Mechanisms of enhanced lung injury during sepsis

A major complication in sepsis is progressively impaired lung function and susceptibility to intrapulmonary infection. Why sepsis predisposes the lung to injury is not clear. In the current studies, rats were rendered septic by cecal ligation/puncture and evaluated for increased susceptibility to in jury after a direct pulmonary insult (deposition of IgG immune complexes or airway instillation of lipopolysaccharide). By itself, cecal ligation/punc ture did not produce evidence Of lung injury. However, after a direct pulmo nary insult, lung injury in septic animals was significantly enhanced. Enha nced lung injury was associated with increased accumulation of neutrophils in lung, enhanced production of CXC chemokines (but not tumor necrosis fact or-alpha) in bronchoalveolar lavage fluids, and increased expression of lun g vascular intercellular adhesion molecule-1 (ICAM-1). Complement depletion or treatment with anti-C5a abolished all evidence of enhanced lung injury in septic animals. When stimulated in vitro, bronchoalveolar lavage macroph ages from septic animals had greatly enhanced CXC chemokine responses as co mpared with macrophages fr-om sham-operated animals or from septic animals that had been complement depleted. These data indicate that the septic stat e causes priming of lung macrophages and suggest that enhanced lung injury in the septic state is complement dependent and related to increased produc tion of CXC chemokines.