Abstract
Introduction
To understand the “state of the art” in research on inflammation, it is necessary to first understand some basic points of thought and knowledge of the area. We started this reflection by taking us to the evolution of species and their success and permanence on our planet. We can easily imagine that the ability to defend ourselves against external aggressions, whether from the environment itself, predators, or from ourselves, is a primordial condition for us to continue to exist, in the current form, on this planet. So, regardless of the scale of actions we can take to defend ourselves, the ability to defend is, therefore, fundamental to our survival and maintenance as a species on the face of the Earth. But that is not all, because a fight can always leave wounds, which, if not adequately healed, can also harm us or even kill us. So, we can add to the ability to defend ourselves, our ability to recover from the fight, to renew ourselves for new battles, to repair even if it leaves us a little different than we were before the fight.
If we study the living beings more closely, at least among the animals, we will realize that, even differently from mammals, or from human beings, even if in a simpler or rudimentary way, each animal species that now inhabits the biosphere presents some type of defense mechanism or reaction in your body. We know that even organisms that live in hostile habitats, under extreme conditions, have some type of defense reaction against aggressions from the external environment, and consequently, some type of repair or tissue regeneration mechanism, more or less efficient.
In this context, we ask ourselves: If the inflammatory process is an essential reaction for survival, why do we often use anti-inflammatory drugs and therapies? The most logical answer would be to relieve short-term suffering and especially pain. A second reason would be the inhibition of a possible amplification and chronification of the process, which can lead to undesirable results and even the loss of function of tissues or organs.
For a long time we have not understood a crucial point in the broader picture that shows us that inhibiting the inflammatory process is not the same as resolving the inflammation. The first option often leaves sequelae or causes undesirable side effects. The second option is probably closer to what we really want to achieve.
In 1984, Serhan et al. 1 isolated trihydroxytetraenes, a novel series of oxygenated derivatives formed from arachidonic acid in human leukocytes. In the same year, the authors demonstrated an interaction between the 5- and 15-lipoxygenase pathways of human leukocytes leads to formation of a new series of oxygenated derivatives of arachidonic acid that could be involved in regulating specific cellular responses. The names lipoxin A (5,6,15L-trihydroxy-7,9,11,13-icosatetraenoic acid) and lipoxin B (5D,14,15L-trihydroxy-6,8,10,12-icosatetraenoic acid) were then proposed for the new compounds. 2 Such mediators, and later resolving, protectins and maresins, the so-called “specialized proresolving mediators” were identified as key elements in resolving the inflammatory process (for a comprehensive review, see Serhan and Levy 3 ). According to that, lipoxins are potent modulators capable of stopping signals of leukocyte infiltration. In fact, some inflammatory mediators are responsible themselves to stimulate the anti-inflammatory ones, for instance, neutrophils exposed to prostaglandin E (PGE)2 induce 15-lipoxigenase to switch the production of leukotriene B4 to lipoxin and stop leukocyte recruitment. Besides, even pharmacological agents such as aspirin itself in low doses can acetylate COX-2 resulting in protectin and resolving mediators. 2
Lipoxins, resolvins, protectins and maresins have been recognized as specialized proresolution mediators acting actively against the inflammatory response with potent anti-inflammatory, tissue-protective, and resolution-stimulating functions, acting as agonists at receptors triggering specific responses about the inflammatory process, mainly in the inhibition of leukocyte traffic, in the catabolism of proinflammatory mediators, in the phagocytosis of apoptotic cells, in the clearance of polymorphonuclear cells (PMNs) and in the removal of cell debris, without further damage by hydrolases and proteases secreted by inflammatory cells, such as PMNs.
COX-2 acetylation is one of the pathways for the production of lipoxin that has an important proresolving role in relation to the inflammatory process, such as inhibiting the transmission of PMN leukocytes to reduce the generation of reactive oxygen species by PMNs, inhibit the proliferation of fibroblasts and matrix metalloprotease (MMP)-3, regulate the activation of nuclear factor-kappa B, and inhibit the production of some proinflammatory mediators.
Likewise, resolvins are mediators that, after binding to specific receptors, are capable of provoking several functions on the resolution process, such as limiting the migration of PMNs, regulating the production of proinflammatory chemokines, increasing the nonphlogistic recruitment of monocytes and phagocytosis.
It is already known that COX-2 knockout mice present impaired resolution of the inflammatory process, showing the need for COX-2 for inflammation to resolve. This indicates that strong nonsteroidal anti-inflammatory drug (NSAID) therapy inhibit inflammation but impairs the resolution of the process. Besides, pharmacological inhibition or gene interruption of COX-2 blocks the resolution lung injuries and the inhibition of COX-2 and PGE2 in some experimental models of collagen-induced arthritis perpetuated inflammation in addition to the reduction LXA4.
In the past 20 years we have been studying the effects and possible mechanisms of action of photobiomodulation especially using laser radiation on several experimental models and clinical conditions involving inflammation. During two decades we have collected evidence showing that, or at least suggest that photobiomodulation can act as a therapy resolving inflammation, and not inhibiting the process, which is a huge difference.
We have demonstrated during the past two decades that photobiomodulation (PBM) is able to reduce or inhibit production of important inflammatory mediators such as IL-1, IL-6, PGE2, and MMPs and significantly reduce leukocyte infiltration in different inflammatory conditions. There are some results that point out to resolution of inflammation instead of inhibition, by PBM. In several studies we have demonstrated that PBM can inhibit neutrophil recruitment or infiltration. 4 –6 Curiously, in some experimental models, PBM performed with laser irradiation could increase COX1 and COX-2 activity, whereas a reduction of main signals was observed. 6 –11
PBM also reduced MMP-3, MMP-9, and MMP-13 gene expression, as well as PGE2 production in collagenase-induced tendinitis, whereas diclofenac only inhibited PGE2 production. Concerned with functional aspects we have demonstrated that PBM significantly preserved mechanical behavior of inflamed tendons, whereas NSAIDs did not and PBM significantly accelerated tendon healing, whereas neither diclofenac nor dexamethasone did. 9
Finally, we recently suggest that photobiomodulation therapy (PBMT) performed with laser irradiation should increase the expression of lipoxin A4 receptors and enhanced production of resolvins. Taken together, the evidence raises the hypothesis that PBM actually resolves and does not inhibit inflammation.