title: Combined activities of secretory phospholipases and eosinophil lysophospholipases induce pulmonary surfactant dysfunction by phospholipid hydrolysis.
abstract: BACKGROUND
  Surfactant dysfunction is implicated in small airway closure in asthma. Increased activity of secretory phospholipase A(2) (sPLA(2)) in the airways is associated with asthma exacerbations. Phosphatidylcholine, the principal component of pulmonary surfactant that maintains small airway patency, is hydrolyzed by sPLA(2). The lysophosphatidylcholine product is the substrate for eosinophil lysophospholipases.
  
  
  OBJECTIVE
  To determine whether surfactant phospholipid hydrolysis by the combined activities of sPLA(2)s and eosinophil lysophospholipases induces surfactant dysfunction.
  
  
  METHODS
  The effect of these enzymes on surfactant function was determined by capillary surfactometry. Thin layer chromatography was used to correlate enzyme-induced changes in surfactant phospholipid composition and function. Phosphatidylcholine and its hydrolytic products were measured by using mass spectrometry.
  
  
  RESULTS
  Eosinophils express a 25-kd lysophospholipase and group IIA sPLA(2). Phospholipase A(2) alone induced only a small decrease in surfactant function, and 25-kd lysophospholipase alone degraded lysophosphatidylcholine but had no effect on surfactant function. The combined actions of sPLA(2) and lysophospholipase produced dose-dependent and time-dependent losses of surfactant function, concomitant with hydrolysis of phosphatidylcholine and lysophosphatidylcholine. Lysates of AML14.3D10 eosinophils induced surfactant dysfunction, indicating these cells express all the necessary lipolytic activities. In contrast, lysates of blood eosinophils required exogenous phospholipase A(2) to induce maximal surfactant dysfunction.
  
  
  CONCLUSIONS
  The combined activities of sPLA(2)s and eosinophil lysophospholipases are necessary to degrade surfactant phospholipids sufficiently to induce functional losses in surfactant activity as reported in asthma.
  
  
  CONCLUSIONS
  The phospholipases and lysophospholipases expressed by eosinophils or other airway cells may represent novel therapeutic targets for blocking surfactant degradation, dysfunction, and peripheral airway closure in asthma.
authors.affiliation: Department of Biochemistry and Molecular Genetics, University of Illinois at Chicago, Chicago, IL 60607-7170, USA.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Kwatia
authors.forename: Christine B
authors.initials: CB
authors.lastname: Doyle
authors.forename: Wonwha
authors.initials: W
authors.lastname: Cho
authors.forename: Goran
authors.initials: G
authors.lastname: Enhorning
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Ackerman
mesh_terms: D000818:Animals; D002384:Catalysis; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D004357:Drug Synergism; D004789:Enzyme Activation / Q000502:physiology; D004804:Eosinophils / Q000201:enzymology* / Q000378:metabolism; D006023:Glycoproteins / Q000378:metabolism* / Q000502:physiology; D054501:Group II Phospholipases A2; D006801:Humans; D006868:Hydrolysis; D008245:Lysophospholipase / Q000378:metabolism* / Q000502:physiology; D051379:Mice; D010741:Phospholipases A / Q000378:metabolism* / Q000502:physiology; D010743:Phospholipids / Q000378:metabolism* / Q000502:physiology; D011663:Pulmonary Surfactants / Q000037:antagonists & inhibitors* / Q000378:metabolism*
chemical_list: D006023:Glycoproteins; D010743:Phospholipids; D011663:Pulmonary Surfactants; D010741:Phospholipases A; D054501:Group II Phospholipases A2; D008245:Lysophospholipase; C011711:lysolecithin acylhydrolase