Effects of photobiomodulation as an adjunctive treatment in chronic obstructive pulmonary disease: a narrative review

Abstract

Chronic obstructive pulmonary disease (COPD) is a disease characterized by chronic airway inflammation and remodeling and lung parenchymal inflammation and destruction, which result in many pulmonary and extrapulmonary manifestations. The anti-inflammatory effect of photobiomodulation (PBM) has been reported in previous studies. This review was conducted to evaluate the direct effect of PBM on lung inflammation in COPD. The other effects of PBM on modulation of peripheral and respiratory muscle metabolism and angiogenesis in lung tissues were also discussed. The databases of PubMed, Cochrane Library, and Google Scholar were searched to find the relevant studies. Keywords included PBM and related terms, COPD-related signs, and lung inflammation. A total of 12 articles were selected and reviewed in this study. Based on the present review, PBM is helpful in reducing lung inflammation through decreasing the inflammatory cytokines and chemokines at multiple levels and increasing anti-inflammatory cytokines. In addition, PBM also improves both peripheral and respiratory muscle metabolism and promote angiogenesis. This review demonstrated that PBM is a promising adjunctive treatment modality for COPD management which merits further validation.

Introduction

Chronic obstructive pulmonary disease (COPD) is a global health problem and the third leading cause of death worldwide [1]. The primary cause of COPD is exposure to tobacco smoke, with other risk factors comprising exposure to indoor and outdoor air pollution and occupational dusts and fumes [2]. All these exposures stimulate a persistent innate immune response, which then triggers an adaptive immune response in the lungs. Lung inflammation is characterized by increased numbers of neutrophils, T lymphocytes, and alveolar macrophages recruited from the circulation. These immune inflammatory changes contribute to impaired tissue repair and a remodeling process that overproduces mucus in the airways and cause emphysematous destruction in the small bronchioles and lung parenchyma, resulting in persistent and progressive airflow limitation. Furthermore, this chronic inflammatory response in the lung is associated with systemic inflammatory response that contributes to morbidity and mortality of the disease [3]. Therefore, inhibition of the inflammatory process could represent an important therapeutic strategy for COPD. One such potential treatment approach is photobiomodulation (PBM), which is a non-pharmacological modality.

PBM by low-level laser therapy (LLLT) and light-emitting diodes (LED) is a non-thermal therapy characterized by coherent and incoherent beams, respectively [4]. Both LLLT and LED therapy exert similar effects through absorption of photons by chromophores in tissue-specific wavelengths. The noninvasive LLLT and LED therapy irradiate the tissues to activate cellular photoreceptors. Laser is absorbed by internal photoreceptors such as cytochrome c oxidase, porphyrins, and light-sensitive ion channels, whereas photons are absorbed by light-sensitive ion channels, increasing the concentration of intracellular calcium (Ca²⁺) ions. Cytochrome c oxidase belongs to complex IV of the mitochondrial respiratory chain, absorbing the red and near-infrared wavelengths. This leads to increases in electron transport, mitochondrial membrane potential, and adenosine triphosphate (ATP) production. These processes activate several signaling pathways through cyclic adenosine monophosphate, nitric oxide (NO), Ca²⁺, and reactive oxygen species, which is followed by the activation of transcription factors such as hypoxia-inducible factor 1-alpha (HIF-1α), nuclear factor erythroid 2-related factor 2 (NRF2), and nuclear factor-κB (NF-κB), resulting in a massive genetic response directed toward inflammation, proliferation, and repair [5]. On the basis of these mechanisms, PBM has been confirmed to be an effective treatment in playing a vital role in tissue repair and regeneration, pain relief [6, 7], wound healing [8], reduction of oxidants, and anti-inflammation [9, 10].

Considering the anti-inflammatory effects of PBM, it may be a reasonable approach to be applied in improving inflammation of pulmonary diseases. In this context, there has been an extensive research demonstrating the efficacy and safety of PBM in different pulmonary diseases such as COPD, asthma, and pulmonary fibrosis [11–15]. Nevertheless, due to the lack of large-scale clinical trials as evidence, PBM is not a treatment option in routine practice according to the latest COPD guidelines. Hence, in the present investigation, we explored the currently available evidence and conducted a narrative review, focusing on the anti-inflammatory effect of PBM in in vivo, in vitro, and clinical studies, in addition to exploring other biostimulatory effects such as improving muscle metabolism and promoting angiogenesis, to recommend PBM as an effective and promising tool in the management of COPD.

Moreover, because musculoskeletal dysfunction is a major extra pulmonary manifestation in COPD, we focused on discussing the potential effects of PBM in peripheral and respiratory muscles in COPD. Therefore, the purpose of this investigation was to conduct a narrative review and emphasize PBM as a novel non-pharmacological modality for populations with COPD that deserve further attention. Although PBM might not replace current pharmacotherapy or pulmonary rehabilitation, it could serve as an adjunctive therapy in the comprehensive management of COPD.

Methods

We conducted a literature search in PubMed, Cochrane Library, and Google Scholar databases in June 2021. To avoid missing any relevant papers, we did not set any time or language limitations, and the search terms were “photobiomodulation,” “low-level laser therapy,” “light-emitting diodes,” “chronic obstructive pulmonary disease,” and “lung inflammation.” Both animal and human studies were included in the research.

Studies focusing on other inflammatory diseases such as asthma, pneumonia, and coronavirus disease 2019 (COVID-19) were excluded because the pathophysiology of these diseases differ from that of COPD. The titles and abstracts of all articles found through the electronic search were reviewed, and the articles were independently evaluated by two authors (YSL and YJC), with the final selection being based on the full text of the publication. Any disagreements were resolved by mutual consensus or by a third author when needed. A manual review of references from eligible publications was also individually conducted by the authors. To ensure quality assessment of this review, the design and reporting were conceived and conducted in agreement with Scale for the Assessment of Narrative Review Articles (SANRA) guidelines for the narrative review of articles [16].

Results

A total of 21 articles met the inclusion criteria, among which three studies focusing on asthma and six studies focusing on COVID-19 were excluded. Finally, the remaining 12 articles, including eight studies associated with lung inflammation and four studies associated with muscle effects, were selected and reviewed. Figure 1 shows the process of study selection. Of the eight studies associated with lung inflammation, seven were experimental animal studies, and one study focused on human subjects. All the experimental animal studies reported that PBM could reduce lung inflammation, neutrophil recruitment, and proinflammatory cytokine production in inflammatory lung diseases such as COPD. The dosimetric parameters for PBM were variable as follows: wavelength in the range of 660–830 nm and energy density in the range of 3–10 J/cm². The other randomized controlled trial conducted by Mehani et al. demonstrated that LLLT could modulate the immune system in patients with COPD [12], as shown in Table 1.

Fig. 1.

The process of study selection

Table 1.

Profiles of studies associated with lung inflammation

First author and year	Lung inflammation model	Light source/parameters	Target tissue/organ	Results
Animal study
Moraes et al. (2018) [14]	Mice exposed to cigarette smoke	Diode laser 660 nm, 30 mW Spot size: 0.785 cm2 Irradiation time: 30 s Energy density: 3 J/cm2	Trachea and both lung lobes	1.↓leukocytes in bronchoalveolar lavage fluid (BALF) and in lung tissue 2.↓IL-6, IL-1β, IL-17, TNF-α, CINC-1/KC in BALF; ↑IL-10 in BALF 3.↓collagen deposition and alveolar enlargement in lungs 4.↓expression of purinergic P2X7 receptor 5.↑lung mechanics
Miranda da Silva et al. (2015) [13]	Rat exposed to 1% formaldehyde inhalation	Diode laser 660 nm, 30 mW Spot size: 0.14 cm2 Irradiation time: 60 s Energy density: 12.86 J/cm2	Trachea and both lungs, each 3 points	1.↓number of total cells, monocytes, and lymphocytes in blood 2.↓neutrophil influx 3.↓lung microvascular permeability 4.↓IL-6, TNF in BALF; ↑IL-10 in BALF 5.↑expression of IL-10 in lung tissue 6.↓leukocyte infiltration and mast cell degranulation
de Lima et al. (2014) [31]	Rat ARDS induction by intestinal ischemia and reperfusion	Diode laser 660 nm, 30 mW Spot size: 0.08 cm2 Irradiation time: 2.6, 8, 13.3, and 20 s Energy density: 1, 3, 5, and 7.5 J/cm2	Upper bronchus	1.↓myeloperoxidase activity in lung by 3/5/7.5 J/cm2 2.↓protein level and gene expression of IL-6 and TNF in lung by all doses 3.↑level of IL-10 only by 1 J/cm2 4.↓gene expression of IL-1β by all doses 5.↓protein level of IL-1β by 3/5/7.5 J/cm2
Cury et al. (2016) [32]	Rat intratracheal lipopolysaccharide (LPS) induction	GaAlAs diode laser 660 nm, 30 mW Spot area: 0.028 cm2 Irradiation time: 9 s Energy density: 10 J/cm2	Bilateral midaxillary line	1.↓number of neutrophils and macrophages in alveoli and lung interstitium 2.↓mRNA expression of TNF-α, IL-1β, IL-6, and MCP-1 3.no difference in lung mechanics
Oliveira et al. (2014) [28]	Rat ARDS induction by LPS	Infrared laser 830 nm, 35 mW Spot area: 0.93 cm2 Irradiation time: 80 s Energy density: 3 J/cm2	3 points, at end part of trachea and both lungs	1.↓total cell count and neutrophils in BALF 2.↓number of polymorphonuclear cells in lung parenchyma 3.↓IL-6, IL-1β, KC, TNF-α in BALF 4.↓IL-6, TNF-α in serum
Sergio et al. (2018) [33]	Rat acute lung injury induction by LPS	GaAlAs diode laser 808 nm, 100 mW Spot size: 0.028 cm2 Irradiation time: 2 and 5 s Energy density: 10 and 20 J/cm2	4 points per lung	1.↑Bcl-2 mRNA level by both doses 2.↓caspase 3 mRNA level by both doses 3.↓DNA fragmentation rate in alveolar cells by both doses 4.↑DNA fragmentation rate in inflammatory cells by both doses
De Brito et al. (2020) [15]	Rat pulmonary fibrosis induction by bleomycin	Diode laser 780 nm, 30 mW Irradiation time: 60 s Irradiated area: - In vivo: 0.6 cm2 - In vitro: 1.91 cm2 Energy density: - In vivo: 3 J/cm2 - In vitro: 0.945 J/cm2	In vivo: main bronchus In vitro: type II pneumocytes and fibroblasts	1.↓total cell count, macrophages, neutrophils, and lymphocytes in lung and serum 2.↓TNF, IL-1β, IL-6, CXCL1/KC, IFN-γ, and TGF-β in BALF and fibroblasts 3.↑IL-10 in BALF and fibroblasts 4.↓TNF, IL-1β, and IL-6 in type II pneumocytes 5.↓collagen deposition in lung
Human study
Mehani et al. (2017) [12]	40 male patients with mild to moderate COPD	GaAlAs, He–Ne laser 904 nm, 5 W Pulse length: 200 ns Irradiation time: 90 s Energy density: –	Large intestine 11, kidney meridian 27, large intestine 4, lung meridian 1, and lung meridian 7	1.↓plasma IL-6 2.↑plasma CD4+/CD8+ ratio

–: Data not available from the study

We also added four articles focusing on the muscle effect of PBM, among which three studies investigated the peripheral muscle effect, and one study focused on the respiratory muscle effect. Miranda et al. first investigated the effects of PBM on the function of quadriceps muscle in patients with COPD and showed that a single application of PBM could alleviate muscle fatigue and increase isometric endurance time [17]. Subsequently, the same research group also confirmed that the application of PBM alone or in combination with a magnetic field could increase exercise capacity and reduce lower extremity fatigue in patients with COPD [18, 19]. Regarding the effects of applying PBM to respiratory muscles in patients with COPD, de Souza et al. were the first group to validate that PBM application to respiratory muscles was effective in increasing functional capacity in patients with COPD [20]. Table 2 summarizes the parameters, outcome measures, and effects of PBM application on peripheral and respiratory muscles reported in these four studies. We describe the details of these included articles and the possible mechanisms of action of PBM on COPD in the “Discussion” section.

Table 2.

Profiles of human studies associated with peripheral and respiratory muscle effects

First author and year	Participants	Light source/parameters	Target tissue/organ	Results
Peripheral muscle effect
Miranda et al. (2014) [17]	10 patients with COPD	69 LED clusters (34 red LEDs and 35 infrared LEDs) Red: 660 nm, 10 mW Infrared: 850 nm, 30 mW Spot size: 0.2 cm2 Irradiation time: 30 s Energy density: 1.5 J/cm2 each red LED; 4.5 J/cm2 each infrared LED	Muscle belly of rectus femoris, vastus medialis, and vastus lateralis; each muscle 3 points	1.↑isometric endurance time 2.↓median frequency (MF) during isometric endurance test 3.↓MF slope over time 4.↓dyspnea score
Miranda et al. (2015) [18]	13 patients with COPD	12 diode clusters of super-pulsed lasers and LEDs (4 super-pulsed lasers, 4 red LEDs, 4 infrared LEDs) Super-pulsed: 905 nm, 0.3125 mW Red LEDs: 640 nm, 15 mW Infrared LEDs: 875 nm, 17.5 mW Irradiation time: 228 s Energy density: - Super-pulsed laser: 0.162 J/cm2 - Red LEDs: 3.8 J/cm2 - Infrared LEDs: 4.43 J/cm2	Muscle belly of rectus femoris, vastus medialis, and vastus lateralis; each muscle 2 points	1.↑maximum voluntary isometric contraction, peak torque, total work 2.↓dyspnea and leg fatigue
Miranda et al. (2019) [19]	21 patients with COPD	12 diode clusters of super-pulsed lasers and LEDs (4 super-pulsed lasers, 4 red LEDs, 4 infrared LEDs), combined magnetic field Super-pulsed laser: 905 nm, 0.3125 mW Red LEDs: 640 nm, 15 mW Infrared LEDs: 875 nm, 17.5 mW Magnetic field: 35 mT Irradiation time per site: 228 s Energy density: - Super-pulsed laser: 0.162 J/cm2 - Red LEDs: 3.8 J/cm2 - Infrared LEDs: 4.43 J/cm2	1.Muscle belly of rectus femoris, vastus medialis, and vastus lateralis; each muscle 3 points 2. Muscle belly of biceps femoris and semimembranosus; each muscle 2 points 3. Muscle belly of medial and lateral gastrocnemius, each muscle 1 point	1.↑number of steps during 6-min stepper test 2.↓dyspnea and lower limb fatigue
Respiratory muscle effect
de Souza et al. (2020) [20]	12 patients with COPD	69 LED clusters Red: 630 nm, 10 mW Infrared: 830 nm, 10 mW Irradiation time: 45 s Energy density: 2.25 J/cm2	Upper trapezius, sternocleidomastoid, pectoralis major, rectus abdominis, intercostal muscles	1.↑walk distance during 6-min walk test

Discussion

COPD is a disease characterized by chronic airway inflammation and remodeling, as well as lung parenchymal inflammation and destruction, which result in expiratory airflow obstruction, hyperinflation of the lung with loss of elastic recoil, and eventually, disturbance of gas exchange. The pathogenesis of COPD appears to be influenced by tissue damage associated with airway remodeling and thickening and inflammation and fibrosis of the small airways. The inflammatory response in the lung parenchyma, oxidative stress, apoptosis, and proteolysis ultimately result in the emphysematous destruction of alveolar walls [3].

Various mediators are involved in lung inflammation in COPD. Inhaled irritants such as cigarette smoke trigger the initial immune response, causing the aggregation of neutrophils and the activation and migration of macrophages and T lymphocytes from the circulation to the lung parenchymal space. The infiltration of inflammatory cells in the lung parenchyma results in the activation of matrix metalloproteinases (MMPs), degradation of the extracellular matrix, and tissue damage. This is followed by the intense release of proinflammatory cytokines, such as interleukin (IL)-1, IL-6, and IL-12 [3]; tumor necrosis factor alpha (TNF-α); and transforming growth factor beta (TGF-β), along with chemokines such as C–C motif chemokine ligand 2 (CCL2) and C-X-C motif chemokine ligand 1 (CXCL1), as well as lipid mediators such as prostacyclin and leukotriene B4 [21], all of which enhance inflammation. Furthermore, chronic exposure to irritants causes the intense infiltration of T helper type 1 and cytotoxic T-cell type 1 lymphocytes in the small airways and lung parenchyma, producing interferon gamma (IFN-γ). Due to the proinflammatory role and in association with other cytokines and chemokines, IFN-γ induces the activation of immune cells and lung parenchymal cells and ultimately results in fibrosis and lung parenchymal destruction [22].

Systemicinflammation in COPD

The chronic inflammatory response in the lung is also associated with systemic inflammation, which might lead to adverse effects on clinical health [2, 3]. This systemic response is characterized by the activation of the acute-phase response, release of inflammatory mediators into the circulation, stimulation of the bone marrow to release leukocytes and platelets, and the priming and activation of circulating leukocytes and vascular endothelium. Several organ systems are affected by this systemic inflammatory response. It amplifies the inflammatory response in the lung, decreases skeletal muscle and bone mass, activates blood vessels, and decreases peripheral tissue insulin sensitivity, resulting in several extrapulmonary manifestations such as cardiovascular diseases [23], skeletal muscle dysfunction [24, 25], and osteoporosis [26, 27]. These extrapulmonary manifestations and systemic alterations associated with COPD directly influence the course and prognosis of the disease itself.

Anti-inflammatory effects of PBM

PBM can induce antioxidant and anti-inflammatory effects, playing an immunomodulatory role [28]. There is extensive research investigating the signal transduction pathway of PBM, confirming that a reduction of Ca²⁺ sensitivity is accountable for its anti-inflammatory effects [29]. A systematic review of LLLT in cell and animal studies has suggested strong evidence that the magnitude of the anti-inflammatory effect of LLLT was comparable to that of non-steroidal anti-inflammatory drugs (NSAIDs) [10]. Compared with other immunosuppressive medications, including corticosteroids, PBM primarily exerts local effects with scarcely no systemic effect. The potential application of PBM as an adjunctive treatment modality for patients with COPD is discussed in the next section.

Effects of PBM on lung inflammation

Several trials have demonstrated that PBM exerts beneficial on lung inflammatory diseases. A study by Moraes et al. showed that application of LLLT (660 nm, 30 mW, 3 J/cm²) in an experimental COPD animal model could reduce lung emphysema, airway remodeling, and chronic bronchitis. The study also revealed that such effects were followed by an increased production of an anti-inflammatory cytokine (IL-10) and attenuation in the production of proinflammatory cytokines (IL-1β, TNF-α, IL-6, and IL-17) and chemokine (CXCL1/KC), along with decreases in peribronchial density, collagen production, alveolar enlargement, P2X7 purinergic receptor expression, and cell death. The result of that study demonstrated that LLLT was effective in reducing the migration of macrophages, neutrophils, and lymphocytes into the lungs, as well as inhibiting the secretion of proinflammatory cytokines, which is directly associated with the severity and mortality of COPD [14].

Miranda da Silva et al. reported a model of lung inflammation induced by formaldehyde (FA) exposure, demonstrating that LLLT (660 nm, 30 mW, 12.86 J/cm²) reduced the number of leukocytes, mast cell degranulation, myeloperoxidase (MPO) activity, and microvascular lung permeability. The distribution of cytokines in the lung was also altered after LLLT, with reduced levels of IL-6 and TNF-α and elevated levels of IL-10 [13]. Formaldehyde is a type of environmental pollutant that is related to tobacco smoke, building materials, burning processes, and occupational settings, and it can induce neutrophilic lung inflammation by mast cell degranulation [30]. Formaldehyde activates mast cells through neuropeptides, with the mast cells playing a role as immunological sentinels, and once activated, they release a wide spectrum of inflammatory mediators. The results reported by Miranda da Silva et al. showed that LLLT could significantly reduce mast cell degranulation and inflammatory cytokine production [13], thereby providing important information on the mechanisms of action of LLLT in lung inflammation induced by a pollutant.

An animal study conducted by de Lima et al. supported that PBM could reduce lung edema, neutrophil influx, and MPO activity by reducing oxidative stress and the production of inflammatory cytokines such as IL-1β, IL-6, and TNF-α but increasing the production of IL-10. In that study, mice were subjected to acute lung injury induced by gut ischemia and reperfusion, and the upper bronchus was irradiated with 660 nm PBM for 30 min after the beginning of reperfusion, providing various fluences (1, 3, 5, and 7 J/cm²). The result indicated that PBM could attenuate ischemic reperfusion-induced acute lung inflammation by modulating the release of proinflammatory and anti-inflammatory cytokines. Furthermore, that study was the first to confirm that various laser fluences may be effective in reducing acute lung injury [31].

Cury et al. also demonstrated that a single dose of LLLT (660 nm, 30 mW, 10 J/cm²) could reduce lipopolysaccharide (LPS)-induced lung inflammation [32]. Their study showed that PBM reduced the production of both proinflammatory cytokines (TNF-α, IL-1β, and IL-6) and chemokines (MCP-1 or CCL2) without affecting lung mechanics and recovery. Unlike most studies utilizing irradiation directly on the bronchi [13, 14, 31], they applied the laser irradiation to the midaxillary line of both sides to reach the maximum extent of the lung parenchyma. Their study also revealed that the anti-inflammatory effect of PBM could occur even when most of the inflammatory process has been established, because the animals were irradiated at 6 h after exposure to LPS.

This phenomenon provides information for utilizing PBM in COPD, because most patients seek medical care for pulmonary diseases long after the inflammatory process has begun. In another study, Oliveira et al. showed that LLLT of 830 nm (35 mW, 9 J/cm²) could also reduce acute pulmonary inflammation in both pulmonary (orotracheal instillation) and extrapulmonary (intraperitoneal injection) models of LPS-induced acute respiratory distress syndrome (ARDS) in BALB/c mice, as demonstrated by reduced numbers of total cells and neutrophils, as well as reduced levels of IL-1β, IL-6, CXCL1/KC, and TNF-α [28].

In another study using an LPS-induced acute lung injury model, the effect of PBM on the apoptosis profile was investigated in inflammatory cells and pulmonary parenchyma using an 808-nm-wavelength laser. The results demonstrated that compared with the control group, the levels of Bcl-2 mRNA in the irradiated group were increased, whereas those of caspase-3 mRNA were decreased. This indicated that PBM can modify the expressions of apoptosis-related genes, facilitating the healing process by promoting the apoptosis of inflammatory cells and suppressing the apoptotic pathways in the lung tissue [33]. The study by Brito et al. also supported the evidence that PBM can contribute to the healing process. Their study demonstrated that LLLT could attenuate the airway remodeling of bleomycin-stimulated pulmonary fibrosis by reducing the levels of proinflammatory cytokines, inversely increasing the secretion of anti-inflammatory cytokines, and inhibiting the fibroblast secretion of profibrotic cytokines [15].

In addition, PBM can be utilized as an adjunctive therapy to improve the immune system. A randomized controlled clinical study by Mehani et al. was conducted to evaluate the effectiveness of PBM acupuncture stimulation compared with inspiratory muscle training (IMT) in regulating immune disturbances in patients with stable COPD [12]. The GaAlAs, He–Ne laser acupuncture device was used, and each acupuncture point (large intestine 11, kidney meridian 27, large intestine 4, lung meridian 1, and lung meridian 7) was irradiated for 90 s (904 nm, 5 W) twice per day, three times per week, for 2 months. The results demonstrated reduced concentrations of plasma IL-6 and an increased CD4 + /CD8 + ratio in both the laser and IMT groups, with the laser group demonstrating a superior effect over the IMT group.

To summarize, scientific evidence shows that PBM could modulate the inflammatory process, probably by attenuating the production of inflammatory cytokines and chemokines at multiple levels and increasing the production of anti-inflammatory cytokines. Moreover, PBM promotes the apoptosis of inflammatory cells and protects alveolar cells from damage. These results illustrate that PBM can reduce inflammation without impairing the lung function in acute lung injury and is a promising therapeutic approach for pulmonary inflammatory diseases such as COPD. Although there is no available evidence suggesting that PBM can replace the current gold standard pharmacotherapies such as beta 2 agonists, anticholinergics, and inhaled corticosteroids, PBM exerts almost none of the possible adverse effects of the abovementioned drugs, such as dizziness, dry mouth, gastrointestinal discomfort, palpitations, oral candidiasis, hoarseness, and pharyngitis [34]. Consequently, PBM is a promising non-pharmacological complementary modality in the comprehensive management of COPD. The studies reviewed in this section are summarized in Table 1.

Effects of PBM on peripheral and respiratory muscle functions in COPD

COPD is a systemic inflammatory disease with various extrapulmonary manifestations, with musculoskeletal dysfunction being a commonly associated problem limiting the functional capacity, cardiorespiratory fitness, and quality of life of patients with COPD. Irrespective of the degree of airflow limitation, musculoskeletal impairment indicates poor prognosis in this population [24]. Several studies have reported abnormalities in the skeletal muscles of patients with COPD, with the typical ones being reduction in muscle mass, muscle strength, and muscle endurance [35]; deficits in oxidative capacity and increased glycolytic capacity [36]; redistribution of fiber type [37]; and alteration in muscle capillarization [38]. These macrostructural and microstructural changes in the skeletal muscles increase the susceptibility to muscle fatigue, resulting in the early termination of exercise and declined functional performance. Accordingly, interventions to improve the endurance of peripheral and respiratory muscles in patients with COPD have been proposed [39].

In addition to the anti-inflammatory effect of PBM discussed in previous sections, several studies have described the mechanisms of action that explain how PBM improves muscle function [40–42]. For instance, recent studies indicate an increment in ATP synthesis, driving greater cell energy by increasing mitochondrial metabolism; improvement in oxidative and nitrosative stress by upregulating or increasing the activity of antioxidant enzymes [41]; increased muscle glycogen synthesis and proliferation of muscle cells [42]; and increment in oxygen availability in the muscle tissue after laser treatment [43]. These mechanisms may potentially reverse the disturbances found in the respiratory and peripheral muscles of patients with COPD [44]. Nevertheless, to date, only a few studies have reported the use of PBM in improving muscle performance in individuals with COPD.

As pioneers, Miranda et al. first explored the acute effect of PBM on quadriceps femoris muscle function during isometric exercise in patients with COPD in 2014 [17]. In their study, clusters of 69 LEDs (660 and 850 nm) were applied to provide large irradiation areas in the quadriceps femoris muscle. The results demonstrated that LED therapy could delay the development of peripheral muscle fatigue during exercise. They also found that the combination of super-pulsed lasers and LED significantly increased the peak torque, total work, and the maximum isometric contraction of quadriceps muscle and decreased dyspnea and lower limb fatigue in patients with COPD [18]. Recently, Miranda et al. also published a randomized, triple-blinded clinical trial using PBM combined with a magnetic field to stimulate the peripheral muscles in patients with COPD to determine whether there were changes in exercise capacity [19]. PBM combined with the magnetic field or placebo administration was performed before each 6-min stepper test (6 MST) (17 sites on each lower limb, with a dose of 30 J per site, using a cluster of 12 diodes as follows: 4 × 905-nm super-pulsed laser diodes, 4 × 875-nm infrared LEDs, and 4 × 640-nm red LEDs, with a magnetic field of 35 mT). The result revealed that the combined application of PBM and magnetic field to the peripheral muscle could increase the number of steps during the 6 MST and decrease the sensation of dyspnea and lower limb fatigue in patients with COPD.

All the abovementioned studies focused on the peripheral muscles of patients with COPD, with two of them evaluating quadriceps femoris endurance as parameters of muscle function, and both of them demonstrated the preventive effects of PBM on muscle fatigue, thereby increasing the endurance time in patients with COPD. Another study utilized 6 MST, which indicated functional capacity to evaluate the muscular effect where the increase in the number of steps after one session of PBM and magnetic field also reached statistical significance [19]. Although these studies did not evaluate biomarkers such as blood creatine kinase and blood lactate, the other abovementioned positive physiological effects corresponded to the results of PBM irradiation in healthy individuals and athletes [40], indicating positive muscular effects.

Furthermore, a randomized, double-blind crossover clinical trial was conducted to evaluate the effects of PBM on respiratory muscles [20]. The authors utilized a cluster of 69 LEDs consisting of 35 red (630 nm; 10 mW; 0.2 cm²) and 34 near-infrared (830 nm; 10 mW; 0.2 cm²) LEDs on main respiratory muscles, including the upper trapezius, sternocleidomastoid, pectoralis major, rectus abdominis, and intercostal muscles of 12 patients with COPD, whereas the control group received sham irradiation. The results demonstrated no significant change in lung function, respiratory muscle strength, or thoracoabdominal mobility, but there was a significant improvement in functional capacity compared with baseline and control groups as measured by the distance walked in the 6-min walk test at 24 h after irradiation. This finding can be attributed to the possible impact of PBM on improving the performance of laser-irradiated respiratory muscles. Table 2 lists the studies reporting the effects of PBM on the muscle function of patients with COPD.

In the past few decades, skeletal muscle dysfunction has been increasingly recognized as a serious and prevalent comorbidity of COPD, not only contributing to poor exercise performance but also indicating poor prognosis for this population. In this section, we summarize the existing evidence to illustrate the effectiveness of PBM in improving both peripheral and respiratory muscle function through clinical studies. Although these studies strengthen the potential clinical application of PBM as a rehabilitation modality for patients with COPD, there is a need for more detailed research regarding treatment sites, sessions, and duration to better clarify the effectiveness of PBM on the muscle function of patients with COPD.

Effects of PBM on angiogenesis in COPD

Angiogenesis is a crucial component of lung pathophysiology, not only in cancer but also in inflammatory disorders such as COPD. In COPD, the inflammatory process promotes angiogenesis through the influx of inflammatory cells into the lumen and the walls of the bronchial and bronchiolar airways and parenchyma, controlling and orchestrating the progression of airway remodeling. In this process, one of the most important regulators of angiogenesis is the vascular endothelial growth factor (VEGF), as it modulates vascular permeability and the survival of endothelial cells. A decrease in the expression of VEGF and VEGF-receptor-1 (VEGFR-1) in the lung eventually causes the death of the alveolar epithelium, whereas an early release of VEGF can increase lung permeability [46]. Previous research has reported decreased protein levels and mRNA expression of both VEGF and its receptor in the lung tissue of patients with emphysema, with the decrease in VEGF expression possibly affecting the pathogenesis of emphysema [47]. Another study also demonstrated that a decreased sputum concentration of VEGF was associated with airflow limitation and alveolar destruction in patients with severe COPD with emphysema [48].

PBM can influence the proliferation of endothelial cells and the secretion of angiogenic factors, which help regulate angiogenesis to improve the management of diseases requiring blood vessel repair and formation [49]. An in vivo study by Cury et al. showed that both 660- and 780-nm lasers could modulate VEGF secretion, HIF-1α expression, and MMP-2 activity in a dose-dependent manner [50]. Regarding hypoxia and damaged tissues, Hsieh et al. demonstrated that PBM could reduce the overexpression of HIF-1α, TNF-α, and IL-1 and increase the levels of VEGF, S100 proteins, and nerve growth factor in rats with chronic constriction injury [50]. These studies indicate that PBM might provide a novel complementary treatment approach to modulate angiogenesis in patients with COPD with lung emphysema.

Conclusion and implications for future study

This review highlights the mechanisms of action of PBM in regulating and restoring the immune response in injured lung tissue, supported by cell, animal, and clinical evidence. Consequently, it is essential to understand the effectiveness of PBM in regulating the immune response in pulmonary diseases. The dosimetric parameters for PBM in experimental animal studies are variable, with wavelengths ranging from 660 to 830 nm and energy density ranging from 3 to 10 J/cm². We also investigated two other effects that support the application of PBM in patients with COPD, including improving muscle metabolism and promoting angiogenesis. Although a standardized protocol has not yet been established, current evidence suggests the following dosimetric parameters for PBM for muscle effects in humans: a wavelength of 630–905 nm and energy density of 1.5–4.5 J/cm². The abovementioned two effects might attenuate the complications of COPD, such as improving exercise tolerance and functional capacity and alleviating the development of emphysema. Therefore, PBM could serve as a potential adjunctive treatment modality in patients with COPD that merits further validation by robust and rigorous randomized, double-blind, placebo-controlled clinical trials to evaluate its equitable results and safety.

Author contribution

Chen CH and Chen YJ had the idea for the article; Lu YS and Lee CL performed the literature search; Lu YS, Kuo FY and Tseng YH performed data analysis; Lu YS and Chen YJ drafted the work; Lee CL, Kuo FY, Tseng YH, and Chen CH critically revised the work.

Funding

We thank the Ministry of Science and Technology (grant number: MOST-110–2628-B-037–008, 110–2314-B-037–039-MY3), the Kaohsiung Medical University Hospital (grant number: KMUH-IIT-110–1-07), and the Ministry of Health and Welfare (grant number: MOHW110-TDU-B-212–124006) for the funding.

Data Availability

Data are available from the corresponding author upon reasonable request.

Declarations

Conflict of interest

The authors declare no competing interests.