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C.S. Enwemeka, et al. Journal of Photochemistry & Photobiology, B: Biology 207 (2020) 111891 fibrosis, could be ameliorated with photobiomodulation, as evidenced by early results in laboratory animals [85–87]. For example, following induction of pulmonary inflammation in rats, de Lima et al. [85] showed that irradiation of the skin over the inflamed bronchus with a single dose of 1.3 J cm−2 of continuous wave (CW) red 650 nm laser administered 1 h after induction of inflammation, inhibited pulmonary edema and downregulated several measures of inflammation. The treatment reduced activation and influx of neutrophils, damage to en- dothelial cytoskeleton, and the amount of TNF-α, and IL-1β in the lung and bronchoalveolar lavage fluid. In a similar study, Brochetti et al. [86] induced pulmonary fibrosis in mice, and then treated the animals with red 660 ± 20 nm light (5 J cm−2 radiant exposure and 33 mW cm−2 irradiance) daily for eight days, beginning from day 14. They found that the treatment reduced collagen production and the number of inflammatory cells in the al- veoli, decreased interstitial thickening, and static as well as dynamic pulmonary elasticity. Further, cultures of pneumocytes and fibroblasts obtained from the animals showed downregulation of pro-inflammatory cells and collagen deposits in the lungs [86]. Another study of the same murine model showed that infrared 780 nm light reduced inflammation and collagen deposits in the lungs of mice, downregulated pro-in- flammatory cytokines, and upregulated the secretion of IL-10 from fi- broblasts and pneumocytes. Moreover, it significantly reduced total lung TGFβ [87]. Taken together, these early results suggest that red and near infrared light have the potential to reduce some of the critical complications of coronavirus infections, i.e., pulmonary inflammation and lung fibrosis. The preliminary nature of these results and the need for improved experimental methods and data reporting should not di- minish their significance; rather it should draw attention to another spectrum of light that may be beneficial in the ongoing fight against coronavirus diseases, which continues to challenge healthcare systems worldwide. In the race against the anticipated devastation of COVID-19, clin- icians have deployed chloroquine and hydroxychloroquine—two ana- logue medications commonly used to treat malaria but rarely used for coronavirus disease—to mitigate the disease, even though their me- chanisms of action against viral infections remains poorly understood [84,88–90]. The rapid spread of COVID-19 and its clear capacity to kill on a massive scale obviously justify deployment of treatments that seem to work, even though their underlying mechanisms are not clear. Thus, given the potential capacity of red and near infrared light to reduce the life-threatening respiratory complications of COVID-19, it goes without saying that every effort should be made to advance the work so that an effective therapy can be fashioned from the body of research work achieved to date. It will be a wise investment to urgently investigate these initial results clinically, and not wait for another deadly cor- onavirus pandemic to remind us of the inherent potential of light as a therapeutic tool. The urgency of this call is heightened by recent clin- ical results, which indicate that patients with chronic obstructive lung disease and others with bronchial asthma and allergy improved sig- nificantly following treatment with light [91,92]. Even more striking are reports showing that certain wavelengths of light inactivate viruses. Light has been shown to inactivate baculo- viruses [93] and prolonged exposure to blue light in the 420–430 nm range inactivates leukemia virus [94]. One may argue that baculo- viruses are confined to invertebrates and are not known to replicate in humans; but the fact that COVID-19 traversed species barrier to humans [84] is a cause to worry. One or more of the 76 species of baculoviruses could mutate to survive and replicate in human hosts, more so because shrimps consumed by humans and mosquitoes that suck human blood are among their 600 or more invertebrate hosts. These prospects make urgent the need to intensify efforts to test the effect of blue light on common viruses, including COVID-19. Further, that light in the visible spectrum constitutes the basis for photodynamic treatment of plasma to inactivate several viruses, including herpes simplex and human im- munodeficiency virus (HIV) [95–97], offers strong reason to suggest relation to COVID-19, some relatively easy targets are the nasal and oral cavities, and the upper respiratory tract, particularly as the nasal pas- sage is an acclaimed point of entry of the virus into the human body [81]. Antimicrobial blue light may serve another useful purpose in re- ducing the COVID-19 pandemic; it could be used effectively to sanitize equipment, tools, hospital facilities, emergency care vehicles, homes, and the general environment as pilot studies have shown [54–56]. Recent works now show that there may be as many as four me- chanisms underlying the antimicrobial effect of blue light. The first and most well-grounded of which is that blue light triggers endogenous bacterial chromophores such as porphyrins, flavins, NADH and other photosensitive receptors to produce reactive oxygen species, which in adequate amount results in cell death [39,46–50,64–79]. Indeed, por- phyrins with absorption peaks in the 405 to 470 nm range have been identified in microbial cells [39,46–50,64–79]. In three recent papers [34–36], we took advantage of this theory by timing in vitro irradiation of P. acnes and MRSA to coincide with periods of abundant endogenous porphyrins and hence elicit maximal bacterial suppression. The out- come was impressive. The dominant chromophores in P. acnes and MRSA emit red light with peak emission between 612 and 660 nm when excited with blue/violet light [36,46,47,64]. Thus, by monitoring the fluorescence—red glow—emitted by both bacteria, we were able to correlate bacterial kill rate with quantitated amounts of remnant bac- terial colonies. Not only did it show bacterial suppression, it revealed that their red fluorescence diminished as bacterial colonies were de- pleted and vice versa [36], further affirming the theory that porphyrins play a major role in antimicrobial blue light treatment. The second mechanism, which is continuing to gain traction, is that irradiation with blue light alters bacterial cell membrane integrity with a consequent decrease in membrane polarization and rapid alteration of cellular functions [64]. Our recent electron microscopic study affirms this finding. It shows that even at a sub-lethal dose level, treatment with pulsed blue 450 nm light disrupts the structural architecture of MRSA cell membrane and its internal organelles. The third and fourth me- chanisms of action, deserving further investigation and affirmation are that blue light alters A-DNA [82], and upregulates prophage genes to promote bacteria kill [83]. These findings clearly explain Finsen's remarkable achievement in healing many patients with tuberculosis, and suggests that similar successes could be attained in reducing secondary bacterial infections associated with coronavirus infections—the common flu, SARS, MERS, COVID-19, etc. It would be highly beneficial to patients with cor- onavirus disease if their loads of opportunistic bacterial infection could be reduced with blue light; such treatment—when fully developed—- will give their immune systems a better chance of overcoming the deadly disease. 6. Photobiomodulation and Acute Pulmonary Disorder Emerging data show that light in the red and near infrared light spectra can reduce lung inflammation, lung fibrosis, pneumonia, acute respiratory disorders, and other severe complications of coronavirus infections. This is an encouraging development since the experience of those at the frontline of the COVID-19 outbreak in Wuhan, China clearly show that acute respiratory disorder was the major cause of death [84]. Moreover, lack of effective antiviral drugs against COVID- 19 remains a serious concern, making it unlikely that such life-threa- tening complications may be resolved with medication in the short run. Early reports on the Wuhan COVID-19 outbreak show that commonly used antiviral drugs, such as neuraminidase inhibitors (oseltamivir, peramivir, zanamivir and others), acyclovir, the corticoster- oid—methylprednisolone, and ribavirin were ineffectual in treating the disease [81,84]. There are indications that Acute Respiratory Distress Syndrome (ARDS) a critical complication of COVID-19 infection [81,84], often characterized by airway edema, pulmonary inflammation, and lung 4PDF Image | Light as a potential treatment for pandemic coronavirus infections
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