Research Interests: My lab conducted studies on two rather distinct topics: 1) Phospolipases in lung inflammation (asthma, ARDS) and 2) Regulation of programmed cell death (apoptosis) in lung inflammation. Research: Phospholipases A2 have gained widespread interest, focused on their ability to release arachidonic acid, the first step in formation of a myriad of potent mediators of inflammation. Cystolic PLA2 is a prototype of this role. In contrast, secretory PLA2s (sPLA2) are released from many cells, and are activated outside of the cell. There are nine different isotypes of sPLA2, with distinct cellular localization and substrate specificity. Their roles are less well defined. Probable functions vary from digestion (via the pancreas) to antimicrobial defense ("innate immunity") in the lung. We are examining the concept that certain of these sPLA2s contribute to airway diseases. sPLA2s are released in airways of asthmatics, and airway lavage shows phospholipid hydrolysis of airway cells and/or of surfactant (with damage to surfactant function). We have found that several sPLA2s (the Group V, X, and IID) are specifically expressed by airway epithelial cells and one (Group IId) is specific to eosinophils. These specific sPLA2s have unusually potent abilites to hydrolyze the external membrane of intact mammalian cells, and to hydrolyze pulmonary surfactant. We are studying how these proteins are regulated, what damage they cause, and how their damage might be prevented or reversed. Granulocytes (eosinophils [Eos], neutrophils [PMN]) are central to allergic and acute inflammation. Downregulation of inflammation requires clearance of these cells, and this in turn requires programmed cell death (apoptosis) of the granulocytes. A 30-year interest of my lab has been the control of Eos, from their production in the bone marrow to their death by apoptosis. Apoptotic pathways in Eos and PMN are unusual. For example, mitochondrial respiration is central to apoptosis of many cells, but Eos and PMN have very few mitochondria and do not have respiration. Adrenal corticosteroids cause apoptosis of Eos but steroids delay apoptosis of PMN. Mechanisms of these opposite effects are poorly defined and potentially clinically important. The opposite effects provide a door to examine the regulation of apoptotic pathways in these cells. Current studies are using multiple methods (DNA arrays, real time PCR, etc.) to identify candidate genes that are up- or downregulated in Eos vs. neutrophils following exposure to steroids. The pathways regulating these candidate genes will then be studied in detail. Recent Publications: Sivertson KL, Seeds MC, Long DL, Peachman KK, Bass DA. The differential effect of dexamethasone on granulocyte apoptosis involves stabilization of Mcl-1L in neutrophils but not in eosinophils.Cell Immunol. 2007 Mar;246(1):34-45. Epub 2007 Jun 14. Hite RD, Seeds MC, Jacinto RB, Grier BL, Waite BM, Bass DA. Lysophospholipid and fatty acid inhibition of pulmonary surfactant: non-enzymatic models of phospholipase A2 surfactant hydrolysis. Biochim Biophys Acta. 2005 Dec 30;1720(1-2):14-21. Hite RD, Seeds MC, Safta AM, Jacinto RB, Gyves JI, Bass DA, Waite BM. Lysophospholipid generation and phosphatidylglycerol depletion in phospholipase A(2)-mediated surfactant dysfunction. Am J Physiol Lung Cell Mol Physiol. 2005 Apr;288(4):L618-24. Hite RD, Seeds MC, Bowton DL, Grier BL, Safta AM, Balkrishnan R, Waite BM, Bass DA. Surfactant phospholipid changes after antigen challenge: a role for phosphatidylglycerol in dysfunction. Am J Physiol Lung Cell Mol Physiol. 2005 Apr;288(4):L610-7. Seeds MC, Bowton DL, Hite RD, Gyves JI, Bass DA. Human eosinophil group IID secretory phospholipase A2 causes surfactant dysfunction. Chest. 2003 Mar;123(3 Suppl):376S-7S. Review. No abstract available. Publications:
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