Differential Role of CD18 Integrins in Mediating Lung Neutrophil Sequestration and Increased Microvascular Permeability Induced byEscherichia coliin Mice

Abstract

The in vivo contributions of CD18 integrin-dependent and -independent mechanisms in mediating the increases in lung neutrophil (polymorphonuclear leukocyte; PMN) sequestration and microvascular permeability are not well understood. We determined the time course of these responses to Gram-negative sepsis in the mouse lung and addressed the specific contributions of CD18 integrins and ICAM-1. PMN sequestration in the lung was assessed by morphometric analysis, and transalveolar PMN migration was assessed by bronchoalveolar lavage. Lung tissue PMN number increased by 6-fold within 1 h after i.p. Escherichia 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 airspace 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 tissue PMN sequestration and migration; however, peak responses at 3 and 6 h were inhibited by 40%, indicating that only a small component of PMN sequestration and migration was CD18 dependent at these times. In contrast to the time-dependent decreased role of CD18 integrins in mediating PMN sequestration and migration, CD18 and ICAM-1 blockade prevented the increase in lung microvascular permeability and edema formation at all times after E. coli challenge. Thus, Gram-negative sepsis engages CD18/ICAM-1-independent mechanisms capable of the time-dependent amplification of lung PMN sequestration 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.

Inefficiency of C3H/HeN Mice to Control Chlamydial Lung Infection Correlates with Downregulation of Neutrophil Activation During the Late Stage of Infection

“…Firm adhesion and transmigration is predominantly dependent on  2 -integrins on PMN interaction with their counterreceptors, believed to be predominantly ICAM-1 (8)(9)(10). Mice receiving anti-CD11b antibody and/or anti-ICAM-1 antibody demonstrated a dramatic reduction in pulmonary neutrophils recruitment compared with control mice (24). In the present study, we observed a significant increase in the expression of selectins, ICAM-1 and CD11b in C3H and B6 mice following infection with Cm on day 7 postinfection.…”

Blockade of Class IA Phosphoinositide 3-Kinase in Neutrophils Prevents NADPH Oxidase Activation- and Adhesion-dependent Inflammation

“…Purity of PMN preparations as assessed by examination of HEMA3 (Fisher)-stained cytospin (Shandon, Pittsburgh, PA) preparations (27) was ϳ90 -95% and viability assessed by Trypan blue exclusion was Ͼ95%.…”

“…Pulmonary Microvascular Permeability and Edema Formation-K f,c was measured to determine pulmonary microvascular permeability to liquid and the rate of edema formation was continuously monitored by determining lung wet weight changes as described (25,27).…”

“…Lung PMN Sequestration-Sequestration of PMNs in lung tissue was assessed by determining myeloperoxidase (MPO) activity in lungs and by morphometrically quantifying PMN infiltration as described (2,27).…”

“…Results are representative of three independent experiments. ment, PMN number in lungs was measured as described (27). Lung tissue PMN counts increased from 551.3 Ϯ 52.1 cells/30 mm 2 lung tissue to 3395.3 Ϯ 73.8 cells/30 mm 2 1 h after TNF-␣ challenge in WT mice.…”