This study reviewed the pathophysiological examination findings of corneal alkali-burn injury model representing a severe corneal tissue injury as a refractory disease state associated with impaired corneal wound healing and proposal of new treatment strategies as well as the pathophysiological analyses of a mouse model of neuroparalytic keratopathy representing impaired corneal homeostasis due to a sensory nerve injury and results from research on new treatment strategies. Previous studies have not reported many cases of these disease conditions; therefore, detailed pathophysiological analyses are largely dependent on animal models.
The first-line treatment of a severe corneal alkali-burn injury at a primary care facility includes thorough irrigation, corneal and conjunctival inflammation suppression, and subsequent ocular surface fibrotic scarring control during the healing process. Studies on animal models have demonstrated that transforming growth factor β signals play central roles in inflammation and fibrotic scarring during a corneal injury; however, various crosstalk factors are further regulated. This study describes the results of experimental analyses performed to elucidate the roles of transient receptor potential (TRP) ion channels, which are a group of plasma membrane ion channels among the crosstalk factors, and the possibility of therapeutic effects with the regulation of TRP ion channels. TRP ion channels are involved in nociceptive receptors with nonselective cation channel functions that are permeable to calcium ions and form a family of channel-type receptors, each with specific ligands or activating temperature bands. TRP vanilloid 1 (TRPV1), TRPV4, or TRP ankyrin 1 (TRPA1) knockout (KO) mice showed reduced corneal inflammation and fibrotic scarring after exposure to an alkali. Reciprocal bone marrow transplantation experiments between KO and wild-type mice showed that the phenotypes of TRPV1-KO and TRPA1-KO mice were more dependent on tissue resident cells than on bone marrow-derived cells, whereas the phenotypes of TRPV4-KO mice were equally dependent on both. Lastly, these results were reproduced with the systemic administration of small molecule inhibitors, thus suggesting the possibility of new treatment strategies.
Subsequently, the pathophysiological analysis results of a mouse model of neuroparalytic keratopathy representing a disease state of refractory impaired corneal wound healing are compared with the results reported in the literature. A strong intracranial coagulation of the first branch of the trigeminal nerve in mice resulted in spontaneous corneal ulceration. Conversely, when the coagulation level of the first branch of the trigeminal nerve decreased, healing was delayed after the development of epithelial defects, although spontaneous lesions did not develop in the cornea. In such cases, the nerves remained in the limbus. At this stage, the decrease in the expression of stem cell markers of limbal epithelium basal cells and nerve growth factors (NGFs) and the inhibition of cell proliferation were observed. Decreased expression of TRPV4 mRNA was detected in the corneas during the process of wound healing at this stage. Similar limbal epithelial stem cell damage was observed during the process of corneal epithelial wound healing in TRPV4-KO mice, and TRPV4 gene transfer into the intracranial trigeminal nerve using adeno-associated viral vectors rescued the phenotype of KO mice. Additionally, TRPV4 gene transfer rescued delayed corneal epithelial damage in trigeminal neuropathy models. In TRPV4-KO mice, an increased expression of NGF was observed in transfected ganglia and cultured corneal epithelial cells when trigeminal ganglia transfected with or without the TRPV4 gene were cocultured with corneal epithelial cells. The efficacy of the local administration of NGF as a drug for neuroparalytic keratopathy was recognized worldwide, and its clinical use was approved. The challenge of identifying humoral factors responsible for the communication between ganglia and epithelial cells is needed to further understand this phenomenon in vivo and to develop future treatment strategies.
This study demonstrated that cell involved in inflammation and fibrotic scarring in a corneal alkali-burn injury and signals derived from TRP ion channels regulate the wound healing process in the trigeminal nerve in a model of neuroparalytic keratopathy. In the latter disease state, some humoral factors from the trigeminal nerve were determined as fulfilling important roles in the maintenance of limbal stem cells as well as homeostasis in the corneal epithelium. Therapeutic strategies targeting TRP ion channel signals and related factors are expected to improve the prognosis of refractory diseases associated with impaired corneal wound healing.
Nippon Ganka Gakkai Zasshi (J Jpn Ophthalmol Soc) 124: 185-219, 2020.