Transient Receptor Potential Channels and Corneal Stromal Inflammation.

Corneal transparency is dependent on the maintenance of the structural integrity and functional activity of its epithelial and endothelial limiting layers and the stroma. Different transient receptor potential (TRP) channel subtypes are expressed in cells and on corneal sensory nerve endings. They serve as sensors and transducers of environmental stimuli that can reduce tissue transparency. These nonselective cation channels are members of a superfamily sharing TRP box protein sequence homology having 6 membrane spanning domains with a pore between the fifth and sixth segments. TRP channels are composed of 4 monomeric subunits that oligomerize in homomeric or heteromeric configurations derived from different TRP subtypes belonging to the same or any of 6 different subfamilies. TRP subfamily members identified in the cornea include those belonging to the canonical, vanilloid, ankyrin, or melastatin subfamilies. In this review, we specifically focus on the functional roles of TRPV1 and TRPA1 expression in the cornea as their activation provides adaptive nociceptive and immune responses to noxious environmental stresses such as irritating ligands, temperature fluctuations, rises in ambient osmolarity, mechanical stretch, decline in pH, and tissue injury. Our previous studies have indicated that TRPV1 and TRPA1 subtypes are potential drug targets for improving corneal wound healing after alkali burns, because injury-induced fibrosis, neovascularization, and inflammation in either TRPV1 or TRPA1 gene-silenced mice were all significantly reduced.

Pathobiology of wound healing after glaucoma filtration surgery.

Conjunctival and subconjunctival fibrogenesis and inflammation are sight compromising side effects that can occur subsequent to glaucoma filtration surgery. Despite initial declines in intraocular pressure resulting from increasing aqueous outflow, one of the activated responses includes marshalling of proinflammatory and pro-fibrogenic cytokine mediator entrance into the aqueous through a sclerostomy window and their release by local cells, as well as infiltrating activated immune cells. These changes induce dysregulated inflammation, edema and extracellular matrix remodeling, which occlude outflow facility. A number of therapeutic approaches are being taken to offset declines in outflow facility since the current procedure of inhibiting fibrosis with either mitomycin C (MMC) or 5-fluorouracil (5-FU) injection is nonselective. One of them entails developing a new strategy for reducing fibrosis induced by wound healing responses including myofibroblast transdifferentiation and extracellular matrix remodeling in tissue surrounding surgically created shunts. The success of this endeavor is predicated on having a good understanding of conjunctival wound healing pathobiology. In this review, we discuss the roles of inappropriately activated growth factor and cytokine receptor linked signaling cascades inducing conjunctival fibrosis/scarring during post-glaucoma surgery wound healing. Such insight may identify drug targets for blocking fibrogenic signaling and excessive fibrosis which reduces rises in outflow facility resulting from glaucoma filtration surgery.

TRPA1 is required for TGF-ß signaling and its loss blocks inflammatory fibrosis in mouse corneal stroma.

We examined whether the loss of transient receptor potential ankyrin 1 (TRPA1), an irritant-sensing ion channel, or TRPA1 antagonist treatment affects the severity inflammation and scarring during tissue wound healing in a mouse cornea injury model. In addition, the effects of the absence of TRPA1 on transforming growth factor ß1 (TGF-ß1)-signaling activation were studied in cell culture. The lack of TRPA1 in cultured ocular fibroblasts attenuated expression of TGF-ß1, interleukin-6, and α-smooth muscle actin, a myofibroblast the marker, but suppressed the activation of Smad3, p38 MAPK, ERK, and JNK. Stroma of the healing corneas of TRPA1(-/-) knockout (KO) mice appeared more transparent compared with those of wild-type mice post-alkali burn. Eye globe diameters were measured from photographs. An examination of the corneal surface and eye globes suggested the loss of TRPA1 suppressed post-alkali burn inflammation and fibrosis/scarring, which was confirmed by histology, immunohistochemistry, and gene expression analysis. Reciprocal bone marrow transplantation between mice showed that KO corneal tissue resident cells, but not KO bone marrow-derived cells, are responsible for KO mouse wound healing with reduced inflammation and fibrosis. Systemic TRPA1 antagonists reproduced the KO phenotype of healing. In conclusion, a loss or blocking of TRPA1 in mice reduces inflammation and fibrosis/scarring in the corneal stroma during wound healing following an alkali burn. The responsible mechanism may include the inhibition of TGF-ß1-signaling cascades in fibroblasts by attenuated TRPA1 signaling. Inflammatory cells are considered to have a minimum involvement in the exhibition of the KO phenotype after injury.