title: Gprc5a-deficiency confers susceptibility to endotoxin-induced acute lung injury via NF-κB pathway.
abstract: Susceptibility to acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) varies greatly among patients in sepsis/septic shock. The genetic and biochemical reasons for the difference are not fully understood. G protein coupled receptor family C group 5 member A (GPRC5A), a retinoic acid target gene, is predominately expressed in the bronchioalveolar epithelium of lung. We hypothesized that Gprc5a is important in controlling the susceptibility to ALI or ARDS. In this study, we examined the susceptibility of wild-type and Gprc5a-knockout (ko) mice to induced ALI. Administration of endotoxin LPS induced an increased pulmonary edema and injury in Gprc5a-ko mice, compared to wild-type counterparts. Consistently, LPS administration induced higher levels of inflammatory cytokines (IL-1β and TNFα) and chemokine (KC) in Gprc5a-ko mouse lungs than in wild-type. The enhanced pulmonary inflammatory responses were associated with dysregulated NF-κB signaling in the bronchioalveolar epithelium of Gprc5a-ko mouse lungs. Importantly, selective inhibition of NF-κB through expression of the super-repressor IκBα in the bronchioalveolar epithelium of Gprc5a-ko mouse lungs alleviated the LPS-induced pulmonary injury, and inflammatory response. Thus, Gprc5a is critical for lung homeostasis, and Gprc5a deficiency confers the susceptibility to endotoxin-induced pulmonary edema and injury, mainly through NF-κB signaling in bronchioalveolar epithelium of lung.
authors.affiliation: a Department of Pathophysiology; Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education ; Shanghai Jiao Tong University School of Medicine ; Shanghai , China.
authors.forename: Yueling
authors.initials: Y
authors.lastname: Liao
authors.forename: Hongyong
authors.initials: H
authors.lastname: Song
authors.forename: Dongliang
authors.initials: D
authors.lastname: Xu
authors.forename: Huike
authors.initials: H
authors.lastname: Jiao
authors.forename: Feng
authors.initials: F
authors.lastname: Yao
authors.forename: Jingyi
authors.initials: J
authors.lastname: Liu
authors.forename: Yadi
authors.initials: Y
authors.lastname: Wu
authors.forename: Shuangshuang
authors.initials: S
authors.lastname: Zhong
authors.forename: Huijing
authors.initials: H
authors.lastname: Yin
authors.forename: Shuli
authors.initials: S
authors.lastname: Liu
authors.forename: Xiaofei
authors.initials: X
authors.lastname: Wang
authors.forename: Wenzheng
authors.initials: W
authors.lastname: Guo
authors.forename: Beibei
authors.initials: B
authors.lastname: Sun
authors.forename: Baohui
authors.initials: B
authors.lastname: Han
authors.forename: Y Eugene
authors.initials: YE
authors.lastname: Chin
authors.forename: Jiong
authors.initials: J
authors.lastname: Deng
mesh_terms: D055371:Acute Lung Injury / Q000139:chemically induced* / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D000818:Animals; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D004731:Endotoxins; D020672:I-kappa B Proteins / Q000235:genetics / Q000378:metabolism; D018836:Inflammation Mediators / Q000378:metabolism; D008168:Lung / Q000378:metabolism* / Q000473:pathology; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D011014:Pneumonia / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D011654:Pulmonary Edema / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D043562:Receptors, G-Protein-Coupled / Q000172:deficiency* / Q000235:genetics; D020545:Respiratory Mucosa / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction; D013997:Time Factors; D015854:Up-Regulation
chemical_list: D016207:Cytokines; D004731:Endotoxins; C554251:GPRC5A protein, mouse; C083487:I kappa B beta protein; D020672:I-kappa B Proteins; D018836:Inflammation Mediators; D016328:NF-kappa B; D043562:Receptors, G-Protein-Coupled; C044101:endotoxin, Escherichia coli
keywords: Gprc5a; NF-κB; acute lung injury; animal model; endotoxin; inflammation