Lfa-1 and Mac-1 Mediate Pulmonary Recruitment of Neutrophils and Tissue Damage in Abdominal Sepsis

Abstract

Neutrophil-mediated lung damage is an insidious feature in septic patients, although the adhesive mechanisms behind pulmonary recruitment of neutrophils in polymicrobial sepsis remain elusive. The aim of the present study was to define the role of lymphocyte function antigen-1 (LFA-1) and membrane-activated complex 1 (Mac-1) in septic lung injury. Pulmonary edema, bronchoalveolar infiltration of neutrophils, levels of myeloperoxidase, and CXC chemokines were determined after cecal ligation and puncture (CLP). Mice were treated with monoclonal antibodies directed against LFA-1 and Mac-1 before CLP induction. Cecal ligation and puncture induced clear-cut pulmonary damage characterized by edema formation, neutrophil infiltration, and increased levels of CXC chemokines in the lung. Notably, immunoneutralization of LFA-1 or Mac-1 decreased CLP-induced neutrophil recruitment in the bronchoalveolar space by more than 64%. Moreover, functional inhibition of LFA-1 and Mac-1 abolished CLP-induced lung damage and edema. However, formation of CXC chemokines in the lung was intact in mice pretreated with the anti-LFA-1 and anti-Mac-1 antibodies. Our data demonstrate that both LFA-1 and Mac-1 regulate pulmonary infiltration of neutrophils and lung edema associated with abdominal sepsis. Thus, these novel findings suggest that LFA-1 or Mac-1 may serve as targets to protect against lung injury in polymicrobial sepsis.

Direct in vivo observations of P-selectin glycoprotein ligand-1-mediated leukocyte–endothelial cell interactions in the pulmonary microvasculature in abdominal sepsis in mice

“…The systemic inflammatory response causes tissue damage in the lung, which is the most insidious component in sepsis due to compromised gas exchange [4,21]. Convincing evidence has demonstrated that neutrophil recruitment is a critical component in the pathophysiology of septic lung injury [22][23].…”

“…It is well established that pulmonary infiltration of neutrophils is a rate-limiting step in septic lung injury. For example, depletion of neutrophils or immunoneutralization of specific adhesion molecules, including P-selectin glycoprotein ligand-1 (PSGL-1), LFA-1 and Mac-1 are effective ways to protect against sepsis-induced lung injury [4][5]. Although the therapeutic potential of inhibiting certain adhesion molecules is well documented, the detailed role of these molecules in regulating leukocyte-endothelium interactions in the lung microcirculation in sepsis is not known.…”

“…Polymicrobial sepsis was induced by cecal ligation and puncture (CLP) as described previously [4]. In brief, the abdomen was opened, the exposed cecum was filled with feces by milking stool backwards from the ascending colon, and a ligature was placed below the ileocecal valve.…”

“…However, the recruitment process of leukocytes in the lung is more complex and less studied than in other organs. Under homeostatic conditions, most 4 neutrophils, which have a diameter larger than that of pulmonary capillaries, must deform in order to pass through the pulmonary microcirculation [17][18]. Upon activation neutrophil stiffness increases.…”

Targeting CD162 protects against streptococcal M1 protein-evoked neutrophil recruitment and lung injury

“…Lung tissue was thawed and homogenized in 1 ml 0.5% hexadecyltrimethylammonium bromide. Samples were freezethawed, after which, the MPO activity of the supernatant was determined spectrophotometrically as the MPO-catalyzed change in absorbance in the redox reaction of H2O2 (450 nm; with a reference filter, 540 nm; 25°C), as described previously (5). Values were expressed as MPO units per gram tissue.…”