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1 Department of Internal Medicine/Section on Pulmonary and Critical Care Medicine, Wake Forest University Schooll of Medicine, Winston-Salem, NC, USA
2 Department of Internal Medicine/Section on Pulmonary and Critical Care Medicine, Wake Forest University Schooll of Medicine, Winston-Salem, NC, USA; Section on Molecular Medicine, Wake Forest University School of Medicine, Winston-Salem, NC, USA
3 Department of Microbiology and Immunology, Wake Forest University School of Medicine, Winston-Salem, NC, USA
4 Section on Molecular Medicine, Wake Forest University School of Medicine, Winston-Salem, NC, USA; Department of Internal Medicine/Section on Pulmonary and Critical Care Medicine, Wake Forest University Schooll of Medicine, Winston-Salem, NC, USA
5 Department of Biochemistry, Wake Forest University School of Medicine, Winston-Salem, NC, USA; Department of Internal Medicine/Section on Pulmonary and Critical Care Medicine, Wake Forest University Schooll of Medicine, Winston-Salem, NC, USA
* To whom correspondence should be addressed. E-mail: dhite{at}wfubmc.edu.
Pulmonary surfactant's complex mixture of phospholipids and proteins reduce the work of breathing by lowering alveolar surface tension during respiration. One mechanism of surfactant damage appears to be the hydrolysis of phospholipid by phospholipases activated in the inflamed lung. Humans have several candidate secretory phospholipase A2 enzymes in lung cells and infiltrating leukocytes that could damage extracellular surfactant. We considered two mechanisms of surfactant disruption by five human sPLA2s; including generation of lysophospholipids and the depletion of specific phospholipids. All five sPLA2s studied ultimately caused surfactant dysfunction. Each enzyme exhibited a different pattern of hydrolysis of surfactant phospholipids. Phosphatidylcholine, the major phospholipid in surfactant and the greatest potential source for generation of lysophospholipids was susceptible to hydrolysis by group IB, group V and group X sPLA2s, but not groups IIA or IID. Group IIA hydrolyzed both phosphatidylethanolamine and phosphatidylglycerol while group IID was active against only phosphatidylglycerol. Thus, with groups IB and X, the generation of lysophospholipids corresponded with surfactant dysfunction. However, hydrolysis of and depletion of phosphatidylglycerol had a greater correlation with surfactant dysfunction for groups IIA and IID. Surfactant dysfunction caused by group V sPLA2 is less clear and may be the combined result of both mechanisms.
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