alpha-Thrombin increases cytosolic calcium and induces human airway smooth muscle cell proliferation.
In a variety of diseases including asthma, inflammation causes microvascular leakage and activates thrombin. In addition to cleaving fibrinogen to fibrin, thrombin may have other important cellular effects. Because airway inflammation and vascular permeability are important determinants of airway hyperreactivity, we have studied the effects of thrombin on airway smooth muscle. Using cultured human airway smooth muscle cells, we have examined whether alpha-thrombin can evoke calcium responses, phosphoinositide turnover, or cell proliferation. We have demonstrated that alpha-thrombin does increase cytosolic calcium and phosphoinositide hydrolysis in a dose- and time-dependent manner that may be inhibited by pretreating cells with r-hirudin. In addition, we have shown that thrombin stimulates airway smooth muscle cell proliferation. By contrast, bradykinin, which evoked comparable increases in cytosolic calcium and phosphoinositide turnover, did not stimulate airway smooth muscle cell growth. We conclude that thrombin effectively increases cytosolic calcium and induces PI hydrolysis and, in addition, is capable of stimulating airway smooth muscle cell growth. However, the lack of an effect of bradykinin on cell growth suggests that increases in calcium and PI turnover alone will not induce airway smooth muscle cell proliferation. We suggest that alpha-thrombin may be important in the pathogenesis of both increased airway resistance as well as the structural changes seen as a consequence of chronic asthma.
Panettieri
R A
RA
Department of Medicine, University of Pennsylvania, Philadelphia, USA.
Hall
I P
IP
Maki
C S
CS
Murray
R K
RK
D001920:Bradykinin / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism*; D002455:Cell Division / Q000502:physiology; D002478:Cells, Cultured / Q000378:metabolism; D003600:Cytosol / Q000737:chemistry; D004247:DNA / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D019204:GTP-Binding Proteins / Q000378:metabolism; D006629:Hirudins / Q000494:pharmacology; D006801:Humans; D006868:Hydrolysis; D007295:Inositol Phosphates / Q000096:biosynthesis / Q000378:metabolism; D009130:Muscle, Smooth / Q000166:cytology* / Q000201:enzymology; D018129:Phosphatidylinositol Phosphates / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D013917:Thrombin / Q000494:pharmacology*; D013997:Time Factors; D014132:Trachea / Q000166:cytology* / Q000201:enzymology; D010566:Virulence Factors, Bordetella / Q000494:pharmacology
D006629:Hirudins; D007295:Inositol Phosphates; D018129:Phosphatidylinositol Phosphates; D010566:Virulence Factors, Bordetella; D004247:DNA; D013917:Thrombin; D019204:GTP-Binding Proteins; D001920:Bradykinin; D002118:Calcium