Sheikh Arshad Saeed*,1, Connor JD2, Imran1, Javeria Quadri1 and Shumaila Tasneem1. 1Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi-75270, Pakistan and 2The Aga Khan University Hospital, Karachi. Pakistan. Phosphoinositide 3-kinase (PI 3-kinase) exists in cells as a family of isoforms. The enzymes are important regulators of fundamental metabolic processes, such as energy utilization, growth, cell proliferation and survival. They are activated by cell surface receptors for hormones, and by G-protein coupled receptors. Enzyme p110 gamma, in particular, catalyzes production of second messengers from inositol phospholipids, including phosphoinositide (3,4,5) triphosphate or Ptdins (3,4,5) P3, Ptdins (3,4) P2 and Ptdins (3) P. The latter mediates specialized responses related to particular functions of cells. The neutrophils, products of PI 3-kinase are thought to be important in chemotaxis motility, phagocytosis and lysosomal breakdown of microorganisms. Neutrophils cause tissue damage by their capacity to release toxic oxygen radicals (generated by the NADPH oxidase complex), the exocytosis of granules containing highly histotoxic compounds such as elastase and collagenases, and the elaboration and release of additional pro-inflammatory cytokines. PI-3Ks have been shown to be key regulators of both neutrophil recruitment and activation. Neutrophils and platelets were obtained from human blood and macrophages from mouse peritoneal cavity. Reactive oxygen species (ROS) production was measured by a luminol-enhanced chemiluminescence assay; aggregation was measured in platelet-rich plasma (PRP) with a Chronolog Dual Channel Lumi-Aggregometer. Effects of graded concentrations of four enzyme inhibitors (wortmannin, LY-294002, resveratrol and quercetin) were evaluated. All inhibitors caused concentration-dependent depression of ROS generation and human platelet aggregation. They differed only in their potencies as revealed by concentration-response data. Moreover, inhibitors blocked three physiologically important stimulants of aggregation: ADP, collagen and epinephrine. We conclude that inhibition of PI 3-kinase would appear to be a useful therapeutic goal in those conditions where the activities of platelets and/or phagocytes become aberrant.