Differential role of CD18 integrins in mediating lung neutrophil sequestration and increased microvascular permeability induced by Escherichia coli in mice

The in vivo contributions of CD18 integrin-dependent and -independent mecha nisms in mediating the increases in lung neutrophil (polymorphonuclear leuk ocyte; PMN) sequestration and microvascular permeability are not well under stood. We determined the time course of these responses to Gram-negative se psis in the mouse lung and addressed the specific contributions of CD18 int egrins and ICAM-1 PMN sequestration in the lung was assessed by morphometri c analysis, and transalveolar PMN migration was assessed by bronchoalveolar lavage. Lung tissue PMN number increased by 6-fold within I h after i.p. E scherichia coli challenge; this value peaked at 3 h (7-fold above control) and decreased at 12 h (3.5-fold above control). PMN migration into the airs pace was delayed; the value peaked at 6 h and remained elevated up to 12 h. Saturating concentrations of anti-CD18 and anti-ICAM-1 mAbs reduced lung t issue PMN sequestration and migration; however, peak responses at 3 and 6 h were inhibited by 40%, indicating that only a small component of PMN seque stration and migration was CD18 dependent at these times. In contrast to th e time-dependent decreased role of CD18 integrins in mediating PMN sequestr ation and migration, CD18 and ICAM-1 blockade prevented the increase in lun g microvascular permeability and edema formation at all times after E. coli challenge. Thus, Gram-negative sepsis engages CD18/ICAM-1-independent mech anisms capable of the time-dependent amplification of lung PMN sequestratio n and migration. The increased pulmonary microvascular permeability induced by E. coli is solely the result of engagement of CD18 integrins even when PMN accumulation and migration responses are significantly CD18 independent .