Transcellular biosynthesis of lipoxin A4 during adhesion of platelets and neutrophils in experimental immune complex glomerulonephritis

Abstract

Polymorphonuclear neutrophils are important effectors of injury in host defense and inflammation. Many inflammatory diseases are self-limiting, raising the possibility that compounds are generated in vivo during the course of inflammation that inhibit neutrophil recruitment and tissue destruction. Lipoxins, a more recent addition to the families of bioactive eicosanoids, are potential candidates in this regard. Lipoxins are generated via pathways that initially involve the dual lipoxygenation of arachidonic acid and are potent inhibitors of several neutrophil trafficking events in vitro. Here, we present evidence that lipoxin A4 is generated in rat kidneys during experimental immune complex-mediated glomerulonephritis in vivo. Renal lipoxin A4 levels were markedly reduced by prior depletion of animals of either neutrophils or platelets, suggesting that most lipoxin A4 generated in vivo was derived from transcellular biosynthetic pathways during platelet-neutrophil interactions. Electron microscopic examination of glomerulonephritic kidneys revealed areas of intimate contact between neutrophils and platelets within the lumen of glomerular capillaries. P-selectin on platelets is an important mediator of platelet-neutrophil adhesion in vitro and in vivo. Prior treatment of animals with a blocking monoclonal antibody (mAb) against P-selectin (mAb CY1747), but not an isotype-matched non-blocking control mAb (mAb PNB1.6), caused striking inhibition of lipoxin A4 generation without attenuating neutrophil recruitment. Anti-P-selectin mAb also blunted transcellular lipoxin A4 generation during coincubations of activated neutrophils and platelets in vitro.(ABSTRACT TRUNCATED AT 250 WORDS)

Lipoxin A4stable analogs inhibit leukocyte rolling and adherence in the rat mesenteric microvasculature: Role of P-selectin

“…In vitro data indicate that one member of the naturally occurring lipoxins, (i.e., lipoxin A 4 , namely LXA 4 ), inhibits both neutrophil and eosinophil chemotaxis at nanomolar concentrations (2,3) and blocks polymorphonuclear neutrophil (PMN) transmigration across epithelial cells (4) and endothelial monolayers (5). Similar actions also are demonstrable in vivo where LXA 4 exerts vasodilator properties (6)(7)(8)(9), blocks both PMN diapedesis from postcapillary venules (10), and inhibits PMN entry in inflamed renal tissues in animal models of glomerulonephritis (11).…”

“…Under such conditions, these eicosanoids transmit transcellular bioregulatory signals, as demonstrated in in vitro models of platelet-neutrophil interaction (28). In contrast to other lipid mediators, which are proinflammatory substances, lipoxins have anti-inflammatory properties that may serve a counterregulatory role limiting the effects of inflammatory signals in neutrophil recruitment and tissue destruction (1,11). Recently, the anti-inflammatory activity of lipoxins has been correlated to the expression of adhesion molecules.…”

“…In this regard, 15-epi-lipoxins are potent inhibitors of leukotriene B 4 -mediated PMN adhesion to endothelial cells in vitro (12). Moreover, cell adhesion via selectins and integrins in conjunction with their respective cognate carbohydrate and immunoglobulin-like receptors strongly influences transcellular biosynthesis of lipoxins (1,11). For example, lipoxin biosynthesis via platelet-PMN interactions during immunocomplexinduced glomerulonephritis is blocked by antibodies against P-selectin (11).…”

Re‐expression of functional P‐selectin molecules on the endothelial cell surface by repeated stimulation with thrombin

“…Anti-P-selectin mAbs WGA-1 (Katayama et al, 1992) and CY-1747 (Papayianni et al, 1995) were kindly provided by Takara Shuzo Co. (Otsu, Japan) and Dr S. Morooka (Sumitomo Pharmacy Co., Osaka, Japan), respectively. Anti-E-selectin mAb BBIG-E5 (Pigott et al, 1991) was obtained from British Biotechnology (Oxford, U.K.).…”

Platelet-Leukocyte Cross Talk in Whole Blood

“…Cell-cell adhesion via selectins and integrins may also promote transcellular eicosanoid biosynthesis. 13,14 Furthermore, platelets and leukocytes can produce PAF, but coincubation of activated platelets and activated neutrophils further enhances PAF-acether generation. 15 As visualized previously, 16 platelets and leukocytes may form platelet-leukocyte aggregates or conjugates (PLAs), mainly via platelet-expressed P-selectin and its receptors P-selectin glycoprotein ligand-1 (PSGL-1) and CD15, as well as via fibrinogen bridging between glycoprotein (GP) IIb/IIIa and CD11b/CD18.…”