The body's first-and appropriate-response to injury or microbial invasion is infiltrating the affected site with polymorphonuclear leukocytes (neutrophils). Activated by humoral factors such as products of the complement cascade (C5a) or immune complexes, neutrophils adhere to endothelial cells (heterotypic aggregation), undergo directed migration (chemotaxis), release lysosomal enzymes (degranulation), generate active oxygen products (O2, H2O2 generation), and ingest opsonized particles (phagocytosis). Thus, neutrophils actively participate in host defense. In autoimmune conditions, such as rheumatoid arthritis, lupus vasculitis, or the adult respiratory distress syndrome (ARDS), these responses are destructive.
Our most current research is directed toward these hypotheses: 1) The yin/yang control of neutrophil function by cAMP/cGMP is exerted at the level of raf phosphorylation in the MAP-kinase cascade; 2) endothelial cells release autocoids (adenosine, PGI2, and nitric oxide) that inhibit neutrophil-mediated endothelial activation (judged by translocation of NFkB, induction of cyclooxygenase, nitric oxide synthases, and expression of E-selectin, VCAM-1, and ICAM-1); 3) lipid metabolites formed in the course of neutrophil/endothelial interactions, e.g., arachidonate (20:4) and phosphatidate (PA), regulate the association of ras-related proteins with their inhibitor/chaperones (GDIs) and the plasmalemma; 4) the physical state of phospholipids (lamellar vs. HexII) as regulated by phospholipases A, C, and D regulates the association of prenylated proteins with the plasmalemma and the effect of autocoids (PGE1; 14,15 di-HETEs, 13-HODE; 22:6; lipoxins) on the activity of prenycysteine-directed carboxyl methyl transferase and the oxidase system in natural and artificial bilayers.
Research Professor, Department of Medicine
Professor Emeritus of Medicine, Department of Medicine
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