Heme Oxygenase-2 as a novel target to treat inflammation and chronic neuropathic pain associated with corneal injury and surgery

Corneal refractive surgery aims at correcting alteration of the shape of the cornea correlated with myopia, hyperopia and astigmatism. More than 12 million patients have undergone refractive surgery since it was approved (see http://www. laser-eye-surgery statistics.com/). Laser-assisted in situ keratomileusis (LASIK) and photorefractive keratectomy (PRK) are the most used techniques to perform experimental corneal surgery. Several studies demonstrated that after epithelial removal (first step of refractive surgery) an inflammatory response arises and corneal subbasal nerve density does not recover for up to five years. Furthermore, the number of stromal nerves decreases by nearly 90% after LASIK leading to possible complications. One of the most notable adverse effects of refractive surgery correlated with the trans-section of basal nerve, is pain, which typically occurs within the first 72 h after surgery. Topical ocular nonsteroidal anti-inflammatory drugs (NSAIDs) has demonstrated efficacy in controlling pain after surgery and they are commonly used during the postoperative period. However, some studies reported delayed epithelial wound healing as most notable side effect following topic administration of this class of drugs. During the inflammatory response the epithelial cells activate a series of endogenous protective mechanisms in the attempt to reduce and/or limitate the propagation of the inflammatory response. Among these mechanisms, the heme oxygenases systems seem to play a major role. In the recent years the heme oxygenase system (HO-1 and HO-2) has emerged as a fundamental endogenous cytoprotective and anti-inflammatory system in many tissues. It is readily upregulated in response to injury and its activity (heme degradation to bilirubin an carbon monoxide) attenuates tissue damage with significant reductions in inflammatory events including leukocyte adhesion and migration, and production of inflammatory cytokines. Furthermore HO has been shown to provide neuroprotection and participates to neuronal development in a number of models. We evaluated the role of HO-1 and HO-2 in the corneal inflammatory and reparative response to injury and we assessed the putative mechanisms underlying the cytoprotective/anti-inflammatory function of the HO system in the cornea. Specifically we determined the spatial and temporal changes in HO-1 and HO-2 expression and HO activity in response to injury and correlate these changes to cell infiltrate and wound closure. Furthermore, we determined whether supplementation of HO by-products (CO and/or biliverdin) rescue the cornea from the aberrant inflammatory and reparative response in a model where the HO system is impaired.