In the current study, MTV did not cause ALI, but exacerbated CLP-mediated increases in alveolar-capillary permeability and indices of pulmonary inflammation (histopathology, cytokines, chemokines, neutrophil influx and activation of MAPK) in wildtype mice: the effects of this two-hit model were completely abrogated in TLR4 null mutants and partially inhibited by neutralizing antibodies to either WISP1 or integrin β5. Here, TLR4 is linked to acute respiratory distress syndrome.