The Probable Protective Effect of Photobiomodulation on the Immunologic Factor’s mRNA Expression Level in the Lung: An Extended COVID-19 Preclinical and Clinical Meta-analysis

Abstract

Background:

Different expression of cytokine genes in the body determines the type of immune response (Th1 or Th2), which can play an important role in the pathogenesis of the COVID-19 disease.

Aims:

This meta-analysis was conducted to evaluate the probable effect of photobiomodulation (PBMT) therapy on the cytokine’s mRNA expression in the lung.

Methods:

We systematically searched indexing databases, including PubMed/Medline, ISI web of science, Scopus, EMBASE, and Cochrane central, using standard terms without language, study region or type restrictions. Studies on using PBM in lung injury modeling with samples collected from lung tissue to observe IL-1β, TNF-α, IL-10, and IL-6 mRNA expression were included. RevMan 5.3 software was used for data analysis and standardized mean difference as effect size.

Results:

Of the 438 studies found through initial searches, 17 met the inclusion criteria. The main properties of 13 articles on 384 animals included in this meta-analysis with a wide range of species include rats (n = 10) and rabbits (n = 3). The analysis revealed that PBMT reduced the mRNA expression of TNFα (SMD: −3.70, 95% CI: −6.29, −1.11, P = .005,I² = 71%) and IL-1β (SMD: −5.85, 95% CI: −8.01, −3.69, P < .00001,I² = 37%) significantly, but no statistically significant reduction in IL-6 (SMD: −2.89, 95% CI: −5.79, 0.01, P = .05,I² = 88%) was observed compared with the model controls. Also, PBMT increased IL-10 mRNA expression significantly compared with the model controls (SMD: 1.04, 95% CI: 0.43, 1.64, P = .0008,I² = 17%).

Conclusion:

This meta-analysis revealed that the PBMT utilizes beneficial anti-inflammatory effects and modulation of the immune system on lung damage in animal models and clinical studies. However, animal models and clinical studies appear limited considering the evidence’s quality; therefore, large clinical trials are still required.

Keywords

SARS-CoV-2 photobiomodulation therapy (PBMT)anti-inflammatory Meta-analysis mRNA expression

Introduction

Acute respiratory distress syndrome (ARDS) is a potentially fatal lung injury, of which patients with this disorder are already admitted to the hospital due to trauma or are critically ill.^1,2 The pathogenesis of ARDS includes an inflammatory response to damage in the lung due to increased vascular and epithelial permeability in the lung.³ The ARDS-induced systemic inflammatory response appears to cause multiple organ dysfunction syndromes (MODS) if not treated timely.⁴ Interleukins (ILs) are immune system cytokines that regulate the activity of white blood cells, including lymphocytes and leukocytes.⁵ Recent studies have acknowledged imperative roles for IL-1beta, IL-6, and IL-10 in inflammation and severity of COVID-19. Most patients with COVID-19 recover, but a significant proportion also die. The mortality rate of the Covid-19 virus was initially reported to be 15%, but this estimate was calculated from a small group of hospitalized patients. After that, with more data, the COVID-19 mortality rate was announced to be between 4.3%and 11% and later reached 3% to 4.3%. These rates were obtained using demographic data, and the study was performed on a group of individuals.⁶

Photobiomodulation (PBM), formerly known as low-level laser therapy (LLLT), phototherapy, biological stimulation, cold lasers, or soft lasers, gives us a unique feature of a non-invasive method that enhances recovery by using low-level beams.⁷ The main use of PBM therapy (PBMT) is to accelerate wound healing and reduce pain and inflammation. Given the anti-inflammatory properties of PBM, it seems to be a sensible method to control the symptoms of COVID-19, especially when ARDS is present.⁸ However, the role of PBMT in COVID-19-induced inflammation of the airway and lung remains controversial.⁹ PBMT is an innovative option in this area that has been shown to have significant anti-inflammatory effects in treating pain, lymphedema, wound healing, and musculoskeletal injuries.¹⁰ The photo-biological effects of PBMT and their interference with the immune system are very well known.^11
-14 Studies also reported the effect of PBMT on cytokine (IL-4, IL-10, or IL-13) and chemokine (CCL2, CXCL10, and TNF-α) production and elucidate the mechanism via histone modification of cytokine expression in monocytes, as well as enhanced cytokine and chemokine expression in mRNA and protein levels.¹⁵ The effect of PBMT on proinflammatory cytokines or other mediators and their important role in the pathophysiology of inflammatory diseases such as osteoarthritis (OA) has also been reported.¹⁶

PBMT uses non-ionized and non-thermal light sources in the visible and infrared spectrum (600-1200 nm), reducing inflammation and stimulating healing.¹⁷ The light absorption causes the production of ROS, such as hydrogen peroxide (H2O2) and superoxide. This ROS influence many cellular processes such as proliferation, differentiation, and adenosine triphosphate (ATP) formation and can also reduce inflammation. So PBM is useful for modulating the inflammatory process when the cellular function is impaired, especially by hypoxia. Light is applied through the skin on the damaged targets or inflamed tissues. The light energy absorbed by intracellular photo-receptors initiates a series of intracellular photochemical reactions that enhance cellular activity and tissue healing.¹⁸

The primary use of PBMT is to accelerate wound healing and reduce pain and inflammation. Therefore, this systematic review and meta-analysis were conducted to evaluate the probable effect of the PBMT on the cytokines mRNA expression in the lung.

Methods

This meta-analysis was conducted following the Meta-analyses Of Observational Studies in Epidemiology (MOOSE)¹⁹ and Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA)²⁰ guidelines.

Literature search

We systematically searched major indexing databases, including Pubmed/Medline, ISI web of science (WOS), Scopus, EMBASE, and Cochrane central, using terms (“Radiotherapy”[Mesh] OR “Low-Level Light Therapy”[Mesh] OR “Photochemotherapy”[Mesh] OR “Phototherapy”[Mesh] OR “Lasers”[Mesh]) AND (“COVID-19”[Mesh] OR “SARS-CoV-2”[Mesh] OR “SARS-CoV-2 variants” [Supplementary Concept] OR “Viral Envelope Proteins”[Mesh] OR “SARS Virus”[Mesh] OR “Respiratory Distress Syndrome”[Mesh]) without any language, study region or type restrictions.

Inclusion and Exclusion Criteria

Studies on using PBM in lung injury modeling with samples collected from lung tissue to observe IL-1β, TNF-α, IL-10, and IL-6 mRNA expression were included. Studies with no induced lung injury, and cytokine measurement not in lung tissue, not using PBMT were excluded.

Outcome measures

We collected information regarding outcome measures. The first outcome of interest includes the assessment of IL-1β, TNF-α, IL-10, and IL-6 mRNA expression in the lungs.

Study selection

Two authors (FR and BA) independently performed the title and abstract screening. Any disagreement was resolved by double-checking the reference paper or discussion with a third author (AA).

Methodological quality assessment

Two authors (FR and BA) independently conducted the methodological quality assessment with particular consideration for potential sources of risk of bias. We used the Cochrane Collaboration’s quality assessment tool for risk of bias assessment in RCTs.²¹ Any disagreement was resolved by double-checking the reference paper or discussion with a third author (AA).

Data extraction

One reviewer (FH) performed data extraction and double-checked by another author (BA). Authors extracted data, including the author’s name, publication year, country, intervention, comparators, and outcomes of interest. If the outcomes of interest were missing, we contacted the authors three times; besides, if the outcomes were only presented in figures, we used WebPlotDigitizer to extract the data.²² Median and range were converted to mean and standard deviation (SD) using a standard formula.

Data analysis

We used RevMan 5.3 software for data analysis and standardized mean difference as effect size. If data were present as median and range, we used Wan et al. methods to estimate the mean and standard deviation.²³ The Biochemical units such as LDL and TC were transformed from mg/dL to mmol/L as appropriate. Heterogeneity was described as the total variability (I²). The significant heterogeneity was tested by χ² test. Low heterogeneity was indicated as I² < 40%. In case the heterogeneity was significant (I² > 75%), the source of heterogeneity was detected before the meta-analysis. We conducted sub-group analyses based on various comparators. To assess publication bias, we used funnel plots.

Results

Description of the included studies

Of the 438 studies found through initial searches, 13 met the inclusion criteria (Figure 1).^24
-36 After applying the exclusion criteria, the main properties of 13 articles on 384 animals included in this meta-analysis with a wide range of species, including rat (n = 10) and mice (n = 3) (Table 1)

Table 1.

Basic characteristics of the included studies.

Study ID, Reference	Animals	SEX	Total (No. per group)	Lunge disorder model	PBM technique and dose	altered inflammatory agents	Outcome
Aimbire et al,²⁵ Brazil	Wistar rats 200-220 g	Male	35 (7)	LPS	A diode laser (Ga-AsI-Al; model Thera laser) with doses of 0.04, 0.11, and 0.22 Joules	TNFα	TNFα activity in bronchoalveolar lavage
Aimbire et al²⁴, Aimbire et al,²⁶ Brazil	Wistar rats 230-250 g	Male	84 (7)	LPS	A diode laser with an output power of 30 mW and a wavelength of 660 nm (model: laser unit, Kondortech) with dosage of 7.5 J/cm²	MOP, Neutrophils, IL-1β, PML	Effect of PBM on lung permeability and bronchoalveolar lavage and IL-1β
de Lima et al,³² Brazil	Wistar rats 150-180 g	Male	35 (7)	LPS	GaAsAl diode laser (model Thera lase, Brazil) operating in the wavelength of 650 nm with a dose of 1.3 J/cm²	TNFα, MOP, Neutrophils, IL-1β	The inflammatory mediators that are driven for PBM
de Lima et al,^30,31Brazil	Wistar rats 150-180 g	Male	63 (7)	i-IR	A 660 nm laser diode (MM Optics, CW diode laser, Sa~o Carlos, SP) with a dose of 5.4 J	TNFα, MOP, Neutrophils, IL-10, PML	TNF-a and IL-10 in reperfusion-induced
de Lima et al,^29,33 Brazil	Wistar rats 220-250 g	Male	35 (7)	i-IR	A 660 nm laser diode (MM Optics, CW diode laser, Sa~o Carlos, SP) with a dose of 6.9 J/cm²	TNFα, ICAM-1, GSH L, anti-inflammatory protein HSP70	PBM could modulate the acute lung inflammation by HSP70
de Lima et al,²⁸ Brazil	C57/Bl6 mice 20-22 g	NA	28 (7)	i-IR	A 660 nm laser diode (MM Optics, CW diode laser, São Carlos, SP) with doses of 1, 3, 5,and 7.5 J/cm²	MPO, IL-1β, IL-6 and TNFα	The effects of PBM on the lung inflammatory response in a model of ARDS
Oliveira et al,³⁶ Brazil	C57/Bl6 mice 25-30 g	Male	38 (6-9)	LPS	infrared laser administration [continuous wave, 830 nm, 3 J/cm²	MPO, IL-1β, IL-6 and TNFα, Neutrophils	The effects of PBM on the lung inflammatory response in a model of ARDS
da Silva et al,³⁵ Brazil	Wistar rats 220-250 g	Male	18 (6)	FAI	infrared laser (CW Diode Laser- MMOptics, São Paulo, Brazil) with a dose of 12.86 J/cm²	MPO, IL-1β, IL-6 and TNFα, Neutrophils, Macrophage, Lymphocyte	The mechanisms of PBM with regard to lung inflammation
da Cunha Moraes et al.²⁷ Brazil	C57/Bl6 mice 19-22 g	Female	24 (8)	COPD	A diode laser (power 30 mW, energy density of 3 J/cm² at 660 nm of wavelength)	MPO, IL-1β, IL-6, IL-10, IL-17, TNFα, Neutrophils, Macrophage, Lymphocyte	LLLT is effective in reducing lung inflammation
Fazza et al,³⁴ Brazil	Wistar rats 220-250 g	Male	24 (6)	PMV VILI	infrared laser (Photon Lase III, aluminum gallium arsenide – AlGaAs)	IL1-β, IL-6, TNF-α, CXCL2, IL-10, Neutrophils, Macrophage, Lymphocyte	The effect of LLLT on the inflammation response of VILI

Abbreviations: BALF, bronchoalveolar lavage fluid; PBM, photobiomodulation; LPS, lipopolysaccharide; MOP, myeloperoxidase activity; PML, pulmonary microvascular leakage; i-IR, intestinal ischemia and reperfusion; FAI, formaldehyde inhalation; PMV, protective mechanical ventilation; VILI, ventilator-induced lung injury.

Figure 1.

Flow chart of the study selection process.

Methodological quality

All 13 included studies were divided and assigned the animals randomly to either PBM or control. Moreover, neither the data analysis nor the animal modeling and PBM administration indicates the blinding method. In addition, the data about the inflammatory factors varied significantly between included studies. The dose of PBM varied greatly among included studies, and none of the selected studies mentioned the safety issues regarding the dose of the laser.

Meta-analysis

TNFα mRNA expression

Of the 13 included studies, 3 measured TNFα mRNA expression,^28,34,37 which were included in the meta-analysis. The analysis revealed that PBMT reduced TNFα mRNA expression significantly compared with the model controls (SMD: −3.70, 95% CI: −6.29, −1.11, P = .005,I² = 71%) (Figure 2).

Figure 2.

Comparison of the effect on TNF-α, IL-1β, IL-6, and IL-10 between PBMT and control in the animal lung injury models. The figure represents the SMD () result of the overall experimental data and the horizontal lines represent the 95% CIs for each study.

IL-1β mRNA expression

Of the 13 included studies, 3 measured IL-1β mRNA expression^26,28,34, which were included in the meta-analysis. PBMT reduced IL-1β mRNA expression significantly compared with the model controls (SMD: −5.85, 95% CI: −8.01, −3.69, P < .00001, I² = 37%) (Figure 2).

IL-6 mRNA expression

Of the 13 included studies, 3 measured IL-6 mRNA expression^28,34,35, which were included in the meta-analysis. PBMT reduced IL-6 mRNA expression compared with the model controls (SMD: −2.89, 95% CI: −5.79, 0.01, P = .05,I² = 88%), but the effect was not statistically significant (Figure 2).

IL-10 mRNA expression

Of the 13 included studies, 4 measured IL-10 mRNA expression^32
-35, which were included in the meta-analysis. PBMT increased IL-10 mRNA expression significantly compared with the model controls (SMD: 1.04, 95% CI: 0.43, 1.64, P = .0008,I² = 17%) (Figure 2).

Sensitivity analyses

There was no substantial variation in the comparators of included studies; thus, we did not perform a sensitivity analysis of the effects of various comparators on study outcomes. We also observed any publication bias using funnel plots for immunologic factor measures and BALF cells outcomes, in which all plots appeared to be non-symmetrical with obvious publication bias (Figure 3).

Figure 3.

Begg’s tests for publication bias of the effect of PBM therapy.

Discussion

Our meta-analysis of present shreds of evidence supports the conclusion that the immunologic response demonstrated at the level of gene expression may shed light on the protective, anti-inflammatory, and anti-oxidative effects of PBMT in lung injury-induced animal models. It should be noted that in the body, after rapid expression of the cytokine gene and due to its instability of mRNA, if the invading agent is cleared from the body, the cytokine level rapidly returns to its original value. Otherwise, long-term expression of the cytokine gene will cause autoimmune diseases and allergies. In addition, cytokines are not precursor molecules and cannot be stored in cells.

Cytokines such as TNF-α, IL-1β, IL-6, and IL-10 not only recruit and activate leukocytes in lung diseases but also impact lung inflammation.³⁸ The present meta-analysis revealed that PBMT may reduce inflammation by inhibiting the mRNA expression of TNF-α, IL-1β, and IL-6. In line with our findings, research also shows that PBMT may reduce inflammation by inhibiting the release and expression of inflammatory mediators and cells.^16,39 The possible mechanism is the strong ability of the PBMT through inhibiting the production of prostaglandins, leukotriene and cyclooxygenase (COX) as the most important inflammatory mediators.⁴⁰ In addition, the inhibitory effect of PBMT on the release of the proinflammatory cytokine, TNF-α, and interleukin expressions, which are important mediators of inflammation, has been reported and demonstrated. This function may be present by down-regulating nuclear factor-κB (NF-κB) transcriptional activity or increasing the intracellular levels of cyclic adenosine monophosphate (cAMP).⁴¹

Clinical Implications: Potential Treatment for COVID-19

A recent coronaviruses of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a cause of COVID-19 disease, appeared in the world at the end of 2019 and caused severe public health consequences.⁴² Preliminary studies show that many COVID-19-related fatalities are due to over-activity of the immune system, known as the cytokine storm.⁴³ Cytokines, chemical mediators secreted by immune system cells, act on other cells or the secretory cell itself. Different expression of cytokine genes in the body determines the type of immune response (Th1 or Th2), which can play an essential role in the pathogenesis of diseases.⁴⁴ The risk of COVID-19-related acute respiratory distress syndrome (ARDS) in hospitalized patients was directly related to increased neutrophil count and decreased lymphocyte count.⁴⁵ Measurements of interleukin levels indicate the extent of the cytokine storm in COVID-19 and are associated with disease severity.⁴⁶ Large amounts of cytokines can cause widespread (systemic) inflammation that can damage various organs in the body and lead to Multi-Organ Dysfunction syndrome.⁴⁷ Although at first glance, cytokine inhibition may be considered immunosuppression and harmful to COVID-19, inhibiting these cytokines is an anti-inflammatory effect rather than suppression.⁴⁸ Thus, cytokine inhibition not only does not interfere with the clearance of the SARS-CoV-2 but also helps to cure patients with COVID-19 by reducing inflammation.^49,50

Currently, there is no treatment protocol as the gold standard for COVID-19 disease, and only supportive protocols that can reduce the inflammation in severe conditions are often recommended.⁵¹ There is substantial debate about the beneficial effects of antiviral drugs, while dexamethasone has recently been shown to reduce mortality.⁵² Given the anti-inflammatory properties of PBM, it seems to be a sensible method to control the symptoms of COVID-19, especially when ARDS is present.⁸ However, the role of PBMT in COVID-19-induced inflammation of the airway and lung remains controversial.⁹

Recently, much literature evaluated PBM’s impact on improving the regeneration of damaged tissues. A study by Nejatifard et al demonstrated the clinical efficacy of PBM in COVID-19 progression.⁹ Based on their conclusion, PBM is more efficient in the early stages of COVID-19.⁹ This should be remembered that interfering factors such as underlying disorders, inflammation severity, and immunodeficiency diseases influence PBM outcome. To address this, in the current review, we investigate inflammation pathways involved in ARDS in animal studies.

Using search terms through selected databases, there were only 5 studies on using PBMT in patients with COVID-19 (Table 2). Of 5 studies, only 1 clinical trial included PBMT to treat COVID-19, and the rest 4 were either case reports or case series.^8,53
-56

Table 2.

Basic characteristics of the clinical included studies.

Study ID	Study design (No. of cases)	Sex/Age	Laser technique and dose	Outcome
Pelletier-Aouizerate and Zivic⁵³	Case reports (2)	F/69 F/53	RL-PBMT, 3 times daily for 10 days, 50 J/cm² 2-3 times per week RL-PBMT, 50 J/cm²	PBMT could prevent more severe respiratory distress
Sigman et al⁵⁴	Case reports (1)	M/57	Once daily for 4 days, 808 nm (GaAlAs) diode, 7.2 J/cm²	PBMT is a safe and effective potential treatment and improves clinical status in COVID-19 pneumonia
Sigman et al⁵⁵	Case reports (1)	F/32	Once daily for 4 days, 808 nm (GaAlAs) diode, 7.2 J/cm²	PBMT can be safely combined with conventional treatment in patients with severe COVID-19
Teixeira et al⁵⁶	Case series (3)	M/57 F/84 F/70	daily for 4 days, 808 nm (GaAlAs) diode, 7.2 J/cm²	PBMT seemed to be effective in the management of COVID-19
Vetrici et al⁸	RCT (10)	53.4 ± 17.7	28 min of PBMT with a dosage of 7.18 J/cm² and a total energy of 3590 J.	PBMT is a safe and effective potential treatment and improves clinical status in COVID-19 pneumonia

PBMT with stimulating immune response locally and systemically, increasing local circulation, promoting homeostasis, and relieving inflammation in treated organs and tissue accelerate the improvement of COVID-19.⁵⁷ Additional to the influencing immune system, PBMT has directly contribute in pathogen clearance.^57,58

Despite the availability of many anti-inflammatory drugs, there is still the problem of the inability to successfully treat inflammation, especially the type of inflammation associated with COVID-19 disease. Due to the clinical problems caused by inflammation, researchers are still trying to find new, better, more effective treatments with more limited side effects. On the other hand, the primary mechanism of PBM is creating a balance between inflammatory and anti-inflammatory agents. Although this is the principal therapeutic approach to modulating treatments, it was reported that PBM is more efficient than other similar therapeutics.⁵⁹

TNF-α may be a potential biomarker for ARDS and mortality in patients with COVID-19 and opens new exciting areas of research for COVID-19 treatment.⁶⁰ According to previous research and the present meta-analysis, PBMT may reduce inflammation by inhibiting the mRNA expression of TNF-α, which can illustrate the point that PBM could inhibit inflammation and has anti-inflammatory effects. In this context, Chen et al. proposed that inhibiting TNF-α and IL-6 could attenuate COVID-19 disease progression in severe cases by suppressing systemic auto-inflammatory responses.⁶¹ Studies have shown that PBMT can activate NF-kB in normal quiescent cells, decreasing inflammatory markers in activated cells.¹⁸ PBMT has also been shown to have a protective effect on the lungs by reducing the inflammatory process, significantly reducing mRNA expression of TNF-α, Il-6, and IL-1β.

Studies have shown that if IL-10 is increased, the chances of developing COVID-19 are reduced; therefore, levels of IL-10 appear to play an essential role in the development of COVID-19.^62,63 In this context, the present meta-analysis showed that the mRNA expression levels increase significantly in association with PBMT. Studies showed that in patients with various autoimmune diseases, lower expression IL-10 gene is associated with more disease severity compared to controls.⁶⁴

The considerable differences in PBM protocols were not observed across studies. However, it was revealed that with increasing PBM dose, the efficacy of PBM increases, but this improvement is not continuous; from a point out, this efficacy reduces. Additionally, several agents involving inflammatory pathways show various responses to various PBM doses.¹⁸ For example, the wavelength for increasing IL-6 differs from NF-қB.¹⁸ This explains the discrepancies between surveys.

Strengths and Limitations

Interpretation of our results indicated that PBMT has a protective effect on the lungs by reducing the inflammatory process, significantly reducing mRNA expression of TNF-α, Il-6, and IL-1β. In this regard, PBMT is a cost-effective technique for remodeling and reduces inflammation. Also, there are numerous therapeutic aspects of PBM, which causes dramatic increasing studies focusing on the efficacy of LLTL in ARDS treatment, which was not evaluated in the present survey.

The only limitation of this study is that animal models and clinical studies appear limited, considering the quality of the included evidence.

Conclusion

There are various mechanisms by which PBM can influence them. PBMT utilizes beneficial anti-inflammatory effects, modulation of the immune system, lung permeability or bronchoalveolar lavage on lung damage, reducing neutrophil accumulation, accelerating tissue regeneration, and facilitating disease management. Since cytokines play a pivotal role in the immune system, the cascade of inflammation pathways regulates subsequently. In this regard, despite the paucity of data about PBMT in COVID-19, PBMT can be helpful in COVID-19 and ARDS management. However, animal models and clinical studies appear limited considering the quality of the included pieces of evidence; therefore, large clinical trials are still required. Interpreting the results of the current survey alongside other investigations has shown that determining the effective PBM protocol depends on target immune pathways; this is a critical issue that should be considered in further studies.

Footnotes

Funding:

The author(s) received no financial support for the research, authorship, and/or publication of this article.

Declaration of conflicting interests:

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Author Contributions

FR conceived the manuscript and revised it. FR and BA did the statistical analysis, wrote the manuscript, and prepared tables and figures. All authors have read and approved the manuscript.

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