title: Contributions of TRPV1, endovanilloids, and endoplasmic reticulum stress in lung cell death in vitro and lung injury.
abstract: Endogenous agonists of transient receptor potential vanilloid-1 (TRPV1) (endovanilloids) are implicated as mediators of lung injury during inflammation. This study tested the hypothesis that endovanilloids produced following lipopolysaccharide (LPS) treatment activate TRPV1 and cause endoplasmic reticulum stress/GADD153 expression in lung cells, representing a mechanistic component of lung injury. The TRPV1 agonist nonivamide induced GADD153 expression and caused cytotoxicity in immortalized and primary human bronchial, bronchiolar/alveolar, and microvascular endothelial cells, proportional to TRPV1 mRNA expression. In CF-1 mice, Trpv1 mRNA was most abundant in the alveoli, and intratracheal nonivamide treatment promoted Gadd153 expression in the alveolar region. Treatment of CF-1 mice with LPS increased Gadd153 in the lung, lactate dehydrogenase (LDH) in bronchoalveolar lavage (BAL) fluid, and lung wet-to-dry weight ratio. Cotreating mice with LPS and the TRPV1 antagonist LJO-328 reduced Gadd153 induction and LDH in BAL but did not inhibit increases in lung wet-to-dry ratio. In Trpv1(-/-) mice treated with LPS, Gadd153 induction and LDH in BAL were reduced relative to wild-type mice, and the wet-to-dry weight ratios of lungs from both wild-type and Trpv1(-/-) mice decreased. Organic extracts of blood collected from LPS-treated mice were more cytotoxic to TRPV1-overexpressing cells compared with BEAS-2B cells and extracts from control mice, however, most pure endovanilloids did not produce cytotoxicity in a characteristic TRPV1-dependent manner. Collectively, these data indicate a role for TRPV1, and endogenous TRPV1 agonists, in ER stress and cytotoxicity in lung cells but demonstrate that ER stress and cytotoxicity are not essential for pulmonary edema.
authors.affiliation: Department of Pharmacology and Toxicology, University of Utah, Salt Lake City, UT 84112, USA.
authors.forename: Karen C
authors.initials: KC
authors.lastname: Thomas
authors.forename: Jessica K
authors.initials: JK
authors.lastname: Roberts
authors.forename: Cassandra E
authors.initials: CE
authors.lastname: Deering-Rice
authors.forename: Erin G
authors.initials: EG
authors.lastname: Romero
authors.forename: Randal O
authors.initials: RO
authors.lastname: Dull
authors.forename: Jeewoo
authors.initials: J
authors.lastname: Lee
authors.forename: Garold S
authors.initials: GS
authors.lastname: Yost
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Reilly
mesh_terms: D000818:Animals; D001980:Bronchi / Q000378:metabolism; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D002211:Capsaicin / Q000031:analogs & derivatives / Q000494:pharmacology; D016923:Cell Death; D002460:Cell Line; D002461:Cell Line, Transformed; D002478:Cells, Cultured; D059865:Endoplasmic Reticulum Stress / Q000235:genetics*; D006801:Humans; D007249:Inflammation / Q000378:metabolism; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008168:Lung / Q000166:cytology / Q000378:metabolism; D055370:Lung Injury / Q000503:physiopathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011650:Pulmonary Alveoli / Q000378:metabolism*; D011654:Pulmonary Edema / Q000378:metabolism; D050916:TRPV Cation Channels / Q000819:agonists* / Q000235:genetics; D051742:Transcription Factor CHOP / Q000235:genetics / Q000378:metabolism
chemical_list: C497250:Ddit3 protein, mouse; D008070:Lipopolysaccharides; D050916:TRPV Cation Channels; C493921:TRPV1 protein, mouse; D051742:Transcription Factor CHOP; D007770:L-Lactate Dehydrogenase; D002211:Capsaicin; C040937:nonivamide