Pulmonary edema induced by phagocytosing neutrophils. Protective effect of monoclonal antibody against phagocyte CD18 integrin.

Abstract

We studied the changes in pulmonary hemodynamics and lung wet weight induced with opsonized zymosan (OZ) in isolated guinea pig lungs perfused with Ringer-albumin solution containing neutrophils (PMNs). Addition of OZ to the PMN-perfused lungs caused pulmonary vasoconstriction and weight gain; neither OZ nor PMNs added individually to the perfusate altered pulmonary vasomotor tone or wet weight. The steady gain in lung weight by 1,588 +/- 464 mg over the 45-minute study period was associated with pulmonary capillary hypertension and an increase in the capillary filtration coefficient, indicative of increased lung vascular permeability. These responses may not be due to generation of oxygen radicals, because the alterations in pulmonary hemodynamics and lung weight were not reduced by addition of superoxide dismutase, catalase, or superoxide dismutase plus catalase. We examined the basis of the PMN-mediated effects by layering PMNs on bovine pulmonary artery endothelial monolayers. Challenge with OZ resulted in increased endothelial permeability to 125I-albumin. The monoclonal antibody IB4 (directed against CD18, the common beta-subunit of structurally related adhesion receptors on phagocytes, LFA-1, Mac-1, and P150,95) prevented the OZ-mediated increase in PMN adherence to endothelial cells and the increase in endothelial permeability to 125I-albumin. IB4 also inhibited the lung weight gain mediated by the OZ-stimulated PMNs in intact lungs. The protective effect of IB4 could be ascribed neither to inhibition of uptake of OZ by PMNs nor to inhibition of release of oxygen radicals, myeloperoxidase, and elastase.(ABSTRACT TRUNCATED AT 250 WORDS)

Dynamics of neutrophil extravasation and vascular permeability are uncoupled during aseptic cutaneous wounding

“…The observed uncoupling of neutrophil and macromolecular transport across endothelium is in apparent conflict with previous studies that demonstrate a primary role of neutrophils in altering vascular permeability (2,14,20,43,47,49). We believe that this difference can be attributed to variation in the extent of neutrophil activation in aseptic versus infected wounds.…”

“…*P Ͻ 0.05 with respect to thrombin group; n ϭ 5 to 9 in each group. and ␤ 2 -integrin engagement (2,14,20) can trigger alterations in vascular permeability that contribute to vascular injury. For example, in chronic wounds, unresolved inflammation is associated with excessive recruitment of neutrophils, phagocytic activation, and a delay in apoptosis that can prolong the inflammatory response, leading to neutrophil-dependent tissue edema and injury (20,29,33).…”

“…Numerous studies have demonstrated a neutrophildependent alteration in vascular permeability in both in vitro and in vivo experimental models (2,14,20,43,47,49). However, many of these studies have relied on the direct activation of neutrophils by addition of chemokines that can signal activation of ␤ 2 -integrin binding to endothelial ligands (i.e., ICAM-1) and extracellular matrix molecules (i.e., fibrinogen).…”

Neutrophil adhesion to endothelial cells impairs the effects of catalase and glutathione in preventing endothelial injury

“…Previous studies have indicated that the attachment of PMN to endothelial cells is a requisite for PMN-mediated endothelial injury (Shasby et al, 1983;Harlan, 1985). The permeability-increasing effect of activating the adherent PMN has been described by us using a similar target-to-effector cell ratio of 1O:l (Gibbs et al, 1990;Kaslovsky et al, 1990Kaslovsky et al, , 1991. We show in the present study that activation of PMN, which are separated from the endothelial monolayer by a thin microporous filter, can also produce a similar increase in endothelial permeability.…”

Tumor necrosis factor-alpha-mediated decrease in glutathione increases the sensitivity of pulmonary vascular endothelial cells to H2O2.

“…The TNFa-induced release ofinflammatory mediators such as platelet activating factor (8), interleukin 1 (9), granulocyte-macrophage colony-stimulating factor (10), and possibly reactive oxygen species (1 1, 12) may contribute to the permeability-increasing effect of TNFa. The second pathway involving PMN (13)(14)(15)(16) may be the result of TNFa-induced augmentation of PMN activation, resulting in the release of oxygen free radicals (17) and arachidonic acid metabolites (18). The released oxidants, in particular H202, can directly increase vascular endothelial permeability (19).…”