Omega-3 Fatty Acids and Chronic Lung Diseases: A Narrative Review of Impacts from Womb to Tomb

Abstract

The lungs are a mucosal organ constantly exposed to potentially harmful compounds and pathogens. Beyond their role in gas exchange, they must perform a well-orchestrated protective response against foreign invaders. The lungs identify these foreign compounds, respond to them by eliciting an inflammatory response, and restore tissue homeostasis after inflammation to ensure the lungs continue to function. In addition, lung function can be affected by genetics, environmental exposures, and age, leading to pulmonary diseases that infringe on quality of life. Recent studies indicate that diet can influence pulmonary health including the incidence and/or severity of lung diseases. Specifically, long-chain omega-3 polyunsaturated fatty acids (n-3 PUFAs) have gained attention because of their potential to reduce inflammation and promote resolution of inflammation. Docosahexaenoic acid and eicosapentaenoic acid are 2 potentially beneficial n-3 PUFAs primarily acquired through dietary intake. Here we review current literature examining the role of n-3 PUFAs and the biological mechanisms by which these fatty acids alter the incidence and pathologies of chronic lung diseases including asthma, chronic obstructive pulmonary disease, and interstitial lung disease. We also highlight the role of n-3 PUFAs in vulnerable populations such as pre/postnatal children, those with obesity, and the elderly. Lastly, we review the impact of n-3 PUFA intake and supplementation to evaluate if increasing consumption can mitigate mechanisms driving chronic lung diseases.

Introduction

Chronic respiratory diseases are a leading cause of mortality worldwide, accounting annually for 454.6 million cases and >4 million deaths before the COVID-19 pandemic [1]. The lungs are a vital organ tasked not only with facilitating gas exchange but also combating a multitude of environmental exposures that can induce pathologies leading to reduced lung function. The lungs respond to these exposures to quickly restore tissue homeostasis and protect themselves from subsequent pathology. Therefore, failure to initiate a sufficient immune response, or initiating an over-exuberant response can result in lung diseases [[2], [3], [4], [5], [6], [7], [8]]. The potential to develop these diseases is further exacerbated in vulnerable populations, such as those with genetic mutations, children, the elderly, or those with pre-existing metabolic diseases [[9], [10], [11]]. Understanding the biological mechanisms by which lung pathologies develop and identifying interventions that reduce them and promote tissue homeostasis are needed to reduce the public health burden of lung disease.

There is mounting evidence that nutrition can significantly impact the incidence and severity of pulmonary diseases [12,13]. In both clinical and basic research studies evaluating various bioactive nutrients, long-chain omega-3 PUFAs (n-3 PUFAs) modulate the inflammatory response [14]. DHA (22:6n-3) and EPA (20:5n3) are the 2 foremost long-chain n-3 PUFAs with anti-inflammatory and proresolving characteristics [15]. These nutrients are only minimally endogenously synthesized via elongation and desaturation from short-chain n-3 PUFAs and are primarily acquired through diet by consuming oily cold water fish, dietary supplements, or as prescriptions [16,17]. Most western diets are deficient in EPA and DHA. According to the 2011–2012 National Health and Nutrition Examination Survey, adults on average consume ∼0.09 g/d of DHA and EPA [18,19]. Although there are no official recommendations for DHA/EPA intake in the United States or United Kingdom, the British Dietetic Association recommends 2 portions of 140 g fish/wk which, if the fish were salmon, would equate to daily intake of ∼0.9 g/d (100 g serving contains 2.2 g DHA+DPA+EPA), ∼10 times the average intake [[18], [19], [20]]. In addition, a Canadian Survey using the omega-3 index proposed by Harris and von Schacky found that the Canadian population has an average omega-3 index of 4.5% where 8% is considered healthy [21,22]. In a separate global review, only citizens in Alaska, Greenland, Iceland, Norway, or Finland have an omega-3 index >8% [23]. Furthermore, Western diets are high in n-6 PUFAs such as linoleic acid (18:2n-6) or arachidonic acid (AA; 20:4n-6), which can be proinflammatory [24]. The balance of n-6 to n-3 PUFA intake is critical because these PUFAs utilize the same metabolizing enzymes that convert them to either proinflammatory eicosanoids or anti-inflammatory/proresolving specialized proresolving mediators (SPMs), respectively. Current preclinical evidence supports that increased n-3 PUFA intake and/or tissue levels can reduce lung disease pathologies [[25], [26], [27]]. However, there is mixed evidence for the effectiveness of n-3 PUFAs in lung diseases at the clinical level [[28], [29], [30], [31], [32]]. This review evaluates the role of n-3 PUFAs in the context of chronic pulmonary diseases and highlights current literature that examines if n-3 PUFAs could serve as a preventative therapeutic. Furthermore, we will examine the potential mechanisms of how these dietary nutrients reduce lung pathologies and how their intake impacts lung health in vulnerable populations such as the young, elderly, or those with obesity.

Pathophysiology of Lung Diseases

To better understand the role of n-3 PUFAs in lung disease pathophysiologies, it is necessary to first understand the mechanisms that drive chronic lung diseases. Lung diseases are commonly classified based on disease-related changes in lung physiology. For simplicity, we will focus on obstructive lung diseases, which are classified as having delayed exhalation, and restrictive lung diseases, which have a reduced total lung inspiratory capacity. These distinctions are clinically useful for treatment decision making and to differentiate how the lungs are impacted.

Obstructive lung diseases

Obstructive lung diseases, defined by the change in exhalation mechanics, are the most common type of lung disease across the lifespan [33]. In all obstructive diseases, the primary abnormality starts from airway inflammation, the extent and chronicity of this inflammation then determines the disease course. Asthma, a heterogeneous obstructive lung disease, is one of the most common chronic obstructive lung diseases of childhood, and impacts >300 million people globally [34]. Asthma occurs when chronic airway inflammation causes airway hyperresponsiveness, variable airway obstruction, and pulmonary inflammation [35]. Although the exact cause of asthma is unknown, it is known that subsequent inhalation of allergens and/or environmental exposures triggers a heterogeneous immune response. Most often, this is characterized by increased activation of antigen-presenting cells, polarization of naïve T-cells to a Th2 phenotype, and increased airspace cytokine and chemokine production [36]. This increase in cytokines and chemokines results in the recruitment of eosinophils and neutrophils to the lung, increased mucous secretion in the airways, and structural changes to the lung over time [37,38]. Non-Th2, noneosinophilic phenotypes of asthma are more often associated with later onset, poor control, increased age, increased inhalational environmental exposures, and obesity [39]. The Th2 low endotype (which can be Th17 predominant, neutrophilic, or paucigranulocytic) likely results from activation of toll like receptors (TLRs), TLR2, TLR4, CD14, and release of cytokines such as IL-8 and IL-1ß after exposure to these irritants. The resultant cytokine and chemokine cascade causes airway hyperresponsiveness and exacerbation [39].

Chronic obstructive pulmonary disease (COPD), another heterogeneous but common obstructive disease, is similarly caused by chronic inflammation of the airways. In the United States, 10% of people over the age of 40 meet diagnostic criteria for COPD [40], and the disease causes over 150,000 deaths/y in the United States [41]. Like asthma, chronic inflammation in COPD results from inhaled exposures; in contrast, this inflammation causes destruction of the lung parenchyma (such as emphysema), and alterations in pulmonary vasculature. Cigarette smoking is one of the most common causes of COPD [42]. In nonsmokers, COPD can be caused by occupational or environmental exposures, such as biomass fuel or coal exposure [42]. Repeated exposures, elevated oxidative stress, increased proinflammatory cytokines (such as TNF-ɑ, IL-1β, IL-8, and IL-6), and increased concentration of oxylipins such as leukotrienes and prostaglandins drive persistent inflammation [33]. This inflammatory cascade causes an imbalance between proteases and antiproteases, causing alveolar cell death leading to decreased gas exchange [42].

Bronchiectasis is a less common obstructive lung disease, characterized by airway dilation on imaging and significant respiratory secretions. Causes include cystic fibrosis (an abnormality in pulmonary secretions due to genetic alteration in chloride transport), hyperinflammation, autoimmune diseases, genetic disorders, and chronic infections. In the United States, estimated prevalence of this group of diseases is thought to be 139 cases per 100,000; it is more common in women than men [43]. These diseases are more common in indigenous and underserved populations globally, including indigenous peoples in Australia, New Zealand and Pacific Islanders [44,45]. All types of bronchiectasis are characterized by reduced mucociliary clearance, increased neutrophils, and resultant elevations in IL-8, and oxylipins [46]. This chronic inflammation is worsened by recurrent infections, peribronchial fibrosis, and airway remodeling causing obstruction [46].

Restrictive lung diseases

Restrictive lung diseases are a broad group of heterogeneous diseases, all defined by a decrease in total lung capacity on pulmonary function testing. As opposed to obstructive diseases that have airway-specific abnormalities, these diseases cause abnormalities in the lung tissue. This review will focus on a group of restrictive diseases called interstitial lung disease (ILD), named so because of changes seen on imaging and biopsy of the lung tissue. ILDs range from self-limiting and asymptomatic to rapidly progressive and fatal [47]. The pathologies noted in ILD are increased pulmonary inflammation that does not resolve and pulmonary fibrosis [48]. Although the exact etiology of ILD is unknown, there are known genetic predispositions that can drive this chronic lung disease as well as certain occupational and/or environmental exposures that induce epithelial cell injury, changes in tissue architecture, and abnormal lung function.

Idiopathic pulmonary fibrosis (IPF) is a common cause of ILD, most commonly presenting in males over the age of 65, with prevalence increasing with age, and 3–9 cases per 100,000/y in Europe and the United States [49]. Like other ILDs, IPF pathologies are thought to arise from a combination of lung injury (that is, infection, inhalation exposure, etc.), genetics, and aging. These factors disrupt the pulmonary wound healing response, causing basement membrane abnormalities that activate macrophages, fibroblasts, and endothelium leading to abnormal collagen deposition and subsequent fibrosis [47]. Causes for these disrupted repair processes may include age-related increase in senescent cells, impaired surfactant production, and altered epithelial cell metabolism [[50], [51], [52]].

Other ILDs are a result of autoimmune diseases, such as rheumatoid arthritis, idiopathic inflammatory myopathies, and scleroderma, and are called connective-tissue-associated ILD. These autoimmune-related diseases are more likely to occur in women than men and have a prevalence of between 3 and 19 per 100,000 [53,54]. This subset of ILD is largely driven by autoantibodies activating lung macrophages and stromal cells leading to increased proinflammatory cytokines (TNF-ɑ, IL-1, IL-6) that cause aberrant repair process in the lung and eventual interstitial fibrosis [47].

Hypersensitivity pneumonitis is a type of ILD caused by inhalation exposures, including fungal, avian, or heavy metals that can cause chronic inflammation or even fibrosis [55], and is described in 1 cohort to have a prevalence of 2–3 per 100,000 people [56]. In these patients, antigen exposure drives granulomatous inflammation, skewing toward Th1-phenotypes via IL-12 and interferon (IFN)-γ. This broad class of ILDs is currently poorly understood with few mechanistic targets known for potential disease-targeted treatments.

N-3 PUFA Intake Influences Lung Diseases

Dietary intake

Recent studies have identified that dietary intake of n-3 PUFAs has the potential to impact pathologies associated with both obstructive and restrictive lung diseases. Although the exact mechanisms by which n-3 PUFAs alter susceptibility and exacerbations of lung diseases, some studies have reported that increased intake decreases lung inflammation and injury and facilitates the resolution of inflammation and/or wound repair [57]. One of the benefits of increasing dietary n-3 PUFAs is to alter the ratio of n-6 to n-3 PUFAs in patients with lung disease [58]. AA is an n-6 PUFA that is metabolized into mostly proinflammatory eicosanoids such as leukotrienes, prostaglandins, and thromboxanes. These inflammatory bioactive oxylipins contribute to pathologies of several lung diseases such as bronchospasm and inflammatory cell recruitment in asthmatics [59]. Furthermore, higher n-6 PUFA intake is associated with increased asthma severity and systemic inflammation (as measured by neutrophilia in the blood) in response to indoor air particulate matter ≤ 2.5 μm (PM_2.5), whereas increased n-3 PUFA intake is associated with reduced asthma severity and neutrophilia [60]. Observational studies evaluating n-3 and n-6 PUFA dietary intake in patients with COPD show that patients who eat more foods rich in n-3 PUFAs have improved lung function and reduced proinflammatory TNF-ɑ, whereas elevated dietary n-6 PUFAs are associated with reduced lung function and increased IL-6 and C-reactive protein (CRP) [[61], [62], [63], [64]]. In cohorts with pulmonary fibrosis, patients with higher plasma levels of n-3 PUFAs are associated with decreased progression and longer transplant-free survival [65]. Furthermore, high plasma levels of DHA are associated with a lower risk of hospitalization from ILD and fewer imaging abnormalities [66].

Some studies also provide dietary intervention to better control the n-6 to n-3 ratio and evaluate the potential benefits of increased n-3 PUFA dietary intake. For example, the Mediterranean diet is rich in n-3 fatty acids, and when used as a dietary intervention, significantly reduces bronchial inflammation, wheezing, and sneezing, and improves asthma control [[67], [68], [69]]. In addition, healthy individuals provided with a Mediterranean diet are less likely to develop COPD and have improved lung function [70,71]. In mouse studies, dietary DHA and/or EPA supplementation reduced proinflammatory cytokine production and immune cell recruitment in lung inflammation models of agricultural dust extract, tuberculosis infection, Pseudomonas aeruginosa infection, cystic fibrosis, bleomycin-induced fibrosis, and ovalbumin-induced asthma [[72], [73], [74], [75], [76], [77], [78], [79]]. Dietary intervention is the optimal method to increase n-3 PUFAs because of the natural source, and a tendency to replace n-6 rich foods with n-3 PUFAs. However, more dietary intervention studies are required to determine the protective abilities of n-3 PUFAs.

Intake by supplements

Researchers have used fish oil supplements to investigate the protective effects of n-3 PUFAs in lung diseases. These heterogenous studies, however, are confounded by the lack of standardization among supplements in the United States. Table 1 describes the diverse types of supplements available (as reported by the National Institutes of Health Dietary Supplement Label Database; DSLD), as well as the significant differences in bioactive metabolites. The clinical relevance of these different sources is not well studied. In obstructive lung diseases, n-3 PUFAs have been shown to reduce airway inflammation [14]. For example, patients with asthma were given fish oil capsules with low (0.1:1) or high (0.5:1) n-3 to n-6 ratios; patients supplemented with capsules low in n-3 PUFAs had increased airway hyperreactivity following methacholine challenge and increased urinary excretion of leukotrienes (specific doses of n-3 PUFAs were not described) [80]. In this same study, participants with high n-3 PUFA intake had improved lung function and lower exhaled nitric oxide, a measurement of airway inflammation after allergen exposure [80]. Furthermore, in a separate study, asthmatic patients given 0.69 g/d n-3 PUFA supplementation had a decreased inflammatory response as measured by serum eosinophils [28]. Exercise induced bronchospasm, a variant of asthma, has also been studied, where supplementation of 3.2 g/d EPA and 2.0 g/d DHA was effective in reducing hyperpnea induced bronchospasm [81]. Another study demonstrated that doses as low as 1.8 g/d EPA and 1.3 g/d DHA via supplementation were enough to decrease change in forced expiratory volume in 1 second (FEV1) and decrease markers of airway inflammation such as FeNO in asthmatic adults [82]. However, the impact of n-3 supplementation on obstructive lung diseases like asthma and COPD has not been consistent as some studies demonstrated no impact on FEV1 with n-3 supplementation (specific supplementation amount was not described) [83]. In a systematic review of COPD trials of n-3 PUFA supplementation [with no standard doses and regimens including a mix of steric acid (18:0) 400 mg, ɑ-linolenic acid (18:3 n-3) 1200 mg, EPA 700 mg, DHA 340 mg, one of 2 g/d DHA and EPA, another of 1.1g/d EPA, or undefined supplements], there was no change in lung function; however, a trend was noted with lower serum IL-6, higher low-density lipoprotein, and weight gain [84].

TABLE 1.

Comparison of select commercially available n-3 PUFA supplements.

Primary oil	Supplement	Serving size (adult)	Primary ingredient	EPA (mg)	DHA (mg)	Other metabolites	DSLD ID
Algal oil	Vegan omega 3 algal oil	1 capsule	556 mg algal oil	83	167		302276
	Algae omega-3 formulation	2 softgels	1200 mg algae oil	180	360		303148
Fish oil	Omega-3 EPA and DHA	1 capsule	893 mg re-esterified triglyceride concentrated fish oil	410	250	6 mg vitamin E 25 mg vitamin D3	249448
	Omega 3 mood	2 softgels	2000 mg fish oil concentrate	1000	150	20 iU vitamin E	43495
	Omega-3 fish oil	1 softgel	1250 mg fish oil	450	300		302133
Cod liver il	Norwegian cod liver oil	1 softgel	415 mg cod liver oil	37	36	2049 mcg vitamin A, 3.5 mg vitamin D3, 17 mg other fatty acids	244787
	Cod liver oil	1 capsule	1000 mg cod liver oil	80	90	800 mcg vitamin A, 5 mcg vitamin D3	70157
Krill oil	Krill oil	2 softgels	1200 mg krill oil	120	65		307633
	Krill oil	1 capsule	300 mg krill oil, 200 mg fish oil	100	65	19 mcg vitamin K	255310

To the best of our knowledge, n-3 PUFA supplementation has not been studied in ILDs. However, in animal models of ILD, n-3 PUFA interventions alleviate symptoms of fibrosis. For example, as oral administration of n-3 PUFA-rich oil protects against silica-induced pulmonary injury [85], intratracheal DHA decreased lung injury after bleomycin-induced fibrosis [76], oral DHA mitigated paraquat (a pesticide)-induced pulmonary fibrosis [86], and mice with high n-3 intake had decreased markers of lung injury and developed less pulmonary fibrosis [87]. Future clinical research should focus on the ability of n-3 PUFAs to treat or prevent ILDs in people.

Although there have been mixed results in n-3 PUFA clinical supplementation studies for treating lung diseases, differences in study design, EPA:DHA ratio, background levels of n-6 PUFAs, duration of supplementation, quality of the supplement, starting levels of n-3 PUFAs in subjects, endpoints measured, and variable corrections in meta-analyses could account for these differences. On the basis of our review and others, a threshold of ≥2 g/d of total n-3 PUFA may be required for biological impact [88]. Further studies are required to study the duration of diet, EPA:DHA ratio, and other variables to identify the therapeutic potential of n-3 PUFAs in chronic lung diseases.

Influence of n-3 PUFAs in Populations Vulnerable to Developing Lung Disease

Pre/postnatal n-3 PUFA supplementation

Although there is a significant amount of research in adults, the impact of n-3 PUFAs on the lung begins in utero. Synthesis of n-3 PUFAs is required for development into adulthood, because mice lacking an enzyme required for n-3 PUFA synthesis (FADS1) were only able to survive until 12 wk of age (early adulthood) [89]. Furthermore, increased maternal consumption of n-3 PUFAs can significantly improve lung development [90]. DHA supplementation during pregnancy significantly increases gestation duration, reduces preterm births, and increases birth size which are related to lung development [91,92]. Preterm birth increases the risk of impaired alveolarization, neonatal respiratory distress syndrome, bronchopulmonary dysplasia, adult airway hyperreactivity, and lower adult FEV1 [[93], [94], [95]]. Not only does preterm birth prevent the lungs from fully developing, but it also reduces the amount of n-3 PUFAs a mother transfers to the fetus during pregnancy [96]. As a result, preterm infants have decreased levels of DHA that is associated with increased chances of developing chronic lung disease [97].

Several fish oil supplementation clinical studies have been reported to increase maternal and natal n-3 PUFA concentrations, lengthen gestation duration, and observe the physiological benefit of these nutrients. For example, 2.4 g/d fish oil supplementation to mothers reduced the risk of persistent wheeze/asthma and infection in children after a 3-y follow-up [98]. In addition, 2.7 g/d fish oil supplementation reduced the risk of asthma in a 16-y follow-up study [99]. The benefits of n-3 PUFA supplementation extend to early childhood. Fish consumption during the first year of life is associated with reduced risk for allergic disease [100], and regular fish consumption ≤4.5 y old reduces asthma and wheezing in children [101]. Researchers hypothesize that the benefits of prenatal n-3 PUFA supplementation result from DHA’s ability to upregulate peroxisome proliferation-activated receptors that are crucial for lung development [102,103]. However, additional research is needed to elucidate this mechanism fully. Furthermore, others have reported no beneficial effect of supplemental n-3 PUFAs during pregnancy on lung function; although, this study did use a relatively low dose of DHA (0.4 g/d) [32]. Overall, n-3 PUFA supplementation is critical for allowing complete lung development in utero and for preventing later-life pulmonary disease.

Impact of n-3 PUFAs on obesity

Dietary n-3 PUFAs are intrinsically connected with obesity, which is a known comorbidity that impacts the incidence and severity of both obstructive and restrictive pulmonary diseases. Obesity is associated with an elevated n-6 to n-3 PUFA ratio [104,105], presumably because of increased n-6 PUFA consumption in the diet when compared with n-3 PUFA [106,107]. A higher n-6 to n-3 PUFA ratio results in increased proinflammatory eicosanoids from n-6 PUFAs and decreased anti-inflammatory/proresolving oxylipins from n-3 PUFAs [108]. This change in the lipidomic profile can lead to increased inflammation and disease [109,110]. Obesity is most well studied in pulmonary disease in the context of asthma, where obesity is associated with an increased risk of asthma in children and adults [111,112]. Furthermore, patients with obesity-related asthma are more likely to have severe disease with poor control [113]. N-3 PUFAs can combat some of these obesity-related pathologies in asthma, but this needs more investigation. Incorporating n-3 PUFAs in high-fat diets reduces body fat accumulation in rodent studies, which may be driven by specific oxylipins and changes in the microbiota [[114], [115], [116]]. In addition, including n-3 PUFAs in a high-fat diet reduces inflammatory gene expression and macrophage infiltration into adipose tissue in diabetic mice [117]. However, it is currently debatable whether n-3 PUFAs can reverse obesity or obesity-related asthma [[118], [119], [120]].

Influence of n-3 PUFAs on inflammaging and age-associated lung diseases

N-3 PUFAs also significantly impact the later end of the lifespan. The elderly are a growing population. According to the United States Census Bureau, the number of citizens >65 is projected to increase from 58 million in 2022 to 82 million in 2050 [121]. The elderly are susceptible to lung diseases and are already experiencing a low level of systemic inflammation termed “inflammaging” [122]. Inflammaging is often associated with increased systemic proinflammatory cytokines IL-1, IL-6, and TNF-ɑ, and acute phase protein CRP [123]. The impact of aging extends to the lungs as the elderly have impaired lung function in otherwise healthy individuals, have reduced gas exchange, and are predisposed to infection [123]. For example, FEV1 peaks when one reaches their mid-20s, but then declines ∼20% by around 65 y old [124]. Furthermore, COPD and IPF are mostly diagnosed in people >65 y of age [125]. These lung-specific pathologies are associated with an altered pulmonary lipidome, where there are more proinflammatory oxylipins (that is, prostaglandins or leukotrienes) and subsequently fewer proresolving oxylipins [126]. In addition, aged cells have lower concentrations of n-3 PUFAs and downstream metabolites and more readily take up n-3 PUFAs [127,128]. The depletion of n-3 PUFAs and efficient incorporation associated with aging indicate that n-3 PUFAs may be a viable target for reducing age-related lung pathologies.

Currently, there is limited research directly studying the effect of n-3 PUFAs in age-related lung disease pathologies [84]. Several studies in elderly patients with COPD indicate that fish oil supplementation improves clinical markers of COPD such as lung function and serum proinflammatory cytokines [64,84,129]. At the same time, retrospective diet evaluations or interventional cultural diets such as Japanese or Mediterranean are reported to reduce COPD symptoms [[130], [131], [132], [133]]. Furthermore, experimental rodent models of pulmonary fibrosis indicate that n-3 PUFAs reduce inflammation, transforming growth factor-β production, and collagen deposition [76,86]. These findings indicate that n-3 PUFAs have the potential to reduce inflammaging and improve lung function as patients age. Although there is still significant research required to identify the benefits of n-3 PUFAs in inflammaging, these preliminary findings suggest dietary intake of n-3 PUFAs can reduce age-driven lung pathologies.

Potential Mechanisms of n-3 PUFA Protection from Lung Disease

Genetic mutations of n-3 PUFA synthesizing enzymes

Along with aging and developmental changes impacting pulmonary diseases, there is a developing understanding that genetic differences in populations, including single-nucleotide polymorphisms (SNPs), play a role in lipid metabolism and the association with chronic lung diseases.

There is growing research on the role of SNPs associated with lipid metabolism in obstructive pulmonary diseases. For example, patients who had FADS1-associated SNP rs174537 are associated with developing asthma [134]. SNP rs174537 major allele guanine (G) is associated with a more efficient metabolism of n-6 PUFAs, and homogeneous carriers of GG have more proinflammatory eicosanoids [135]. In a study of children with asthma, FADS polymorphism (rs1535) and a high n-3 PUFA diet were associated with a lower incidence of asthma [136,137]. Although the genetic predispositions of restrictive lung diseases and lipid metabolism are beginning to be studied, to date there have yet to be studies evaluating n-3 PUFA diet/supplementation and genetic interaction.

Influence of n-3 PUFAs on the microbiome

Although genetic mutations in n-3 PUFA synthesis may contribute to lung disease, recent studies have highlighted the role of n-3 PUFAs and the gut microbiome. The gut microbiome is disrupted in patients with pulmonary diseases such as COPD and asthma, suggesting a gut-lung axis where disease impacts the microbiome or vice versa [138,139]. Additionally, Jang et al. [140] identified that fecal microbiota transplant from healthy mice to mice with emphysema resulted in improved body weight, reduced lung inflammation, and reduced alveolar damage, indicating that a healthy gut microbiome can help protect against mechanisms known to drive chronic lung diseases. Taken together, these studies indicate that manipulation of the gut microbiome can influence pathologies associated with chronic lung diseases.

There is developing evidence that n-3 PUFAs can significantly impact gut microbiota and potentially mitigate lung pathologies. A transgenic model using the FAT-1 gene that converts n-6 to n-3 PUFAs revealed that increasing n-3 PUFAs increases beneficial gut bacterial species such as bifidobacterium [141]. Furthermore, tuna oil supplementation (rich in n-3 PUFAs) in a mouse model of emphysema led to increased lactobacillus and short-chain fatty acids that correlated with reduced pulmonary inflammation [142]. In other models of lung inflammation, such as PM_2.5 and/or allergic asthma, n-3 PUFAs also recovered dysbiosis and alleviated pulmonary inflammation and injury [143]. Lactobacillus johnsonii supplementation also caused increased serum DHA concentrations and attenuated inflammation and infection during respiratory syncytial virus (RSV) infection, indicating gut microbiome can directly impact circulating n-3 PUFAs [144]. These studies are beginning to establish a connection between gut microbiome, n-3 PUFAs, and lung inflammation, which may be a potential mechanism by which n-3 PUFAs can alter lung pathologies associated with chronic lung disease.

N-3 PUFAs alter the cell membrane

Another mechanism by which n-3 PUFAs exert their beneficial effects is by altering cell membrane microviscosity. Long-chain n-3 PUFA acyl chains are extremely flexible and disordered structures due to the number of double bonds compared with MUFA or SFA [145]. Furthermore, n-3 PUFAs tend to have more double bonds than n-6 PUFAs because the first double bond is at the third carbon in the carbon chain rather than the sixth, leaving room for more double bonds down the carbon chain. Consequently, AA allows less flexibility with its 4 double bonds compared with EPA’s 5 and DHA’s 6 [146]. These changes in flexibility alter membrane properties by differing PUFAs, thereby changing surface receptor conformation and dimerization, cell signal trafficking, vesicle budding, and fusion [[147], [148], [149]].

DHA and EPA incorporate into plasma membrane phospholipids to control the size and distribution of lipid rafts, which are large, ordered assemblies of proteins and lipids that compartmentalize cellular signaling [[150], [151], [152]]. Changes in lipid rafts with n-3 PUFAs can lead to the lateral displacement of proteins, increased surface presentation of major histocompatibility complex I (MHC-I) and its lateral distribution, decreased MHC-II surface presentation and its lateral organization, and inhibited TLR4 dimerization and activation in lipid rafts [[153], [154], [155], [156]]. Furthermore, increased n-3 PUFA in the plasma membrane leads to larger and more ordered rafts on the T-cell side of the immunological synapse between CD4 T-cells and antigen-presenting cells [157,158]. This has been observed to suppress T-cell activation and proliferation [159]. Therefore, this combined effect of altering membrane microviscosity with lipid raft ordering and surface receptor presentation may be 1 of the major mechanisms of n-3 PUFAs' anti-inflammatory and proresolving features. A future area of study is how esterified oxylipins derived from n-3 PUFAs control lipid rafts [160].

Metabolites of n-3 PUFAs reduce lung disease pathologies

Another key driver of the anti-inflammatory and proresolving features of n-3 PUFAs is their metabolism into SPMs. During the inflammatory response, mitogen-activated protein kinase (MAPK) phosphorylates phospholipase A2, which then catalyzes the hydrolysis of membrane phospholipids at the sn2 position, liberating PUFAs into the cytosol. In the cytosol, cyclooxygenases or lipoxygenases oxidize the liberated PUFAs at precise carbons along the fatty acid chain to form oxylipins. N-6 and n-3 PUFAs share these enzymes during their metabolism; therefore, the ratio of n-6 to n-3 PUFAs in the membrane significantly impacts the production of their metabolites. Furthermore, increased n-3 PUFAs in the membrane are accompanied by reduced n-6 PUFAs in the membrane, revealing the significant impact the ratio of these PUFAs can have on their metabolites [161,162].

Replacing n-6 PUFAs with n-3 PUFAs prevents the synthesis of proinflammatory eicosanoids. Examples of key eicosanoids produced from AA are prostaglandin E2 (PGE2), leukotriene B4 (LTB4), or thromboxane A2 (TXA2). PGE2 has several roles in inflammation, apoptosis, angiogenesis, cell proliferation, and immune surveillance [163]. PGE2 acts as a vasodilator to facilitate immune cell infiltration and even stimulates sensory nerves to increase pain [164]. Conversely, PGE2 also plays a role in wound healing and can disrupt NF-κB signaling [165,166]. It is proposed these differences in PGE2 action can be attributed to time-dependent effects during the inflammation and then resolution of inflammation time course [166]; however, this needs further investigation. Leukotrienes and thromboxanes more consistently activate inflammation. LTB4 is a potent neutrophil chemoattractant through receptor BLT1, which activates either/both of the NF-κB and MAPK pathways and upregulates IL-8 (CXCL1/CXCL2 in mice) [167]. LTC4, LTD4, and LTE4 are an additional class of leukotrienes termed cysteinyl leukotrienes (CysLTs) that are associated with blood vessel dilation, mucus production, and immune cell recruitment in asthma and allergic rhinitis [168]. TXA2 and TXB2 are primarily involved in the asthmatic response, where inhibition of their synthesis or knockout of their receptor reduces eosinophil recruitment to the lung and reduces airway hyperresponsiveness [169]. The proinflammatory effects of these eicosanoids can be prevented by increasing n-3 PUFAs in the cell membrane [170].

By increasing n-3 PUFA consumption, presumably more proresolving SPMs can be produced. EPA is metabolized into bioactive intermediate molecules such as 18-hydroperoxyeicosopentaneoic acid, and SPMs resolvin E1 (RvE1), RvE2, RvE3, RvE4, and aspirin-triggered RvE1 (AT-RvE1) and AT-RvE2 [171]. DHA is metabolized into bioactive intermediates 14-hydroperoxy-docosahexaenoic acid (14-HDHA) and 17-HDHA, and SPMs RvD1-RvD6, AT-RVD1–4, maresin 1 (MaR1), MaR2, protectin D1 (PD1), and maresin conjugates in tissue regeneration1 (MCTR1)-MCTR3 [171]. Paradoxically, AA can also be metabolized into the SPM lipoxin A4 through a pathway that branches off from leukotriene metabolism, which also exerts anti-inflammatory and proresolving properties [172]. SPMs were only identified within the last few decades, and the list is continuously growing as more species are identified. SPMs inhibit proinflammatory cytokine production by blocking NF-κB and upregulating anti-inflammatory/proresolving mechanisms such as macrophage phagocytosis of apoptotic immune cells (efferocytosis), and wound healing [173]. MCTRs can also compete with CysLTs to bind their receptor, CysLT1 [174]. There has been substantial research supporting that these SPMs protect the lungs from disease [173]. For example, in asthma, RvE1 reduces eosinophil recruitment and RvD1 accelerates resolution of inflammation [175,176]. MaR1 promotes the antiviral interferon-β response to the respiratory syncytial virus while protecting T-regulatory cell function to maintain control of cytotoxic T-cells [177]. RvD1 inhibits cytokine release from human alveolar macrophages isolated from patients with COPD [178]. Although the mechanisms of these SPMs are still being elucidated, it is clear that increasing systemic and pulmonary SPMs is beneficial to lung health, and they are a key driver to the benefits of n-3 PUFAs. It is important to acknowledge that there are challenges to the SPM model, which relate to detection and the biologically relevant concentration of these metabolites in circulation [179].

Conclusions and Future Directions

As summarized in Figure 1, we have highlighted how n-3 PUFAs can support healthy lung development and mitigate risk of lung injury from pulmonary diseases. N-3 PUFAs can reduce symptoms of lung diseases and have the potential to protect susceptible populations such as pre/postnatal children, those with obesity, or the elderly from developing lung diseases. Furthermore, genetic mutations in endogenous n-3 PUFA synthesis can have serious health consequences. N-3 PUFAs exert their beneficial effects by controlling the size and distribution of plasma membrane lipid rafts and thereby lowering inflammatory signaling, and by being metabolized into potent anti-inflammatory and proresolving molecules. In addition, there is some evidence that n-3 PUFAs influence the microbiome that can impact pulmonary inflammation and disease.

FIGURE 1.

n-3 PUFAs impact chronic lung diseases through several mechanisms. DHA/EPA alter the cell membrane or are metabolized into bioactive metabolites to influence inflammation and resolution of inflammation. DHA/EPA can also directly reduce inflammation and increase resolution of inflammation. Single-nucleotide polymorphisms or the microbiome can impact levels of DHA/EPA in the body. Populations such as children, those with obesity, or the elderly are vulnerable to lung disease. In children, low levels of DHA/EPA could lead to asthma development. Those with obesity and the elderly tend to have higher n6:n3 ratios, lower levels of DHA/EPA, and increased inflammation. These populations also have higher chances of developing asthma or COPD. COPD, chronic obstructive pulmonary disease.

Although there is evidence that n-3 PUFAs can protect the lungs, there is still substantial work required before they can be used therapeutically. To the best of our knowledge, n-3 PUFA supplementation has not been studied in the context of human ILD. Furthermore, very little work describes the direct impact of n-3 PUFAs on the microbiome or on inflammaging and age-associated lung diseases. In addition, heterogeneity in study design has made it difficult to interpret if n-3 PUFAs are effective in clinical studies. To better understand clinical efficacy, research is required on dietary supplement quality, dose, duration of supplementation, patient demographics, and lung diseases being treated. It could be that n-3 PUFA supplements, either over-the-counter or pharmacological, are only clinically effective against certain lung disease pathologies, or in people who are particularly deficient in n-3 PUFAs. Therefore, understanding the nuances of n-3 PUFAs’ effectiveness against lung disease will benefit clinicians as medicine continues to shift toward individualized care.

Author contributions

The authors’ responsibilities were as follows – MJY, LL, SRS, KMG: came up with the concept for review article; SRS, KMG: drafted and edited the manuscript; MJY, LL: wrote the paper; MJY, LL, SRS, KMG: had primary responsibility for final content; and all authors: read and approved this manuscript.

Conflict of interest

SRS has received funding from Metagenics and Organic Technologies for research and conference support as it relates to n-3 and n-6 fatty acids. SRS is a Journal of Nutrition Editorial Board Member. SRS is an Editor on the Journal of Nutrition and played no role in the Journal’s evaluation of the manuscript. The other authors report no conflicts of interest.

Funding

The authors were supported financially by the following: F31ES036102–02 (to MJY); P30DK056350 (to SRS); R01ES031378 (to KMG and SRS). This work was not sponsored and there are no restrictions regarding the submission of the report for publication.