Expression of urokinase-type plasminogen activator by rat pulmonary alveolar epithelial cells.
Intra-alveolar fibrin deposition accompanies many forms of inflammatory lung injury. Appropriate clearance of this fibrin matrix is important for normal healing and remodeling. The local generation of plasmin by the action of plasminogen activators (PAs) represents a pivotal step in the fibrinolytic process. To investigate whether the alveolar epithelium plays a role in the modulation of intra-alveolar fibrinolysis, we have studied PA regulation by rat pulmonary alveolar epithelial cells. We have found large quantities of PA activity both in conditioned media and cell lysates from epithelial monolayers in culture. Casein-plasminogen zymography reveals that this PA activity migrates as a tight doublet with an apparent mol wt of 45 kD, clearly distinct from rat tissue-type PA (tPA, greater than 68 kD). Analysis of freshly isolated type II alveolar epithelial cells demonstrates readily measurable PA activity in cell lysates, as well as expression of urokinase-type PA (uPA) mRNA on Northern blot analysis. Upregulation of PA activity occurs progressively with time in culture as the alveolar epithelial cells lose type II cell characteristics and become more flattened. Stimulation of alveolar epithelial cell monolayers with lipopolysaccharide or tumor necrosis factor increases levels of secreted PA activity. The relative abundance of uPA mRNA was shown to change in parallel with PA activity during in vitro differentiation or after exposure to inflammatory mediators. Thus, alveolar epithelial cells are likely an important source of uPA in the lung, the expression of which is influenced by the state of cellular differentiation as well as the presence of inflammatory mediators.(ABSTRACT TRUNCATED AT 250 WORDS)
Gross
T J
TJ
Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor.
Simon
R H
RH
Sitrin
R G
RG
D000818:Animals; D002454:Cell Differentiation; D002478:Cells, Cultured; D004847:Epithelial Cells; D004848:Epithelium / Q000187:drug effects / Q000201:enzymology; D007371:Interferon-gamma / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D010960:Plasminogen Activators / Q000096:biosynthesis* / Q000378:metabolism; D011650:Pulmonary Alveoli / Q000166:cytology / Q000187:drug effects / Q000201:enzymology*; D051381:Rats; D011919:Rats, Inbred Strains; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D014568:Urokinase-Type Plasminogen Activator / Q000096:biosynthesis* / Q000378:metabolism
D008070:Lipopolysaccharides; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma; D010960:Plasminogen Activators; D014568:Urokinase-Type Plasminogen Activator