Lysophospholipid generation and phosphatidylglycerol depletion in phospholipase A(2)-mediated surfactant dysfunction.
Pulmonary surfactant's complex mixture of phospholipids and proteins reduces 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 A(2) (sPLA(2)) enzymes in lung cells and infiltrating leukocytes that could damage extracellular surfactant. We considered two mechanisms of surfactant disruption by five human sPLA(2)s, including generation of lysophospholipids and the depletion of specific phospholipids. All five sPLA(2)s 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 sPLA(2)s, but not group IIA or IID. Group IIA hydrolyzed both phosphatidylethanolamine and phosphatidylglycerol, whereas 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 sPLA(2) is less clear and may be the combined result of both mechanisms.
Hite
R Duncan
RD
Section of Pulmonary Medicine, Wake Forest University School of Medicine, Medical Center Blvd., Winston-Salem, NC 27157-1054, USA. dhite@wfubmc.edu
Seeds
Michael C
MC
Safta
Anca M
AM
Jacinto
Randolph B
RB
Gyves
Julianna I
JI
Bass
David A
DA
Waite
B Moseley
BM
D000818:Animals; D019556:COS Cells / Q000201:enzymology; D006801:Humans; D006868:Hydrolysis; D008168:Lung / Q000201:enzymology; D008246:Lysophospholipids / Q000378:metabolism*; D010715:Phosphatidylglycerols / Q000172:deficiency*; D010741:Phospholipases A / Q000145:classification / Q000235:genetics / Q000378:metabolism*; D013501:Surface-Active Agents / Q000378:metabolism*; D013552:Swine
D008246:Lysophospholipids; D010715:Phosphatidylglycerols; D013501:Surface-Active Agents; D010741:Phospholipases A