Fibronectin degradation products containing the cytoadhesive tetrapeptide stimulate human neutrophil degranulation.

Abstract

We investigated whether adhesive glycoproteins, such as fibronectin or fibrinogen, could function to provide a nidus for neutrophil degranulation. Elastase release in recalcified plasma was normal in afibrinogenemic plasma, but 73% less in plasma depleted of fibronectin. Proteolytic digests of fibronectin, but not intact fibronectin (50-1,000 gg/ml), induced a concentration-dependent release of neutrophil elastase and lactoferrin. MAbs N293, which recognized the mid-molecule of fibronectin, N294, which was directed toward the 11-kD cell adhesive fragment, and N295, generated against the amino terminal of the 11-kD fragment, inhibited the release of elastase by 7, 24, and 60%, respectively. The cytoadhesive tetrapeptide portion of fibronectin, Arg-Gly-Asp-Ser (250-1,000 pg/ml), released 1.94±0.10 jig/ml of elastase from 107 neutrophils, in contrast to the lack of release by the control hexapeptide, Arg-GlyTyr-Ser-Leu-Gly. Plasmin appeared to be the enzyme responsible for fibronectin cleavage, since neutrophil elastase release in plasma that had been depleted of plasminogen was decreased and reconstitution of plasminogen-deficient plasma with purified plasminogen corrected the abnormal release. Plasmin cleaved fibronectin to multiple degradation products, each < 200 kD. This fibronectin digest released 1.05 jig/ml of elastase from 107 neutrophils. We suggest that the activation of plasminogen leads to the formation of fibronectin degradation products capable of functioning as agonists for neutrophils.

WOMEN IN CANCER THEMATIC REVIEW: Ovarian cancer–peritoneal cell interactions promote extracellular matrix processing

“…However, other proteases including MMP-3 (Wilhelm et al 1993), MMP-19 (Stracke et al 2000), MT1-MMP (Ohuchi et al 1997) and MMP-7 (Quantin et al 1989) can also cleave fibronectin, as well as kallikrein-7 which is upregulated in ovarian cancer cells . Plasmin can also cleave fibronectin to similar-sized fragments as those observed in our study (Quigley et al 1987, Wachtfogel et al 1988, Horowitz et al 2008. As we have shown that plasmin levels are increased during ovarian cancer co-culture with LP-9 cells , fibronectin cleavage observed in the peritoneal ovarian cancer cell co-culture is likely to be mediated by plasmin which in turn can also activate MMPs including MMP-2.…”

Effect of Recombinant Hirudin, a Specific Inhibitor of Thrombin, on Endotoxin-induced Intravascular Coagulation and Acute Lung Injury in Pigs

“…Infusion of endotoxin (lipopolysaccharide [LPS]) into animals has been shown to cause an activation of the coagulation cascade and to cause acute lung injury characterized by pulmonary hypertension, pulmonary endothelial injury, increased pulmonary vascular permeability, and pulmonary edema (4)(5)(6)(7)(8). Serine proteases, such as thrombin, plasmin, or plasma kallikrein, generated during activation of the coagulation cascade have been shown to activate polymorphonuclear leukocytes (PMN) as well as to directly increase pulmonary vascular permeability (9)(10)(11)(12). Thus, these proteases are thought to play a major role in the pathophysiology of LPS-induced acute lung injury.…”

Monocytes Stimulated by 110-kDa Fibronectin Fragments Suppress Proliferation of Anti-CD3-Activated T Cells

“…hen parenchymal tissues are injured by ischemiareperfusion or by infection, proteases released by the damaged parenchymal cells and infiltrating leukocytes degrade matrix proteins and produce fragments of fibronectin with novel biologic properties (1)(2)(3). Among these are the 110-to 120-kDa VLA-5 (CD29/CD49e)-binding fibronectin fragments (FNf) 3 that signal MNL to produce TNF-␣ and that stimulate both T cells and monocytes to migrate across vascular endothelial barriers (4).…”