Pentraxin 3 (PTX3) is an acute-phase protein, which can be produced by a variety of tissue cells at the site of infection or inflammation. It plays an important role in innate immunity in the lung and in mediating acute lung injury. The aim of this study was to determine the effect of mechanical ventilation on PTX3 expression in multiple lung injury models. Male Sprague-Dawley rats were challenged with intravenous injection of lipopolysaccharide (LPS) or hemorrhage followed by resuscitation. The animals were then subjected to either relatively higher (12 ml/kg) or lower (6 ml/kg, positive end-expiratory pressure of 5 cmH₂O) volume ventilation for 4 h. High volume ventilation significantly enhanced PTX3 expression in the lung, either alone, or in combination with LPS or hemorrhage. A significant increase of PTX3 immunohistochemistry staining in the lung was seen in all injury groups. The PTX3 expression was highly correlated with the severity of lung injury determined by blood gas, lung elastance, and wet/dry ratio. To determine the effects of hemorrhagic shock, LPS or injurious ventilation (25 ml/kg) alone on PTX3 expression, another group of rats were studied. Injurious ventilation significantly damaged the lung and increased PTX3 expression. A local expression of PTX3 induced by high volume ventilation either alone, or in combination with other pathological conditions suggests that it may be an important mediator in ventilator-induced lung injury.