Gprc5a-defiency Exacerbates Silica-induced Fibrosis And Tissue Damages

Objective: Chronic respiratory exposure to particulate matter（PM） is associated with increased incidence of respiratory diseases including lung cancers. Inhaled PM such as silica may trigger pulmonary inflammation, fibrosis, and even lung cancer via injury to airway epithelial cells. The progression of silicosis is mainly determined by extrinsic factors such as the amount of crystalline silica; however, intrinsic factors such as genetic background also influence the susceptibility to silicosis. G protein coupled receptor family C group 5 member A（GPRC5A）, a retinoic acid-inducible gene, is predominately expressed in bronchio-alveolar epithelium of lung, indicating it is important for lung homeostasis. Taking advantage of the Gprc5 a knock out mouse model, we tried to identify whether Gprc5 a deficency could result in hyper-susceptibility to inhaled silica in mice model and the mechanism behind it.Materials and methods: 1. We compared the inflammatory and fibrotic response of wild-type and Gprc5 a knockout mice to experimental PM（silica, Si O2）. 2. We examined the epithelial changes induced by silica in Gprc5 a knockout mouse tracheal epithelial cells(from a Gprc5a^-/- mouse) vs Gprc5a^+/+mouse tracheal epithelial cells（from a wide-type mouse）. 3. We examined the macorphages activating and programming induced by silica in Gprc5a^-/- and Gprc5a^+/+ mice model. 4. We further explored GPRC5 A expressing profile in human lung cancers.Results: 1. We found that exposure of silica elicited an increased pulmonary inflammation and collagen deposition in Gprc5a^-/- mouse lungs compared to wild-type counterparts. 2. Silica exposure induced more epithelial-mesenchymal transition characters, such as reduced E-cadherin and increased vimentin, in Gprc5a^-/-mouse lungs than in wild-type ones. 3. Silica exposure resulted in an increased macrophages infiltration in Gprc5a^-/- mouse lungs, dominant in M2 programming, which correlates with increased expression of chemokines. 4. Silica-induced fibrosis was associated with obvious preneoplasia.Conclusions: Gprc5 a deficiency exacerbates silica-induced inflammatory response, fibrosis and tissue damages via pithelial-mesenchymal transition and type-2 macrophages activation.