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.
Highlights
Mechanical ventilation can protect injured lungs and improve hypoxemia, but can cause ventilator-induced lung injury (VILI) because of different overlapping interactions, including: lung stress due to increased transpulmonary pressure; overdistension caused by high tidal volume; cyclic closing and opening of peripheral airways during tidal breath; and local and systemic release of lung-borne inflammatory mediators [1].Double-stranded RNA can be produced by many viruses during their replicative cycles [2]
In the poly(I:C) + MTV group, the lung injury score was markedly increased (Figure 2). These results indicated that mechanical ventilation with a tidal volume of 10 ml/kg for 4 h alone had no significant effects on normal lung, but amplified preexisting lung injury induced by intratracheal poly(I:C)
We show that integrin β3 is required for the amplification of inflammation and lung injury mediated through WNT-induced secreted protein 1 (WISP1) when MTV is combined with intratracheal poly(I:C) treatment in mice
Summary
Mechanical ventilation can protect injured lungs and improve hypoxemia, but can cause ventilator-induced lung injury (VILI) because of different overlapping interactions, including: lung stress due to increased transpulmonary pressure; overdistension caused by high tidal volume; cyclic closing and opening of peripheral airways during tidal breath; and local and systemic release of lung-borne inflammatory mediators [1].Double-stranded RNA (dsRNA) can be produced by many viruses during their replicative cycles [2]. Polyinosinic- polycytidylic acid (poly(I:C)), a synthetic analog of dsRNA, initiates cascades of phosphorylation and transcriptional activation events associated with innate immunity. Poly(I:C) can induce loss of epithelial integrity, as well as the production of characteristic inflammatory cytokines and chemokines. It is a critical component in the modulation of infection-associated inflammatory diseases [3]. Moderate tidal volume mechanical ventilation (MTV) has been reported to function as a cofactor in the initiation of acute lung injury (ALI) by amplifying the inflammatory response induced by pathogens [4,5]. A study by Chun CD et al [6] found that mechanical ventilation at 10 ml/kg for 6 h in mice augmented poly(I:C)-induced cytokine release, polymorphonuclear (PMN) counts, 70-kD fluorescein isothiocyanate dextran concentration, and IgM level in bronchoalveolar lavage fluid (BALF). The amplification of the inflammatory response by MTV is related to the production of endogenous ligands, which are recognized by MyD88- dependent transmembrane receptors
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