Abstract
Worldwide interest in photobiomodulation therapy (PBMT) has been growing rapidly in recent years. Published studies have involved mechanistic investigations, laboratory studies in cell culture and in experimental animals, and a wide range of clinical reports. These clinical reports have covered a range of pilot clinical trials, controlled clinical trials, and case reports. The reasons for this relatively sudden growth are interesting to contemplate. They include the wider availability of inexpensive light-emitting diode (LED) devices, the realization that PBMT has fewer side effects compared with many widely used pharmaceutical drugs, the desire for more natural remedies, and the availability of user-friendly devices that can be used at home.
The impressive successes of PBMT have led to a perception in some quarters that PBMT can provide beneficial effects in almost all human diseases. But is this really true? To answer that question, it is necessary to understand the basic biological processes that are triggered by the absorption of red or near-infrared light by cellular chromophores. 1 Some of these mechanisms are relatively well known, whereas others are still being discovered. PBMT stimulates mitochondrial metabolism, increasing oxygen consumption, adenosine triphosphate (ATP) production, nitric oxide release, and creates a brief burst of reactive oxygen species (ROS). Despite this burst of ROS, when longer time scales are examined, antioxidant defenses have been found to be increased, and oxidative stress is reduced. There is a pronounced anti-inflammatory effect that has been proposed to be due to the switching of the macrophage phenotype from M1 to M2 by increasing oxidative phosphorylation and decreasing glycolysis. Cells at risk from dying can be protected by upregulation of antiapoptotic proteins, and consequently reduced apoptosis and less cell death.
Many cellular functions and biological processes that have been suppressed or downregulated in different pathological conditions can be partially or fully restored by administering PBMT. Cells that have died or been damaged can be replaced by the stimulation of stem cells or progenitor cells that can migrate to the site of injury. Cells at risk of dying can be rescued by the upregulation of antiapoptotic signaling pathways. Blood flow and tissue oxygenation is improved. Proteins (such as collagen) that are required for the healing of tissues such as skin, tendons, bones, and cartilage are upregulated. Fibroblasts and endothelial cells migrate and proliferate to accomplish these tasks.
An interesting article by Lim et al. examined the effect of PBMT in an animal model of Meckel syndrome (MKS). 2 Meckel (or Meckel–Gruber) syndrome is a rare type of genetic polycystic kidney disease (PKD) that also has effects on the central nervous system and liver. Mutations in three genetic loci have been found in humans suffering from MKS: MKS1 17q21–24, MKS2, 11q13, and MKS3 (8q21.13–q22.1). MSK3 was found to be syntenic to the Wpk locus in the rat genome, and the 995-amino acid seven-transmembrane receptor protein was called meckelin. 3 The wpk/wpk mutant rat on a Wistar background is used as an animal model of human MKS. 4 The rats display numerous kidney cysts, nephromegaly, hypertension, proteinuria, impaired urine-concentrating capacity, hydrocephalus, and become moribund at around 28 days of age.
Lim et al. treated the wpk/wpk rat pups once per day for 8 days (postnatal days 10–18) using a 670 nm LED array (Quantum Devices, 4 J/cm2 at 50 mW/cm2) and the animals were sacrificed at day 18. 2 The mean body weight of the MKS rats was the same as normal rats; however, PBMT reduced the mean body weight of MKS rats by 25%, but had no effect on normal rats. The mean kidney weight was nine times higher in MKS rats compared with normal rats, but although PBMT significantly reduced the kidney weight by 24%, the ratio of kidney weight to body weight was unchanged. The blood urea nitrogen was six times higher in MKS rats compared with normal rats (75 ± 7.1 vs. 13.1 ± 1.3 mg/dL) and was further increased to 141 ± 22 after PBMT. The mean volume of kidney cysts was reduced by PBMT, but not as a percentage of body weight. The volume of hydrocephalus was increased by PBMT compared with untreated MKS rats (1.02 ± 0.13 vs. 0.69 ± 0.07). The conclusion of this study was that PBMT had a clear deleterious effect on the course of MKS in this animal model.
Because oxidative stress is involved in the pathogenesis of MKS and other types of PKD, the investigators measured antioxidant enzymes and cytochrome c oxidase (CCO) in the kidney tissue. PBMT increased catalase and CCO (which was already significantly higher compared with controls) in MKS rats, and slightly decreased glutathione S-transferase and glutathione reductase. Their explanation of their findings was based on the idea that PBMT further amplified some of the alterations that had occurred in the diseased kidney in response to the reduced blood flow and resulting hypoxia in the polycystic and hypertrophic kidneys.
It should be noted that these authors only used one dose of PBMT (4 J/cm2 at 50 mW/cm2 of 670 nm LED). The biphasic dose response is now widely accepted in PBMT, and states that there is an optimum dose of light for each condition and subject, and doses that are substantially higher or lower than the optimum dose will be likely to have less beneficial effects. 5 Moreover, if the dose is increased to a level very much higher than the optimum value, then deleterious effects could possibly occur. In the case of the Lim study described earlier, how likely is it that they were on the wrong side of the biphasic dose–response curve? It was probably not very likely, because 4 J/cm2 is considered to be very modest dose, and has been used widely without any adverse effects in both animals and humans.
In that case we must accept that MKS is an example of a disease or condition, which should not have been treated with PBMT. Many hereditary diseases are highly complex, with genetic mutations (even in a single protein) leading to complicated disturbances in a host of biochemical and cellular pathways. Although these disturbances often lead to the occurrence of common pathophysiological alterations that we know can be benefited by PBMT, such as oxidative stress, inflammation, and cellular apoptosis, it cannot be assumed that PBMT will always be beneficial. To some degree it might be the case that PBMT could stimulate many biological processes, and if these are pathological processes because of genetic mutations and altered proteins, then PBMT may stimulate them even further. PBMT is beginning to be tested for kidney disease, and has been shown to be helpful for acute ischemic kidney injury, and for chronic kidney failure; however, these kidney conditions are not caused by genetic mutations. For instance, some hereditary diseases are caused by accumulation of an abnormal mutated protein, so will PBMT lead to clearance of this abnormal or aggregated protein by stimulating phagocytosis, or will it actually increase the production of the abnormal protein, in the same way as it stimulates production of normal proteins to repair injuries?
Much additional work will need to be carried out, before we know which hereditary diseases can be successfully treated by PBMT and which cannot. Therefore, caution is recommended before assuming that all hereditary and genetic diseases will automatically benefit from PBMT.