Acute ventilator-induced vascular permeability and cytokine responses in isolated and in situ mouse lungs

Departments of 1 Physiology, 2 Pathology, 3 Microbiology, and 4 Pediatrics, College of Medicine, University of South Alabama, Mobile, Alabama 36688 Submitted 25 March 2004 ; accepted in final form 13 July 2004 To determine the influence of experimental model and strain differences on the relationship of vascular permeability to inflammatory cytokine production after high peak inflation pressure (PIP) ventilation, we used isolated perfused mouse lung and intact mouse preparations of Balb/c and B6/129 mice ventilated at high and low PIP. Filtration coefficients in isolated lungs and bronchoalveolar lavage (BAL) albumin in intact mice increased within 20–30 min after initiation of high PIP in isolated Balb/c lungs and intact Balb/c, B6/129 wild-type, and p55 and p75 tumor necrosis factor (TNF) dual-receptor null mice. In contrast, the cytokine response was delayed and variable compared with the permeability response. In isolated Balb/c lungs ventilated with 25–27 cmH 2 O PIP, TNF- , interleukin (IL)-1 , IL-1 , macrophage inflammatory protein (MIP)-2, and IL-6 concentrations in perfusate were markedly increased in perfusate at 2 and 4 h, but only MIP-2 was detectable in intact Balb/c mice using the same PIP. In intact wild-type and TNF dual-receptor null mice with ventilation at 45 cmH 2 O PIP, the MIP-2 and IL-6 levels in BAL were significantly increased after 2 h in both groups, but there were no differences between groups in the BAL albumin and cytokine concentrations or in lung wet-to-dry weight ratios. TNF- was not be detected in BAL fluids in any group of intact mice. These results suggest that the alveolar hyperpermeability induced by high PIP ventilation occurs very rapidly and is initially independent of TNF- participation and unlikely to depend on MIP-2 or IL-6. ventilator induced lung injury; tumor necrosis factor- ; major intrinsic protein-2; interleukin-6; knockout mice Address for reprint requests and other correspondence: J. C. Parker, Dept. of Physiology, MSB 3024, College of Medicine, Univ. of South Alabama, Mobile, AL 36688 (E-mail: Jparker{at}usouthal.edu )