th2 unbalance	(Takimoto et al. 2008)
		Clinical Trial (n = 60)	Asthma	—	—	—	Specific IgE anti‐Bet v 1 and anti‐t3 ↓	(Mahmood et al. 2019)
Tualang honey	Apis dorsata	Human umbilical vein endothelial cells	Bacterial antigens‐induced inflammation in tonsil epithelial	—	cAMP ↓	—	Oxidative stress ↓	(Devasvaran et al. 2019)
Bovine lactoferrin	Bovine	HeLa S3 cells	Bacterial antigens‐induced inflammation in tonsil epithelial	—	—	—	Apoptotic ↑	(Ajello et al. 2002)
Ethanol extract	Zataria multiflora	Guinea pigs	COPD	—	IL‐8 (serum) ↓	—	White Blood Cells (WBC) ↑ ,malondialdehyde (MDA) ↑ Weight Loss ↓ Oxidative stress ↓	(Boskabady and Gholami Mhtaj 2014)
Extract	Zataria multiflora	Clinical Trial (n = 41)	COPD	—	TNF‐α ↓ IL‐8 (serum) ↓	—	FVC ↑ FEV1 ↑ PEF ↑ Cough ↓, Chest Tightness ↓, dyspnea scale ↓	(Ghorani et al. 2022)
Ginsenoside	Panax ginseng	Clinical Trial (43 cases) and 28‐day cigarette some exposure C57BL/6 Mice model	COPD	FOXP3 ↑, TNF‐α ↑, IL‐17 ↑ (patient sample; mice model)	FOXP3 ↑, TNF‐α ↑, IL‐17 ↑ (Mice model)	—	Pulmonary Function ↑ Quality of life (CAT) ↑ Th17/Treg immune unbalance; Treg ↑, Th17 cell ↓ (Clinical Trial) Pathological damage ↓ (mice model)	(Xu et al. 2020)
Curcumin	Curcuma longa	Pathogen‐free male Kunming mice	COPD	—	IL‐6 ↓, TGF‐β ↑, IκBα ↑, COX‐2 ↑	NF‐κB signaling pathway ↓ COX‐2 pathway ↓	Inflammatory cells in BALF: WBC ↓, lymphocyte ↓, neutrophil counts ↓	(Yuan et al. 2018)
		Clinical Trial (n = 60)	COPD	—	IL‐6 (serum) ↓	—	Weight and body mass index ↑, Pulmonary Function tests: FVC ↑, FEV1 ↑, FEV1/FVC↑	(Zare'i et al. 2024)
Alginate oligosaccharide	Laminaria hyperborea	Clinical Trial (n = 15)	Cystic fibrosis	—	—	—	Burkholderia spp. Infection ↓, sputum viscosity↓	(Fischer et al. 2022)
Curcumin	Curcuma longa	BHK cells expressing F508 CFTR	Cystic fibrosis	—	—	cAMP‐dependent chloride efflux ↑	/	(Dragomir et al. 2004; Egan et al. 2004; Quispe et al. 2022)
(−)‐epicatechin‐3‐gallate	Rhodiola kirilowii (Regel)	Fischer rat thyroid (FRT) epithelial cells	Cystic fibrosis	—	—	—	Cystic fibrosis transmembrane conductance regulator ↓	(Chen et al. 2015a)
Pomegranate juice	Punica granatum	Clinical Trial (n = 48)	COVID‐19	—	IL‐6 ↓	—	Apoptosis ↓	(Yousefi et al. 2023)
Water extract	Rhus verniciflua	RAW264.7 cells	COVID‐19	—	CD86 ↓, TNF‐α ↓, IL‐6 ↓, IL‐12 ↑, class II MHC molecules ↑	NF‐κB signaling pathway ↓, MAPK signaling pathway ↓	/	(Kim et al. 2018)
Sumac juice	Rhus coriaria	Clinical Trial (n = 182)	COVID‐19	—	—		Recovery of symptoms↑	(Forouzanfar et al. 2022)
Ethanol extract	Rhus coriaria	African green monkey kidney Vero E6 cells	COVID‐19	—	3C‐like proteinase (3CLpro) and RNA‐dependent RNA polymerase (RdRp) ↓	—	The replication and multiplication of the virus ↓	(Salikhov et al. 2023)
		Clinical Trial (n = 121)	COVID‐19	—	CRP ↓	—	Recovery of symptoms↑
Liriope platyphylla extract capsule	Liriope platyphylla	Clinical Trial (n = 22)	COVID‐19	—	IL‐8 ↓, TNF‐α ↓, IFN‐γ ↓	—	—	(Won et al. 2022)
Andrographolide	Andrographis paniculata	Pneumonia induced by poly I:C in C57BL/6 mice	COVID‐19	IL‐6 ↓, TNF‐α ↓, IL‐1β ↓, MUC5AC ↓, MUC5B ↓	IL‐6 ↓, TNF‐α ↓, IL‐1β ↓, p‐p65 ↓, MUC5AC ↓, MUC5B ↓	NF‐κB signaling pathway ↓	—	(Cui et al. 2020)
		Clinical Trial (n = 4)	COVID‐19	—	—	—	—	(Songvut et al. 2023)
Glycyrrhizin	Glycyrrhiza glabra	Vero E6 cells	COVID‐19	—	Main Protease ↓	—	SARS‐CoV‐2 replication ↓	(van de Sand et al. 2021)
		Clinical Trial (n = 60)	COVID‐19	—	/	—	—	(Ameri et al. 2023)
Nigella sativa oil	Nigella damascena	Clinical Trial (n = 173)	COVID‐19	—	/	—	Recovery of symptoms↑	(Koshak et al. 2021)
Ethanol extract	Anthemis hyalina	HeLa‐CEACAM1a (the epithelial carcinoembryonic antigen‐related cell adhesion molecule 1) and murine fibroblast LR7 cells	COVID‐19	TRPV4 ↓	IL‐8 ↑	—	SARS‐CoV‐2 replication ↓	(Ulasli et al. 2014)
Ethanol extract	Citrus sinensis	HeLa‐CEACAM1a (the epithelial carcinoembryonic antigen‐related cell adhesion molecule 1) and murine fibroblast LR7 cells	COVID‐19	TRPM8 ↓	IL‐8 ↑	—	SARS‐CoV‐2 replication ↓	(Ulasli et al. 2014)
Ethanol extract	Nigella Sativa	HeLa‐CEACAM1a (the epithelial carcinoembryonic antigen‐related cell adhesion molecule 1) and murine fibroblast LR7 cells	COVID‐19	TRPV4 ↓	IL‐8 ↑	—	SARS‐CoV‐2 replication ↓	(Ulasli et al. 2014)
Oridonin	Rabdosia rubescens	Human wt‐CFTR and the halide‐sensing green fluorescent protein YFP‐H148Q co‐expressed in Fischer rat thyroid (FRT) epithelial cells, ΔF508‐CFTR (the most common mutation of CFTR) cell line using FRT cells transfected with human ΔF508 CFTR and YFP‐H148Q/I152L	Acute Lung Injury	—	Nrf2 ↑, HO‐1 ↑, GCLM ↑, NLRP3 ↓, ASC ↓, CASPASE‐1 ↓, IL‐1β ↓, P‐P65 ↓, P‐IκBα ↓	Nrf2/HO‐1/NLRP3 signaling pathway ↑, NF‐κB signaling pathway ↓	Oxidative stress ↓	(Luan et al. 2015; Yang et al. 2019)
N‐butanol extract	Tamarix nilotica	LPS caused acute lung damage induction in Swiss albino mice	Acute lung injury	TGFB‐1 ↓, NOX1 ↓, NOX4 ↓, iNOS ↓, GPX1 ↑	TNF‐α ↓	—	MDA ↓, SOD ↑, CAT ↑	(Assiri et al. 2023)
Schisandrin	Schisandra chinensis	LPS caused acute lung damage induction in Male Wistar rats	Acute lung injury	—	IL‐1β ↓, TNF‐α ↓, IL‐6↓, CXCL‐1 ↓, cleaved caspase‐3 ↓, keratin ↑, proSP‐C ↑, p‐I‐κBα ↓, I‐κBα ↑, NF‐κB p65 ↓	PI3K/Akt/mTOR signaling pathway ↓, NF‐κB signaling pathway ↓	Apoptosis ↓	(Sun et al. 2018)
Paclitaxel	Taxus brevifolia	Sepsis‐induced acute lung injury in C57BL/6J mice	Acute lung injury	—	MUC 1 ↑, TLR‐4 ↓, TNF‐α ↓, IL‐1β↓, IL‐6 ↓, IL‐10 ↓	NF‐κB signaling pathway ↓	/	(Wang et al. 2019)
Ethanol extract	Fritillaria hupehensis	LPS caused acute lung damage induction in ICR Mice	Acute lung injury	—	TNF‐α ↓, IL‐6 ↓, IL‐4 ↑, IL‐10 ↑	/	Inflammatory cells counting ↓	(Xiang et al. 2022)
Luteolin	Lonicera japonica	Intratracheal instillation of LPS in mice	Acute lung injury	—	MEK ↓, ERK ↓, p‐Akt ↓	PI3K/Akt signaling pathway ↓, MEK/ERK signaling pathway ↓	Leukocyte counting ↓, Lung permeability ↓	(Lee et al. 2010)
Hydroxysafflor yellow A	Carthamus tinctorius L.	Oleic acid‐induced acute lung injury in male Sprague–Dawley rats	Acute lung injury	—	cAMP ↑, PKA ↑, TNF‐α ↓, IL‐6 ↓, IL‐10 ↑, Bcl‐2 ↑, caspase 3 ↓, Bax ↓	cAMP‐PKA signaling pathway ↑	Pulmonary functions ↑ SOD ↑, GPx ↑, MDA ↓, ROS ↓, permeability ↓, infiltration of albumin ↓, total inflammatory cell counts ↓	(Wang et al. 2013)
Naringenin	Citrus fruits	A549 Cell line	Lung cancer	—	Bcl‐2 ↓, Bcl‐xL ↓, Bad ↑, Bax ↑, PUMA ↑	—	Bax‐activated mitochondrial pathway ↑, Apoptosis ↑	(Lu et al. 2020)
Cinnamaldehyde	Cinnamomum cassia	A549, YTMLC‐90 and NCI‐H1299 Cell line, BALB/c/nu/nu nude mice	Lung cancer	GSK3β ↑, β‐catenin ↓, TCF‐1 ↓, c‐Myc ↓, Cyclin‐D1 ↓, Bcl‐2 ↓, Bcl‐xL ↓	GSK3β ↑, p‐β‐catenin ↑, β‐catenin ↓, TCF‐1 ↓, c‐Myc ↓, Cyclin‐D1 ↓, Bcl‐2 ↓, Bcl‐xL ↓	Wnt/β‐catenin signaling pathway ↓	Apoptosis ↑	(Wu et al. 2017)
Glycyrrhetinic acid	Glycyrrhiza uralensis	A549 and NCI‐H1299 Cell line	Lung cancer	—	p‐JNK ↓, p‐c‐Jun ↑, c‐Jun ↑, caspase‐3/7 ↑, cleaved PARP ↑, LC3‐II ↑	IRE1α‐JNK/c‐jun signaling pathway ↑	Apoptosis ↑, autophagy ↑	(Tang et al. 2015)
Platycodin D	Platycodon grandiflorum	NCI‐H460 and A549 Cell line	Lung cancer	LC3‐II ↑	p‐Akt ↓, p‐p70S6K ↓, p‐4EBP1 ↓, p‐p38 MAPK ↑, p‐JNK ↑, Bcl‐1 ↑, Atg‐3 ↑, Atg‐7 ↑, LC3‐II/LC3‐I ↑	PI3K/Akt/mTOR signaling pathway ↓ JNK and p38 MAPK signaling pathways ↑	Autophagy ↑	(Zhao et al. 2015)
Crocin	Crocus sativus	A549 and SPC‐A1 Cell line	Lung cancer	P53 ↑, Bax ↑, Bcl‐2 ↓	—	—	Apoptosis ↑	(Chen et al. 2015b)
Water extract	Trichosanthes kirilowii Maxim	A549, H1299 and H1975 cell lines	Lung cancer	—	—	—	G2‐M arrest, necrosis ↑, apoptosis ↑	(Ni et al. 2015)

3.1. Anti‐Inflammatory Effect of Bioactive Components in Airways

The airway inflammation was commonly initiated by interaction with toxic pollutants or nano‐particles, pathogenic strains or the allergens (Lumb and Thomas 2016). After recognition of Toll‐Like receptors (TLRs), pro‐inflammatory cytokines like IL‐8 followingly recruits and activates neutrophils and other pro‐inflammatory cells (Green, Galluzzi, and Kroemer 2011). Reactive oxygen species (ROS), mediated by stress or mitochondrial dysfunction, is also an airway inflammation initiator, facilitates airway cellular aging at extreme or persistent manner (Green, Galluzzi, and Kroemer 2011; Wang and Klionsky 2011). Inflammation is the defense strategy of body against toxic or harmful subjects external sourced like infective pathogens, irritants, and pollutants. The acute inflammation is providing survival benefits by stabilized the damaged zone and recruiting immune cells for repair. Conversely, the chronic one irritates and worse the problems by facilitating the over mobilization of immune cells and unnecessarily amplifying responses, consequently destroying the health region of tissues (Ahmed 2011). The classical ageing pathways includes the involvement of PI3K/p‐AKT/mTOR pathway, which is initiated by growth factor signaling like insulin like growth factor (IGF)‐1 (Kapahi et al. 2004). Inhibition targeting at mTOR pathway is capable in cellular life elongation. Accordingly, it is found that targeting at PI3K or AMPK for inhibition facilitates the dysregulation of mTOR signaling pathway (Johnson, Rabinovitch, and Kaeberlein 2013). Moreover, the activation of signal‐regulated kinase 1/2 (ERK1/2) is important in the development of airway inflammation (Zhang et al. 2016). Accordingly, airway inflammation control, especially chronic ones, is significant for health of the normal.

Phosphatase and tensin homologs are capable in PI3K and AMPK pathway inhibition and mTOR signaling pathway blockage as anti‐aging chemicals, And this inhibition finally expand lifespans (Hosgood III et al. 2009; Kapahi et al. 2004). The 3,4′,5‐trihydroxystilbene (resveratrol), a polyphenolic stilbene commonly found in red fruit skins, and the similar molecule quercetin, were both found with inhibitory effect against release of IL‐8. It implies the strong treatment potential against inflammatory diseases (Donnelly et al. 2004). Quercetin was proved with modulation capability of AKT initiation, FasL receptor and RAIL receptor, and caveolin‐1 of high expression. Consequently, it reverses pulmonary fibrosis, alleviates the body weight loss, lethality ratio, and the senescence‐associated biomarkers like p21 and p19‐ARF as well as other secretory phenotype in the bleomycin‐induced mice model of pulmonary fibrosis (Hohmann et al. 2019). N‐acetyl‐5‐methoxytryptamine (melatonin), an indole widespread among plants and animals, is proved with suppression in acrolein‐mediated enhancement in IL‐8 through blockage against ERK1/2 and PI3K/AKT pathway in the human pulmonary fibroblasts (HPFs) (Kim et al. 2012; Wang et al. 2022). Also, Dasatinib combing with quercetin was proved with capability in effectively eradication of senescent fibroblasts (Schafer et al. 2017).

Beside basic studies, clinical trials are also applied for consideration of treatment of bioactive components in reality against airway inflammation. In a clinical trial recruiting total 2099 patients, aged from 0 to 93 years old, Eps 7630, the liquid herbal drug soured from roots of Pelargonium sidoides, consumption of 14 days, was confirmed with efficacy and well toleration in treatment against acute bronchitis among adults, teenagers, children as well as infants without consumption of antibiotics, which is supported by the improvement in Bronchitis Severity Score (BSS: cough, sputum, rales/rhonchi, chest pain at cough, dyspnoea), a general indicator of evaluation lasting from baseline to last observation while adverse events are occurred in 26/2099 without serious adverse event reported (Matthys et al. 2007). Meanwhile, another clinical trial including 220 patients about treatment of acute bronchitits proved Eps 7630 is also practicable with well toleration for patients of child and adolescents, proving through descend in BSS core comparing to placebo (Kamin et al. 2012). Similar result was also proved on adult patients of acute bronchitis with consumption of Eps 7630 in a randomized, double‐blind, placebo‐controlled, multi‐center study recruiting 217 patients ranging from 18‐ to 66‐year‐old (Matthys and Heger 2007). In a clinical trial including 268 children with cough ranging from 0‐ to 12‐year‐old, the ivy leaf extract in the form of syrup and of cough drops was proved with effectiveness and safety in treatment against cough in children (Schmidt, Thomsen, and Schmidt 2012). To summarize, reports concerning basic studies or clinical trials supports that bioactive components are good options combating airway inflammation for further research.

3.2. Anti‐Inflammatory Effects of Bioactive Components in Asthma

Asthma is an airway disease alongside chronically inflammatory responses, with multiple variants (phenotypes) (Zhang, Paré, and Sandford 2008). It is usually characterized by chronic airway inflammation, including the involvement of the following inflammatory cells like T lymphocytes, neutrophils, eosinophils, epithelial cells mast cells and macrophages (Woodruff, Bhakta, and Fahy 2016). In susceptible individuals, the inflammation can cause persistent characteristics including coughing, wheezing, dyspnea, and chest comfortability, commonly at deep night or dawn. It burdens life quality of patients and indicates symptoms alleviation is of significance (Clinical Trials are mostly aiming at symptoms alleviation.). Consequently, the airflow is at risk of variable obstruction and following damage though it is commonly spontaneous or reversible with treatment.

Inflammation also causes increased bronchial hyperresponsiveness to various stimuli (Woodruff, Bhakta, and Fahy 2016). In 2019, asthma was ranked 34th of the leading causes of mortality, which responsible for a fifth of total disability adjusted life year from chronic respiratory diseases, and 24th among the leading causes of disease burden globally (Asher and Pearce 2014). Acquired by dendritic cells (DCs), the inhaled allergens are subsequently delivered to CD4+ T cells once the allergens are exposed to respiratory epithelial cells (Banchereau et al. 2000). Meanwhile, cytokines produced by epithelial cells can promote DCs function and induce transformation of the CD4+ T cells to be (T helper 2) Th2 cells (Shikotra et al. 2012; Zissler et al. 2016). Moreover, various cytokines, especially the serial interleukins (IL) including IL‐4, IL‐5, and IL‐13 were synthesized by the Th2 cells, implying Th1/Th2 cell ratio balance is of importance (Lee et al. 2001). Among them, IL‐5 plays a central role in the progression of eosinophils' cellular maturation and differentiation (Kouro and Takatsu 2009), It is commonly regarded as essential effectors cells of asthma progression, and controls of the cytokine‐mediated eosinophil accumulation is of significance against asthma (Cusack et al. 2021). Changing from IgM to IgE, the progress of B cells' immunoglobulin isotype transformation is initiated by IL‐4, IL‐13, and CD40 and participates in relocation and arrangement of DNA accompanying the heavy‐chain locus of immunoglobulin (Oettgen 2000). By integrating with the type I high‐affinity IgE receptors (FcεRI) located on basophils as well as mast cells, IgE facilitates both cells in recognition of the cognate allergen. This progress further induces the secretion of various types of inflammation mediators accounting symptoms of acute and serious sensitivity like histamine (Vitte et al. 2022). Like histamine, chymase, tryptase, and the newly synthesized ones including PGD2 and LTC4, the mediators induced by mast cells, facilitates asthma progression as well as the commonly studied cytokines including IL‐4, IL‐13, IL‐33, TGF‐β1, and TSLP (Elieh Ali Komi and Bjermer 2019). All the three mitogen‐activated protein kinases (MAPK) subfamilies (p38, JNK, ERK) are found activated in pathogenic asthma facilitating inflammation and structural changes. And it is regarded as crucial points of signaling pathway crosstalk and activation of cytokines, growth factors, and inducers of airway remodeling like immunoglobulin E (IgE) (Pelaia et al. 2020), indicating upstream inhibition against p‐38 (p38‐MAPK subfamily) (Bhavsar et al. 2010), p‐JNK (JNK‐MAPK subfamily) (Wu et al. 2015) and p‐ERK1/2 (ERK–MAPK subfamily) (Huang et al. 2017) is of significance as anti‐asthma therapy. Briefly, controls on inflammation cascade are crucial for health of asthma patients.

Several anti‐inflammatory mechanisms exist for plant compounds against asthma. Applying ovalbumin (OVA)‐induced mice model, Safranal was proved with capability in inhibition against mast cell initiation, passive systemic anaphylaxis (PSA) reaction by blockage against MAPKs and NF‐κB signaling pathway in splenocyte (Lertnimitphun et al. 2021). The phosphorylation of p‐JNK, p‐ERK, p‐p38, and p‐IKK was detected decrease post treated with Safranal (Lertnimitphun et al. 2021). Meanwhile, serum IgE, pulmonary mast cell number, and Th1/Th2 cytokine levels were found alleviated by Safranal introduction (Lertnimitphun et al. 2021). Treatment with hydroalcoholic extracts of Nasturtium officinale (NOE) significantly reduced the transcriptional level of α‐SMA, IL‐1β, TNF‐α, and TGF‐β genes and enhanced glutathione peroxidase (GPX) activity compared to the asthma group (Shakerinasab et al. 2022). Transcriptional level of (matrix metalloproteinase‐9) MMP9, IL‐4, IL‐5, and eotaxin was confirmed significant decrease due to soy‐sourced isoflavone introduction in the ovalbumin‐based model. Meanwhile, interferon (IFN)‐γ, and (matrix metalloproteinase‐1) MMP1 inhibitors in lung tissue were detected ascend in transcriptional level in a concentration‐dependent manner alongside with recovery of IFN‐γ/IL‐4 (Th1/Th2) counting in the broncho alveolar lavage fluid (BALF), collagen deposition, eosinophil permeation and airway mucus formation in the pulmonary tissues. It suggests that isoflavone is promising for further development as therapeutic option against asthma‐induced inflammation (Bao et al. 2011). Agaricus blazei water extracts delivery facilitates downregulation of IgG1 and IgE levels in plasma induced by OVA‐sensitization in a murine model of asthma (Takimoto et al. 2008). Meanwhile, the IL‐5 amount, eosinophil, and total cell counts were detected descend in BALF. It implies consumption of Agaricus extracts alleviates the Th1/Th2 unbalance status from Th2‐chaos. Carvacrol introduction provides health benefits in ascend of superoxide dismutase (SOD) and glutathione (GSH), and descend in IL‐4, IL‐5, IL‐13, AEC, iNOS, IFN‐γ, IgE (serum), and MDA in comparison with the asthmatic group alongside pathological change alleviation, indicating carvacrol as a protective agent against asthma inflammation (Ezz‐Eldin, Aboseif, and Khalaf 2020).

Accordingly, on perspective of clinical application, a clinical trial of 2‐month period of carvacrol consumption by patients with asthma, confirmed benefits of carvacrol introduction like pulmonary function recovery, oxidative stress significant alleviation. It is shown by major markers' improvement antioxidants, as well as the cytokine levels in serum including IFN‐γ, IL‐4, IL‐10 (Ghorani et al. 2021). Another trial aiming at evaluating therapeutic effect of saffron supplementation on asthma demonstrated that saffron alleviates patients' clinical symptoms' the frequency (i.e., frequencies including daytime and nighttime shortness of breath, use of albuterol sprays, and awakening caused by asthma symptoms as well as the activity restriction), severity, and systolic and diastolic blood pressure, and triglyceride as well as the low‐density lipoprotein cholesterol (LDLC) level compared with the consumption of placebo (p < 0.001). It proves its effectiveness and safety as treatment option through total antioxidant ability enhancement (Zilaee et al. 2019). Soy isoflavone consumption significantly lower the risks of asthma exacerbation and worsen in patients of high plasminogen activator inhibitor‐1 (PAI‐1) producing genotype. PAI‐1 polymorphisms is considered as a genetic biomarker in asthma patients of treatment with soy isoflavone (Cho et al. 2019). Moreover, in a clinical trial, Agaricus blazei‐based mushroom extract consumption before season provides prophylactic and protective effect against allergy induced by aeroallergen (Mahmood et al. 2019). It is attributed to lgE level decrease of the season and desensitize basophils from fast initiation against allergen. In a clinical trial, treatment with hydroalcoholic extract of NOE, for the period of 1‐month (twice daily), alleviates the levels of malondialdehyde (MDA), protein carbony (PCO) as well as the nitric oxide metabolite markers in decrease, comparing with consumption of the placebo (Shakerinasab et al. 2024). Taking together with in vitro and in vivo tests above, NOE is proved of great therapeutic development potential on asthma by defense against oxidative stress. Taking together, it is worth on studies about bioactive components against asthma through inflammation alleviation.

3.3. Anti‐Inflmmatory Effect of Bioactive Components in Bacterial Antigens‐Induced Tonsil Epithelial Infammation

Streptococcal pharyngitis induced infection has been a public health concern all the recent in the last 10 years (Wijesundara, Sekhon‐Loodu, and Rupasinghe 2017). Streptococcus pyogenes , a group A streptococcus (GAS), is the majorly opportunistic pathogen attributed to the cause of acute pharyngitis among school‐aged children presenting symptoms including but not limiting to sore throat, fever, and cervical lymphadenopathy (Rock et al. 2009). As we known, inflammation of human epithelial cells in the upper respiratory tract (URT) was regarded as the first rontline combating GAS‐mediated infection. The Lipoteichoic acid (LTA) and peptidoglycan (PGN), components of GAS, was regarded as the antigen or biomarker captured by Toll‐like receptors (TLR) from eukaryotic cells, for which this interaction consequently induces following immune responses (Bisno, Brito, and Collins 2003). Followingly, the virulence factor secreted by bacterial cells facilitates the white blood cells (WBCs) and tonsil epithelial cells (TPCs) mediated downstream inflammation like chemokines and cytokines, implying the importance of alleviation on bacterial‐antigen facilitated inflammation in human tonsil epithelial cells (Ricciotti and FitzGerald 2011). So, inflammation control at early stage is important for patients infective with opportunistic pathogens.

Lactoferrin (LF), a major component for immune system of eukaryotic cells, was previously proved with various proactive effects against bacterial infection and followingly induced inflammatory signals. Ajello et al. found that bovine sourced LF (bLF) was capable in counteracting with Toll‐like receptor (TLR)‐induced activation of inflammation signals in antigen presenting cells in a bacterial sourced LPS‐induced cellular model (Ajello et al. 2002). Group A streptococci (GAS) is commonly recognized as key threats in invasion of human epithelia and endothelial cells for its survival intracellularly until conditions are suitable for infection recalcitrance and recurrence. Ajello found that bLF is of anti‐invasion activity against GAS in vitro alongside apoptotic cell amount increasement. Chlamydia trachomatis ( C. trachomatis ), a commonly found pathogen through sexual transmission, is stressing public health by elongation of antibiotic therapy in upper respiratory tract infections (Hammerschlag 2000). However, bLF was found by Devasvaran et al. that it is capable in bacterial infection control against C. trachomatis on pathogenic perspective alongside inflammation (IL‐6 and IL‐8) alleviation on host angle. Besides bLF, Tualang honey (TH), a famous sub‐type of honey proved with various health benefits like antioxidant, anti‐inflammatory, anti‐bacterial and wound‐healing effects, is capable in inhibition of vascular hyperpermeability due to hydrogen peroxide addition in the human umbilical vein endothelial cellular model (HUVECs) and prevention of adherent junction protein re‐allocation in a mice model (Devasvaran et al. 2019).

On perspective of clinical application potential, a small trial on children with pharyngitis requiring tonsillectomy, the constitutive consumption of bLF was found to inhibit intracellular GAS relative to erythromycin in the tonsil specimen samples from these children. (Ajello et al. 2002). Accordingly, considering the anti‐inflammation, apoptotic cell regulation on human sourced tonsil epithelial cells and clinical trial, three research mentioned above indicate bLF is an ideal candidate for further clinical development in therapeutic application. Similar as bLF, in an open labelled prospective clinical trial, TH was found with positive effects in wound healing acceleration among post tonsillectomy patients at a safe dose of oral consumption comparing to sultamicillin (Lazim, Abdullah, and Salim 2013). Taking together, TH is also another ideal option for infection control and meanwhile inflammation alleviation (Devasvaran et al. 2019). More focus should be lay on bioactive sourced components' research on bacterial antigen‐facilitated inflammation alleviation.

3.4. Anti‐Inflmmatory Effect of Bioactive Componentsi COPD

Chronic obstructive pulmonary disease (COPD), the third leading cause of mortality with annal prevalence ascend, is a long‐lasting pulmonary disease alongside with airflow restriction, emphysema, mucus hyper secretion, opportunistic pathogen infection and other syndromes (Lugade et al. 2014; Phipps et al. 2010). The high morbidity and mortality are majorly attributed to acute exacerbation of COPD (AECOPD), induced by various causes including infection of virus or bacterial infection (Long et al. 2020). It causes great economic burden on either the individuals or the society (Guo et al. 2022). Long‐lasting inhalation of toxic external particles like cigarette smoke and air pollutants facilitates multiple inflammations. And it plays the central roles facilitating the development progression of COPD (Polosukhin et al. 2017; Richmond et al. 2018).

Inflammatory cells, especially the penetrated immune ones, contributes to maturation and release of mediators and enzymes causing function loss and structural destruction of lungs in COPD patients (Richmond et al. 2018). The cigarette smoke (CS)‐related inflammation is persistent and induces micro environment changes of the airway (Wang et al. 2018). During COPD progression, inflammation factors are facilitated by enhancement of cytokines like IL‐6, IL‐8, IL‐17, TNF‐α, which is related to monocytic an neutrophilic inflammation (Barnes 2008). For inflammatory response correlated to COPD, oxidative stress, and damage is crucial since it facilitates initiation of transcription factor nuclear factor κB (NF‐κB) pathway, chromosome condensation, and damage, cellular aging, autoantibody formation, antiprotease aggression, as well as corticosteroid resistance via compromise in normal function of histone deacetylase 2 (Barnes 2016). Post treatment of CS mediated Th17 and Treg ratio abnormality in mice model gradually implies participation of Th17/Treg in destruction of self‐tolerance in immunity alongside progression of COPD (Wang et al. 2012). CS exposure facilitates COPD formation alongside emphysema, recognized through airway epithelial cell senescence. Recent research reported that the FOXO3 transcription factor, a member of the forkhead transcription factor protein family, is commonly found in a subtype of CD4+ T cells involved in immune suppression (Kim 2009). It was found facilitated by CS‐mediated expression of NAD‐dependent protein deacetylase sirtuin‐(SIRT1) and following the accumulative of FOXO3 alleviates lung structural and functional damage (Jiang et al. 2023). Deletion of FOXO3 causes autophagic reactions, senescence level enhancement and elicits profound phenotypic characters of COPD. It indicates that stress‐responsive transcriptional factors like FOXO3, activation, and accumulation, to some certain extent, is practicable in rebelling insults of COPD alongside senescence and effective procrastinate progression of COPD (Jiang et al. 2023). Accordingly, perhaps, inflammation suppression is a promising drug development direction in prevention of COPD progression at early stage with strong clinical significance for public health and alleviation on social costs.

About the in vitro anti‐COPD effect of phytochemicals, the ethanol extract of Zataria multiflora alleviates the serum IL‐8 and malondialdehyde (MDA) level enhancement, the total white blood cell (WBC) number, the eosinophil enumeration and weight changes in the guinea pig model of COPD (Boskabady and Gholami Mhtaj 2014). Also, ginsenoside facilitates Treg expression while reducing Th17 cell expression, which is induced by FOXP3 enhancement. In the mice model (28‐day CS exposure), pathological damage was alleviated due to the ginsenoside therapy (Xu et al. 2020).

Moreover, in a reported clinical trial, a 2‐month period of Z. multiflora consumption or placebo among 41 cases was designed for discussion of inflammation cytokine, PFT value and other COPD symptoms alleviation of Z. multiflora in real world. Serum IL‐8 and TNF‐α decrease, pulmonary function recovery proved by parameters like forced vital capacity (FVC), forced expiratory volume in 1 s (FEV1), and peak expiratory flow (PEF) ascend, and alleviation in symptoms including cough, chest tightness, and modified medical research council (mMRC) dyspnea scale, were all confirmed due to Z. multiflora consumption comparing to placebo and it implies the therapeutic development potential (Ghorani et al. 2022). Ginsenoside, the major component of Panax ginseng with anti‐tumor therapeutic effects by inducing apoptosis and inhibiting proliferation, was found to inhibit COPD‐related inflammation by up‐regulating FOXP3 in a small‐scale clinical trial (n = 43). Pulmonary function test and 6‐min walk test (6MWT) distance together, clearly and strongly supports the COPD‐related symptoms stabilization and life quality improvement among patients. Meanwhile, in transcriptional level, FOXP3, TNF‐α, and IL‐17 in mRNA level was detected increased due to treatment of ginsenoside among patients' samples and furthermore verified in mRNA and protein level in a COPD mice model (Xu et al. 2020). Curcumin, a polyphenol originating from Curcuma longa with multiple targets on signaling molecules and demonstrating various activities, was confirmed to have an alleviation effect on COPD‐mediated airway inflammation and remodeling. This effect occurs through the inhibition of COPD‐induced degradation of IκBα and COX‐2, followed by the suppression of the activation of the NF‐κB pathway. Followingly, in a clinical trial, nano‐curcumin introduction was proved facilitation in a sharp decrease of serum IL‐6 level (p < 0.001), and the significant alleviation and improvement in FEV1 (p < 0.001), FVC (p = 0.003), and FEV1/FVC (p < 0.001), in comparison with the consumption of placebo (Zare'i et al. 2024). To summarize, natural sourced components, especially sample like ginsenoside and curcumin are potential candidates' worth academic investment in both on basic studies and clinical trials.

3.5. Anti‐Inflammatory Effect of Bioactive Components Induced by the Cystic Fibrosis

Cystic fibrosis (CF) is a monogenic autosomal recessive disorder on human chromosome 7 that causes multiorgan pathogenesis. And its related genes are named as cystic fibrosis conductance regulator gene (CFTR) (Bear et al. 1992). CFTR is a down‐regulator of Na⁺ channels and an up‐regulator of Cl⁻ channels in the human airway epithelial cAMP‐regulatory pathway, and is absent in the CF airway, resulting in high Na⁺ absorption, low Cl⁻ uptake and to the characteristic increase in mucus viscosity (Mall et al. 1998). Impaired CFTR Cl⁻ channel activity as well as the cellular stress attributed to accumulation of mistrafficked CFTR in the endoplasmic reticulum (ER), together facilitates the endogenous activation of NF‐κB in cells alongside with the CFTR mutation (Weber et al. 2001). For the CF‐related inflammatory response, NF‐κB, as the crucial regulator, contributes, and facilitates the inflammation alongside with other known transcription factors like AP‐1, AP‐2, and MAPK (Nichols and Chmiel 2015). Besides host genetic compromise mentioned above, the exogenous bacteria pathogen invades and accumulate in lungs, followingly forming biofilms, and causing cystic fibrosis through high expression of flagella and type 3 secretion system (T3SS) in the CF patients. So, the direct lowering pathogenic load (infection control) is the most straight therapeutic option. According to pathogenic infection, neutrophil recruitment mediated by CF and driven by endotoxemia, elicits aerobic glycolysis of circulation in the systematic level and followingly induces maturation of the nucleotide‐ binding oligomerization domain, leucine‐ rich repeat, and pyrin domain‐ containing (NLRP3) inflammasome and its related inflammation dysregulation. This indicates targeting at NLRP3 formation is a practicable anti‐inflammatory therapy for CF treatment. Besides NLRP3, the transcription factor nuclear‐factor‐E2‐related factor‐2 (Nrf2), the crucial regulator of cellular redox homeostasis, and inflammation signaling pathways, and the NF‐κB pathway was found dysregulated and facilitating elevation of IL‐8 and resulting in following chronic infection and airway destruction as well as the neutrophilic inflammation as in the CF cells or mice model. Hence, both of signaling pathways are of therapeutic development potential (Borcherding et al. 2019). Followingly, we are trying to summarize bioactive components with CF combating capability through iron channel or inflammation alleviation.

Alginate oligosaccharide (OligoG) interacting with airways mucin causes changes on the 3D permeability network of CF sputum and surface charge of mucin in vitro. Originated and isolated from Rabdosia rubescens, a de novo CFTR inhibitor of natural source, oridonin (C₂₀H₂₈O₆, PubChem CID 34378) was found based on activity‐directed separation and purification, targeting at CFTR Cl⁻ channel by inhibition (Luan et al. 2015). Meanwhile, oridonin was found with capability in up‐regulation of Nrf2 and its related downstream genes like HO‐1 and GCLM, inhibition of NLRP3 inflammasome formation and NF‐κB pathway initiation as well as the histopathological changes' alleviation in the LPS‐induce acute lung injury (ALI) model, indicating (Yang et al. 2019). It implies therapeutic potential against bacterial induced cystic fibrosis. A study showed that curcumin introduction induces an increase in the net cAMP—activated Cl‐ efflux from ΔF508—CFTR expression of baby hamster kidney (BHK) cells, implying the treatment potential for CF patients (Dragomir et al. 2004; Zhang et al. 2014). (−)–Epigallocatechin‐3‐gallate (EGCG) and (−)–epicatechin‐3‐gallate (ECG) were found inhibited on CFTR Cl‐ currents in both cell models of CFTR‐transfected FRT cells and colonic mucosa form rats. Accordingly, it indicates the potential development of CFTR‐related diseases such as secretory diarrhea (Chen et al. 2015a).

Accordingly, in a clinical trial, the OligoG inhalation provides benefits to patients of CF in alteration on sputum's viscoelasticity and deposition in lungs, implying therapeutic development potential (Pritchard et al. 2016). Moreover, OligoG is the first therapy of polymer inhalation under Phase 2b clinical trials on treatment against CF, regarding as a de novo treatment with novel mechanism against chronic respiratory disease. This clinical trial supported application of OligoG the safety and efficacy of pathogenic load in the CF patients (Fischer et al. 2022). To summarize, although only OligoG reported with clinical trials for next stage development till now, more studies of bioactive components should be focus on drug development for iron channel inhibition and inflammation alleviation since uncountable chemicals are still under cover in nature.

3.6. Anti‐Inflammatory Effect of Bioactive Componentts in COVID‐19

Coronavirus (CoVs) are a big family of virus coated with positive‐sense and single‐stranded RNA, hosting on human, avian animals and livestock, causing uncountable loss to either in economy or public health and safety (Amarilla et al. 2021; Pišlar et al. 2020; Siu et al. 2008; V'kovski et al. 2021). Among members, the most famous one is the severe acute respiratory syndrome coronavirus (SARS‐CoV‐2), also known as novel coronavirus disease 2019 (COVID‐19), caused worldwide pandemic previously (Jabbari et al. 2020; Kesharwani and Keservani 2023; Tabary et al. 2020). To combat, scientist spared no efforts in drug and vaccine development and de novo medication discovery. To address this, the structure of COVID‐19 was quickly elucidated by collaborative groups. (Gurung et al. 2022; Jin et al. 2020). Now, we know that the main protease, named as Mpro or 3CLpro, is a family of evolutionally conserved cysteine hydrolase from β‐coronaviruses, taking responsibility of cleaving polyproteins at various sites for maturation of multiple proteins. Since no homolog was found in human genome, it is regarded as one of the most ideal drug targets for development (Anand et al. 2002; Cui et al. 2019; Qiao et al. 2021). Besides Mpro, RNA‐dependent RNA polymerase (RdRp), the major player for replication and transcription of viral RNA genome, is an essential enzyme responsible for RNA synthesis through catalyzation of phosphodiester bonds depending on RNA template (Tian et al. 2021). So, perhaps, candidate leads with Mpro or RdRp inhibition capability is an ideal option with high possibility of successful transformation leading us to terminate this pandemic.

NF‐κB signaling, a pivotal pathway in inflammation reaction mediation, was found hyper activated during the infective progression of COVID‐19, alongside severity deterioration and proinflammatory cytokine release like interleukin‐6 (IL‐6) and tumor necrosis factor‐alpha (TNF‐α). Consequently, it causes the progression of acute respiratory distress syndrome (ARDS), immune dysregulation and other severe symptoms (Carfì, Bernabei, and Landi 2020; Manik and Singh 2022). However, NF‐κB activation, to some certain extent, facilitates several antiviral protein expressions against infection of SARS‐CoV‐2, which in reverse induce virus evolved mechanism to evade immune response. The complicated relation between virus and NF‐κB implies its strong potential for therapeutic introduction based on further research on balance of efficacy and safety (Guo et al. 2024). Besides directly targeting at druggable proteins like Mpro, alleviation on cytokine storm and lung injuries afterwards would be another option of lifesaving after infection of SARS‐CoV‐2.

Glycyrrhizin, found in Glycyrrhiza uralensis Fisch and the primary active ingredient of the licorice root, was found with capability in replication inhibition in vitro against SARS‐CoV‐2 by targeting at Mpro (van de Sand et al. 2021), indicating the potential health benefit by consumption of glycyrrhizin‐containing products and further clinical trial possibility (Ameri et al. 2023). Moreover, Cui et al. found andrographolide sulfate, andrographolide with water solubility, is able to suppress mucin levels (MUC5AC and MU5BC), cytokine amount (IL‐6 and IL‐1β), phosphorylation of p‐65 and activation of NF‐κB signaling pathway in the poly I: C‐induced pneumonia mice model, implying the strong potential in drug development for patients with severe pneumonia induced by respiratory virus including COVID‐19 (Cui et al. 2020). Similarly, the bark of Rhus verniciflua stroke (RVS) was also found capability in COVID‐19 induced inflammation alleviation in the CD86, TNF‐α, IL‐6 and improvement in IL‐12 and class II MHC molecules amount, as well as down‐regulation of NF‐κB and MAPK pathways. Detailed mechanism and further clinical trials should be conducted for next‐stage comprehensive evaluation and study (Kim et al. 2018). Moreover, Mustafa Ulasli et al. found extracts of Nigella sativa (Ns), Anthemis hyalina (Ah) and Citrus sinensis (Cs) extracts facilitates IL‐8 expression enhancement alongside decrease of TRMP8 and TRPV4 in the HeLa‐CEACAM1a the epithelial carcinoembryonic antigen‐related cell adhesion molecule (1) and murine fibroblast LR7 cells infected with COVID‐19 model, meanwhile coronavirus replication was detected significantly decreased (Ulasli et al. 2014). What's more, rutan, originated from Rhus coriaria , was proved in in vitro and in vivo tests as well that it is effective in inhibition against 3C‐like proteinase (3CLpro) and RNA‐dependent RNA polymerase (RdRp) at safe dose to either children or adult, indicating a strong developmental potential for prevention of COVID‐19 (Salikhov et al. 2023).

Followingly, in a clinical trial, Rutan was demonstrated with capability in decrease not only in C‐reactive protein but also viremia period, as well as the frequency of post‐COVID‐19 manifestations with significant difference among patients infected with COVID‐19, comparing to the consumption of placebo, implying the antiviral and prevention with safety among children and adults. (Salikhov et al. 2023) Besides rutan, according to a randomized and placebo‐controlled trial among hospitalized COVID‐19 patients, pomegranate juice intake is of high possibility on improvement on inflammation attenuation and complete blood count (CBC) results as health benefits (Songvut et al. 2023). To summarize, bioactive components are another options worth under consideration in further studies at drug development combating COVID‐19 either directly targeting at Mpro or RdRp or indirectly through inflammation alleviation.

3.7. Anti‐Inflammatory Effect of Bioactive Components in Acute Lung Injury

Acute lung injury (ALI) is a severe respiratory disease that, if left untreated, often develops into acute respiratory distress syndrome, with a mortality rate of up to 40%–60% (Assiri et al. 2023). The characteristics of ALI are systemic inflammatory processes and oxidative stress. Its characteristics include pulmonary edema, pulmonary hemorrhage, severe damage to gas exchange caused by inflammation disorders, and increased alveolar‐capillary permeability (Xiang et al. 2022). The ALI can be caused by direct causes in the lung (pneumonia, lung contusion, aspiration, and inhalation injury) or indirect causes (sepsis, endotoxemia, multiple trauma, burns, ischemia/reperfusion, massive transfusion pancreatitis, and shock) (Bersten et al. 2002). Cyclic adenosine monophosphate (cAMP) is an intracellular second messenger that plays an essential role in regulating the pathogenesis of ALI (Avni et al. 2010). Increasing intracellular cAMP levels is considered a promising therapeutic strategy for ALI. cAMP can inhibit immune response, inhibit ROS generation, reduce caspase three activity, and promote cell survival by activating the protein kinase A (PKA) signaling pathway (Wang et al. 2013). Moreover, the NF‐κB pathway has been considered the central controller of inflammation. In acute lung injury, NF‐κB is essential in rendering the endpoint permission for PMN adhesion and transmission to reach the inflammation (Millar, Fazal, and Rahman 2022). Accordingly, drug development targeting at intracellular cAMP ascend alleviation and inflammation relief is significantly for ALI progression and related lung injury prevention.

Finding phytochemicals to improve acute lung injury in natural products is very promising and feasible. Assiri et al.'s research showed that the N‐butanol extract of the Tamarix nilotica can improve LPS‐induced acute lung damage induction in Swiss albino mice by reducing the expression of inflammatory factor TNF‐α and increasing the expression of related antioxidant enzymes including CAT and SOD (Assiri et al. 2023). Similarly, the study by Xiang et al. revealed that the ethanol extract of Fritillaria hupehensis improves LPS‐induced acute lung injury in the mouse model are related to the anti‐inflammatory activity of pro‐inflammatory proteins regulated by the steroid alkaloids in the extract by inhibiting the NF‐κB signaling pathway (Xiang et al. 2022). In addition to the research on these extracts, there are also many monomeric phytochemicals with biological activity that improve LPS‐induced acute lung injury. A type of lignans from Schisandra chinensis, schisandrin can alleviate pulmonary endothelial and epithelial damage induced by LPS stimulation in animal models by inhibiting the PI3K/Akt/mTOR signaling pathway and NF‐κB signaling pathway (Sun et al. 2018). Oridonin, a diterpenoid compound from Rabdosia rubescens, can regulate the Nrf2/HO‐1/NLRP3 and NF‐κB signaling pathway while reducing oxidative pressure and IL‐1β related inflammatory factors to improve acute lung injury (Yang et al. 2019). Luteolin, the major polyphenolic component of Lonicera japonica , has a beneficial effect on LPS‐induced acute lung injury in mice, and the reduction of neutrophil chemotaxis and respiratory burst by luteolin involves the blockade of MEK, ERK, and Akt related signaling cascades (Lee et al. 2010). Phytochemical monomers can not only improve acute lung injury caused by LPS but also improve CLP (cecal ligation and function) induced acute lung injury and oleic acid‐induced acute lung injury. Wang et al.'s study suggests that paclitaxel from Schisandra chinensis has a protective effect against CLP‐induced acute lung injury, and this protective effect is achieved by inhibiting the NF‐κB signaling pathway (Wang et al. 2019). Moreover, the flavonoid compound Hydroxysaflor yellow A from Carthamus tinctorius L. can improve acute lung injury induced by oleic acid in animal models. More specifically hydroxysaflor yellow A can upregulate the cAMP/PKA signaling pathway, reduce the release of inflammatory cytokines, and enhance antioxidant capacity to alleviate oleic acid‐mediated lung injury (Wang et al. 2013). To summarize, although various bioactive components showed well inflammation alleviation in a well‐studied and commonly accepted LPS‐induced cellular model in vitro mimicking ALI in cell bulk culture level, studies are required for further studies in clinical trial for consideration of druggability in reality.

3.8. Anti‐Cancer Effect of Bioactive Components in Lung

Besides COPD, CF, and asthma mentioned above, cancer is also another ranking forehead item representing the cause of morbidity (Malhotra et al. 2016). Lung cancer is the most commonly one and the leading cause of cancer‐mediated death worldwide comparing to other sub‐types like breast, prostate, and colon ones, remaining as a serious health concern (Gomes et al. 2014). Surgery, the best option, is only effective on the minority of patients (< 20%) without meta‐station or local advance. For the rest 80%, the platinum‐based chemotherapy is preferred but this therapy for survival is modest (Conway et al. 2016). Together, it indicates the effective manner is limited. Inflammation, especially the chronic one, is always found alongside with the progression of the cancer development. And it elicits immune suppression and provides a beneficial micro environment for tumor formation and progression, regardless of the extrinsically or intrinsically induced inflammation (Coussens and Werb 2002). For past decades, how immune system fail in prevention of tumorigenesis has been well studied and now the evasion or escape from immune system is regarded as one of the hallmarks of carcinogenesis (Hanahan and Weinberg 2011). Therefore, chronic inflammation of the lungs is closely related to the occurrence of lung cancer. So, how to combat lung cancer through inflammation is a hot topic worth deep studies with clinical significance.

Various bioactive components from natural sources can improve lung cancer by activating autophagy, apoptosis, and cell cycle arrest, including flavonoids, triterpenoid saponins, and diterpenoids. Lu et al.'s study showed that the Citrus fruits flavonoid naringenin induces apoptotic cell death in A549 cell lines to achieve anti‐cancer effects. More specifically, naringin achieves anti‐cancer effects by downregulating Bcl‐2 and Bcl‐xL, as well as upregulating the expression of Bad, Bax, and PUMA, leading to Bax translocation and Bad cleavage (Lu et al. 2020). Wu et al.'s study showed that cinnamaldehyde from Cinnamomum cassia can activate apoptosis in multiple non‐small cell lung cancer cell lines and mouse models by reducing downregulation of Bcl‐2 and Bcl‐xL. More specifically, this anti‐cancer effect is achieved by cinnamaldehyde inhibiting the Wnt/β‐catenin by inhibiting the expression of GSK3β and β‐catenin, as well as increasing the expression of p‐β‐catenin (Wu et al. 2017). A triterpenoid saponin (glycyrrhetinic acid) from Glycyrrhiza uralensis can induce autophagy in A549 and NCI‐H1299 cells by activating the IRE1α‐JNK/c‐jun signaling pathway to achieve anti‐cancer effects (Tang et al. 2015). In addition, glycyrrhetinic acid can also activate autophagy in A549 and NCI‐H1299 cells. Another triterpenoid saponin from Platycodon grandiflorum , platycodin D, can induce autophagy by inhibiting the PI3K/Akt/mTOR signaling pathway and activating the JNK and p38 MAPK signaling pathways in NCI‐H460 and A549 cell lines (Zhao et al. 2015). The crocin from Crocus sativus flower can inhibit the proliferation of A549 and SPC‐A1 cell lines and enhance their chemotherapy sensitivity to cisplatin and pemetrexed. Its molecular mechanism may be to induce cell cycle arrest and apoptosis through upregulation of p53 and Bax and downregulation of Bcl‐2 (Chen et al. 2015b). Ni et al.'s study demonstrated that Water extract of Trichosanthes kirilowii Maxim fruits can significantly induce G2‐M arrest, necrosis and apoptosis in A549, H1299, and H1975 cell lines through flow cytometry (Ni et al. 2015). Accordingly, in future studies, on the perspective of programmed cell death, how natural sourced bioactive components combat against palmary cancer progression through inflammation alleviation should be well and deeply studied for enhancement of candidate leads with hope in consideration of clinical application.

4. Molecular Mechanisms of Bioactive Component on Inflammatory Diseases of the Airways

Although bioactive components can improve different respiratory inflammatory diseases in various parts of the human body, their anti‐inflammatory molecular mechanisms are closely related. The molecular mechanisms of bioactive components in improving different respiratory inflammatory diseases are summarized in Figure 3. Proper regulation of these signaling pathways can reduce the generation of pro‐inflammatory cytokines and the development of inflammation. Specifically, bioactive components can improve respiratory‐related inflammation by inhibiting the phosphorylation of Akt to inhibit the activation of the PI3K/Akt signaling pathway (Donnelly et al. 2004; Kim et al. 2012; Hohmann et al. 2019; Schafer et al. 2017). Furthermore, inhibition of the PI3K/Akt signaling pathway can indirectly inhibit the activation of the NF‐κB signaling pathway (Donnelly et al. 2004; Hohmann et al. 2019; Schafer et al. 2017). NF‐κB is a classic inflammatory pathway, and its core is the NF‐κB complex composed of P50, P60, and IĸBα (Donnelly et al. 2004). The bioactive components can inhibit the process of IĸBα degradation to inhibit the NF‐κB complex translocation and activate downstream transcription factors, further increasing the production of pro‐inflammatory cytokines (Luan et al. 2015; Yang et al. 2019). Moreover, bioactive components can increase the expression of (Luan et al. 2015; Yang et al. 2019) and, followingly, its downstream genes (HO‐1 and GCLM) as the hallmark of Nrf2/HO‐1/NLRP3 signaling pathway initiation and consequently inhibit the inflammatory‐related cell death (Pyroptosis) (Luan et al. 2015; Yang et al. 2019). Also, bioactive components facilitate the phosphorylation of JNK, ERK, and p38 protein and followingly inhibit the c‐Jun and c‐Fos phosphorylation as well as the activation of three canonical (p‐38, p‐JNK, and p‐ERK1/2) MAPK pathways as an inflammation control method (Zhao et al. 2015). For the MEK/ERK signaling pathway, bioactive components inhibit the expression of MEK, ERK cellular protein level, and the phosphorylation level of Akt and ERK protein as the hallmark of MEK/ERK signaling pathway inhibition (Lee et al. 2010). Moreover, bioactive components induce the intracellular level of cAMP and PKA amount as the hallmark of activation of the cAMP‐PKA signaling pathway, causing the nucleus transcriptional level enhancement of CREB (Wang et al. 2013).

FIGURE 3.

The molecular mechanism of the natural bioactive components improving the inflammatory diseases in respiratory tract.

The bioactive phytochemicals improve the inflammatory disease in the respiratory tract through regulating the various inflammatory pathway. But those phytochemicals may target in different place of the respiratory tract and representing the in vitro study using different cell line. For studying the improving inflammatory effect of phytochemicals in the air way, the A549 cell line, human pulmonary fibroblasts (Donnelly et al. 2004; Kim et al. 2012). And for the asthma, the bone marrow‐derived mast cell line was used for studying its anti‐inflammatory effect of the bioactive phytochemicals and underlying mechanism (Lertnimitphun et al. 2021). The human umbilical vein endothelial cells and HeLa S3 cells were utilized in the studying the improving inflammatory effect of the phytochemicals (Ajello et al. 2002; Devasvaran et al. 2019). Interestingly, the research of the phytochemicals' anti‐inflammatory effect in COPD were conduct in the guinea pig and Kunming mice instead of using other in vitro model (Boskabady and Gholami Mhtaj 2014; Yuan et al. 2018). Furthermore, the BHK cell and the Fischer rat thyroid epithelial cell were chosen for studying the anti‐inflammatory effect in the Cystic fibrosis (Dragomir et al. 2004; Egan et al. 2004; Fischer et al. 2022; Quispe et al. 2022). For studying the anti‐inflammatory effect of phytochemicals in the COVID 19, RAW 264.7 cells and African green monkey kidney Vero E6 cells were applied (Kim et al. 2018; Salikhov et al. 2023). The human wt‐CFTR, Fischer rat thyroid (FRT) epithelial cells, ΔF508‐CFTR cell line were used for studying the anti‐inflammatory effect of phytochemicals in the acute lung injury (Luan et al. 2015; Yang et al. 2019).

5. The Latest Research and Prospects

The review of the last four years of literature underscores the significant anti‐inflammatory and therapeutic effects of bioactive phytochemicals treating various inflammatory diseases in the respiratory tract. Melatonin has been demonstrated to suppress inflammatory cytokines production in human pulmonary fibroblasts, indicating its potential to mitigate airway inflammation (Wang et al. 2022). In asthma, some bioactive phytochemicals such as Safranal and Carvacrol have been reported promise in inhibiting inflammatory pathways and reducing asthma symptoms (Ezz‐Eldin, Aboseif, and Khalaf 2020; Lertnimitphun et al. 2021). Also, some latest clinical trials have further supported the benefits of carvacrol in improving pulmonary function and reducing oxidative stress in asthma patients (Ghorani et al. 2021).

The integration of these bioactive compounds into clinical practice for treating various inflammatory diseases of the respiratory tract appears promising. Further research should optimize dosages and delivery methods and to evaluate long‐term efficacy in these inflammatory diseases. Moreover, exploring synergistic effects when combining these natural compounds with conventional therapies could lead to more effective treatment strategies. However, in the past few years, there has been a lack of clinical data on the use of plant compounds in the treatment of lung cancer and acute lung injury, which may require the attention of relevant experts and scholars in the future. Also, due to the varying levels of bioactive ingredients in drugs and the lack of good clinical evidence to support their use in many cases, further high‐quality studies are needed to firmly establish the clinical efficacy of bioactive ingredients, although results from small‐sample clinical trials have emerged to support some of these drugs (Izzo et al. 2016; Williamson, Liu, and Izzo 2020).

6. Conclusion

Current domestic and foreign studies have shown that bioactive components extracted from natural product improve inflammatory diseases in the respiratory tract, including airway inflammation, asthma, bacterial antigens‐induced tonsil epithelial inflammation, chronic obstructive pulmonary disease (COPD), cystic fibrosis (CF), COVID‐19, acute lung injury, and lung cancer. These natural components include polyphenols, flavonoids, amine hormones, monoterpene phenols, terpenes, diterpenoids, and triterpenoid saponins, which can improve inflammatory diseases in the respiratory tract through multiple signaling pathways and mechanisms. Some of these food‐derived phytochemicals have been clinically proven to improve inflammatory diseases in the respiratory tract, including safranal from Crocus sativus , soy isoflavone from Glycine max , carvacrol from Origanum hirtum, ginsenoside from Panax ginseng , and curcumin from Curcuma longa . These natural components have broad development and application prospects in the development of functional foods or drug in the future. In this review, the molecular mechanisms of bioactive ingredients against respiratory inflammation were summarized as a guide for future development of relevant functional foods as well as pharmaceuticals. However, future research focuses on the upstream binding of specific natural ingredients to their targets, toward the development of targeted drugs. In addition, the effect of bioactive components on improving the prognosis of these inflammatory diseases in the respiratory tract is currently unclear. However, the prognosis of inflammatory diseases in the respiratory tract is vital. Future research in this area needs further in‐depth exploration. Based on the homology theory of medicine and food, the edible and medicinal health‐care value of bioactive components of potential inflammatory diseases in the respiratory tract needs to be fully explored. It is important for the efficient and comprehensive development of drugs or functional foods targeting inflammatory diseases in the respiratory tract to utilize bioactive ingredients from natural sources. Further high‐quality studies are still needed to firmly establish the clinical efficacy of bioactive phytochemicals.

Author Contributions

Jincan Luo: data curation, formal analysis, investigation, resources, validation, visualization, writing – original draft. Jinhai Luo: data curation, formal analysis, investigation, validation, visualization, writing – original draft. Zhonghao Fang: data curation, formal analysis, investigation, validation, visualization, writing – original draft. Yu Fu: data curation, formal analysis, investigation, writing – original draft. Baojun (Bruce) Xu: conceptualization, funding acquisition, methodology, project administration, resources, supervision, validation, writing – review and editing.

Conflicts of Interest

The authors declare no conflicts of interest.

Luo, J. , Luo J., Fang Z., Fu Y., and Xu B. B.. 2025. “Insights Into Effects of Natural Bioactive Components on Inflammatory Diseases in Respiratory Tract.” Phytotherapy Research 39, no. 9: 4199–4229. 10.1002/ptr.8367.

Data Availability Statement

Data will be available upon request.