One Man's Light: Mechanistic Convergence of Photobiomodulation and Biological Effects

As a science watcher and scientist, hardly a day goes by without encountering some interesting tidbit that forms the nucleus for further investigation on my part. It is also quite common to encounter the volleys and serves, as practices and so-called “evidence-based guidelines” are supported or refuted in the scientific and lay press for being appropriate, or not, depending upon the latest analysis or interpretation of a series of events or new experimental results. Consider for a moment the recent flurry of articles on the value of mammography, the utility of robotic or computer-assisted surgery, or whether statins and vitamin supplementation should be more widely used. We generally refine our applications and use of the modality based on the current knowledge base, which itself is not static, but is a moving target as we learn, and not infrequently re-learn, something about an intervention or therapy. Some of these applications and nuggets of knowledge can be seemingly quite tangential or far afield and no less complex than attempting to unravel the details of the big bang from which it is believed the universe and our very existence arose.

Modern medicine is based on allopathic principles, which Webster's Dictionary defines as “a system of medical practice that aims to combat disease by use of remedies (as drugs or surgery) producing effects different from or incompatible with those produced by the disease being treated; a system of medical practice making use of all measures that have proved of value in treatment of disease.” ¹ We administer drugs at therapeutic doses to treat various conditions and, although we are becoming increasingly adept at creating designer drugs and achieving better targeting of the specific disease or process we intend to treat, we are inevitably also accepting a series of side effects and adverse effects of treatment. These events occur in large part because of the effects of these drugs and their metabolites at sites and receptors distant from the originally intended target.

This brings to bear two concepts that I will elaborate upon. The first concept is what I will call the real estate gambit. Pricing of real estate is ultimately driven by the desirability of a building or parcel. All else equal, the mantra is “location, location, location.” Let us now consider this from a medical and biological perspective. An intervention can have dramatically different results and consequences depending upon the site being manipulated. Consider the cases of botulinum toxin and sildenafil, both of which are widely prescribed and used. However, imagine the biological response that would occur if a therapeutic injection of botulinum toxin was administered to the phrenic or recurrent laryngeal nerves rather than branches of the facial, frontal and temporal nerves. The former would cause respiratory embarrassment, whereas the latter reduces wrinkles, both outcomes are mediated by the process of blocking neural transmission. Similarly, sildenafil has significantly different effects relative to its effects on venous dilatation at the intended site and opposite effects in the cardiac and pulmonary circuits, because of the opposite response to nitric oxide and nitrate metabolites centrally and peripherally. My point here is that the site of treatment, whether it is drug, surgery, or light, is important, and failure to appropriately consider these features when designing studies and treating patients can adversely affect low-level light therapy (LLLT) outcomes.

The second concept is the notion that any substance is toxic, even water and oxygen under the proper concentration and circumstances. The corollary of this is that we routinely apply therapies using substances and other interventions using compounds derived from nature or synthesized to mimic natural substances, and that these substances are therapeutic at some concentrations and locations, and lethal or highly toxic at others. Bisset considered this in his treatise on medicinal plants used as the basis for pharmacologic agents. ² Some examples of these seemingly yin and yang effects can be found if one examines atropine, nicotine, theobromine, digitalis, or vinca alkaloids. Examples from the animal realm include the use snake venom derivatives for management of blood pressure or coagulopathy, or various prostaglandins and their derivatives. Some of the effects and toxicities are dose and concentration dependent, and some are also location and timing dependent.

Considering prostaglandins more broadly as inflammatory mediators brings us to the even more basic, but complex inflammatory process. Inflammation is arguably a biological touchstone being integral to wound healing and the biological repair response, as well as playing a role in host defense and immune response, and influencing a number of organs and organ systems. ^{3 –6} Our ability to understand and manipulate inflammation and the inflammatory response can influence pain, prevent devastating sequelae such as the systemic inflammatory response syndrome (SIRS), prevent arthropathy or more severe joint destruction, and modulate events initiated by ischemia reperfusion, bacterial or viral infection, and perhaps cancer and tumor biology. ^{4,6 –10}

Photobiomodulation (PBM) has been demonstrated to accelerate wound healing; ^3,4 reduce pain and inflammation; ^5,11,12 and influence the host response to ischemia, ⁴ infection, and cancer. ^{7 –12} It is possible to augment intracellular metabolism by increasing adenosine triphosphate (ATP) production among other pathways, as well as to induce or reduce production of reactive oxygen species (ROS) and other free radicals as the mechanistic basis for the outcomes observed after using LLLT. ^{12 –16}

Kashiwagi and colleagues ¹⁷ recently demonstrated that near-infrared (NIR) laser light administered to small areas of skin significantly increased immune responses to intradermal influenza vaccination without augmenting immunoglobulin E (IgE), without the need of additional chemical or biological agents. They demonstrated that the expression of specific chemokines in the skin is induced, resulting in recruitment and activation of dendritic cells. It is also known that commonly used anti-inflammatory drugs can downregulate the antibody response, ⁶ and that LLLT has been used both for its anti-inflammatory effects ^5,11,12 and for its other roles. Adding the knowledge that LLLT can influence mast cells, ¹⁸ and the fact that mast cells play a central role in inflammation and immunity, to the even more tantalizing discovery that histamine may play a central role in cancer, ¹⁹ is tantalizing, and may one day broaden the uses of PBM, and elevate it to the mainstream.

Therefore, we are beginning to understand the fact that biological systems are complex, with numerous pathways that may be poised to work in concert with, or in opposition to, one another, depending upon the needs of the organism. There are seemingly several common denominator substances and reactions that can be manipulated by a number of forces, light included.

Tiina Karu is right to assert that we should consider PBM as being a drug equivalent. ²⁰ We must continue to explore new avenues of research and application while remembering the “real estate gambit” and creating more evidence that one person's light is, indeed, another's medicine. The ability to influence such a fundamental process as inflammation may well be the central key.