title: Loss of TRPV4 Function Suppresses Inflammatory Fibrosis Induced by Alkali-Burning Mouse Corneas.
abstract: In humans suffering from pulmonary disease and a mouse model, transient receptor potential vanilloid 4 (TRPV4) channel activation contributes to fibrosis. As a corneal alkali burn induces the same response, we determined if such an effect is also attributable to TRPV4 activation in mice. Accordingly, we determined if the alkali burn wound healing responses in wild-type (WT) mice are different than those in their TRPV4-null (KO) counterpart. Stromal opacification due to fibrosis in KO (n = 128) mice was markedly reduced after 20 days relative to that in WT (n = 157) mice. Immunohistochemistry revealed that increases in polymorphonuclear leukocytes and macrophage infiltration declined in KO mice. Semi-quantitative real time RT-PCR of ocular KO fibroblast cultures identified increases in proinflammatory and monocyte chemoattractant protein-1 chemoattractant gene expression after injury. Biomarker gene expression of fibrosis, collagen1a1 and α-smooth muscle actin were attenuated along with macrophage release of interleukin-6 whereas transforming growth factor β, release was unchanged. Tail vein reciprocal bone marrow transplantation between WT and KO chimera mouse models mice showed that reduced scarring and inflammation in KO mice are due to loss of TRPV4 expression on both corneal resident immune cells, fibroblasts and infiltrating polymorphonuclear leukocytes and macrophages. Intraperitoneal TRPV4 receptor antagonist injection of HC-067047 (10 mg/kg, daily) into WT mice reproduced the KO-phenotype. Taken together, alkali-induced TRPV4 activation contributes to inducing fibrosis and inflammation since corneal transparency recovery was markedly improved in KO mice.
authors.affiliation: Ophthalmology, Wakayama Medical University, Wakayama, Japan.
authors.forename: Yuka
authors.initials: Y
authors.lastname: Okada
authors.affiliation: Ophthalmology, Wakayama Medical University, Wakayama, Japan.
authors.forename: Kumi
authors.initials: K
authors.lastname: Shirai
authors.affiliation: Laboratory Animal Center, Wakayama Medical University, Wakayama, Japan.
authors.forename: Masayasu
authors.initials: M
authors.lastname: Miyajima
authors.affiliation: Wenzhou Medical University School of Ophthalmology and Optometry, Wenzhou, P. R. China.
authors.forename: Peter S
authors.initials: PS
authors.lastname: Reinach
authors.affiliation: Ophthalmology, Wakayama Medical University, Wakayama, Japan.
authors.forename: Osamu
authors.initials: O
authors.lastname: Yamanaka
authors.affiliation: Ophthalmology, Wakayama Medical University, Wakayama, Japan.
authors.forename: Takayoshi
authors.initials: T
authors.lastname: Sumioka
authors.affiliation: Ophthalmology, Wakayama Medical University, Wakayama, Japan.
authors.forename: Masahide
authors.initials: M
authors.lastname: Kokado
authors.affiliation: Ophthalmology, Wakayama Medical University, Wakayama, Japan.
authors.forename: Katsuo
authors.initials: K
authors.lastname: Tomoyose
authors.affiliation: Ophthalmology, Wakayama Medical University, Wakayama, Japan.
authors.forename: Shizuya
authors.initials: S
authors.lastname: Saika
mesh_terms: D000199:Actins / Q000235:genetics; D000468:Alkalies / Q000494:pharmacology*; D000818:Animals; D003315:Cornea / Q000187:drug effects / Q000473:pathology*; D003318:Corneal Opacity / Q000150:complications; D005126:Eye Burns / Q000139:chemically induced* / Q000150:complications / Q000235:genetics / Q000473:pathology*; D005355:Fibrosis; D005786:Gene Expression Regulation / Q000187:drug effects; D055786:Gene Knockout Techniques; D007249:Inflammation / Q000473:pathology; D015850:Interleukin-6 / Q000235:genetics; D051379:Mice; D050916:TRPV Cation Channels / Q000172:deficiency* / Q000235:genetics* / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000235:genetics; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics
chemical_list: D000199:Actins; D000468:Alkalies; D015850:Interleukin-6; D050916:TRPV Cation Channels; D016212:Transforming Growth Factor beta; C486576:Trpv4 protein, mouse; D042461:Vascular Endothelial Growth Factor A; C544013:alpha-smooth muscle actin, mouse