title: MECHANICAL VENTILATION AUGMENTS POLY(I:C)INDUCED LUNG INJURY VIA A WISP1-INTEGRIN β3 DEPENDENT PATHWAY IN MICE.
abstract: Mechanical ventilation can improve hypoxemia, but can also cause the so-called ventilator-induced lung injury (VILI). Polyinosinic-polycytidylic acid (poly(I:C)), an analogue of natural double strand RNA virus, can induce lung inflammation. The purpose of this study was to determine whether moderate tidal volume mechanical ventilation (MTV) augments Poly(I:C)-induced lung injury, and if so, the mechanism responsible for it. Poly(I:C) (2μg/g) were instilled intratracheally in C57BL/6J wide type (WT) mice. They were then randomized to MTV (10ml/kg tidal volume) or spontaneous breath. Lung tissues and bronchoalveolar lavage fluid (BALF) were collected 4h later for various measurements. Our results showed that MTV did not cause significant injury in normal lungs, but augmented Poly(I:C)-induced lung injury. The expression level of WNT-induced secreted protein 1 (WISP1) was consistent with lung injury, and the amplification of lung injury by MTV can be alleviated by anti-WISP1 antibody treatment. MTV further increased Poly(I:C)-induced integrin β3 expression in the lung. And co-immunoprecipitation (Co-IP) results suggested there was an interaction between WISP1 and β3. WISP1 significantly increased Poly(I:C)-induced TNF-α production in macrophages isolated from WT mice but not in macrophages isolated from β3 knock-out mice. Co-treatment with WISP1 and Poly(I:C) markedly increased the phosphorylation of extracellular signal-related kinase (ERK) in macrophages. Pretreating macrophages with an ERK inhibitor, U0126, dose-dependently antagonized WISP's synergistic effect on Poly(I:C)-induced TNF-α release. In conclusion, MTV exaggerates Poly(I:C)-induced lung injury in a WISP1 and integrin β3 dependent manner, involving, at least part, the activation of the ERK pathway. The WISP1-integrin β3 pathway could be an important target for novel therapy.
authors.affiliation: Department of Anesthesiology, Shanghai East Hospital, TongJi University, Shanghai, China.
authors.forename: Shuqing
authors.initials: S
authors.lastname: Jin
authors.affiliation: Department of Anesthesiology, Shanghai East Hospital, TongJi University, Shanghai, China.
authors.forename: Zhixia
authors.initials: Z
authors.lastname: Chen
authors.affiliation: Department of Anesthesiology, Shanghai East Hospital, TongJi University, Shanghai, China.
authors.forename: Xibing
authors.initials: X
authors.lastname: Ding
authors.affiliation: Department of Anesthesiology, Shanghai East Hospital, TongJi University, Shanghai, China.
authors.forename: Xiang
authors.initials: X
authors.lastname: Zhao
authors.affiliation: Department of Anesthesiology, Shanghai East Hospital, TongJi University, Shanghai, China.
authors.forename: Xi
authors.initials: X
authors.lastname: Jiang
authors.affiliation: Department of Anesthesiology, Shanghai East Hospital, TongJi University, Shanghai, China.
authors.forename: Yao
authors.initials: Y
authors.lastname: Tong
authors.affiliation: Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of American.
authors.forename: Timothy R
authors.initials: TR
authors.lastname: Billiar
authors.affiliation: Department of Anesthesiology, Shanghai East Hospital, TongJi University, Shanghai, China.
authors.forename: Quan
authors.initials: Q
authors.lastname: Li