RT Journal Article
SR Electronic
T1 Actin fence therapy with exogenous V12Rac1 protects against Acute Lung Injury
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2021.01.20.427469
DO 10.1101/2021.01.20.427469
A1 Galina A. Gusarova
A1 Shonit R. Das
A1 Mohammad N. Islam
A1 Kristin Westphalen
A1 Guangchun Jin
A1 Igor O.Shmarakov
A1 Li Li
A1 Sunita Bhattacharya
A1 Jahar Bhattacharya
YR 2021
UL http://biorxiv.org/content/early/2021/01/21/2021.01.20.427469.abstract
AB High mortality in Acute Lung Injury (ALI) results from sustained proinflammatory signaling by alveolar receptors, such as TNFα receptor type 1 (TNFR1). Factors that determine the sustained signaling are not known. Unexpectedly, optical imaging of live alveoli revealed a major TNFα-induced surge of alveolar TNFR1 due to a Ca2+-dependent mechanism that decreased the cortical actin fence. Mouse mortality due to inhaled LPS was associated with cofilin activation, actin loss and the TNFR1 surge. The constitutively active form of the GTPase, Rac1 (V12Rac1), given intranasally as a non-covalent construct with a cell-permeable peptide, enhanced alveolar F-actin and blocked the TNFR1 surge. V12Rac1 also protected against ALI-induced mortality resulting from intranasal (i.n.) instillation of LPS, or of Pseudomonas aeruginosa. We propose a new therapeutic paradigm in which actin enhancement by exogenous Rac1 strengthens the alveolar actin fence, protecting against proinflammatory receptor hyperexpression, hence blocking ALI.Competing Interest StatementThe authors have declared no competing interest.