Regulation of hepatocyte growth factor in mice with pneumonia by peptidases and trans-alveolar flux.
Hepatocyte growth factor (HGF) promotes lung epithelial repair after injury. Because prior studies established that human neutrophil proteases inactivate HGF in vitro, we predicted that HGF levels decrease in lungs infiltrated with neutrophils and that injury is less severe in lungs lacking HGF-inactivating proteases. After establishing that mouse neutrophil elastase cleaves mouse HGF in vitro, we tested our predictions in vivo by examining lung pathology and HGF in mice infected with Mycoplasma pulmonis, which causes neutrophilic tracheobronchitis and pneumonia. Unexpectedly, pneumonia severity was similar in wild type and dipeptidylpeptidase I-deficient (Dppi-/-) mice lacking neutrophil serine protease activity. To assess how this finding related to our prediction that Dppi-activated proteases regulate HGF levels, we measured HGF in serum, bronchoalveolar lavage fluid, and lung tissue from Dppi(+/+) and Dppi(-/-) mice. Contrary to prediction, HGF levels were higher in lavage fluid from infected mice. However, serum and tissue concentrations were not different in infected and uninfected mice, and HGF lung transcript levels did not change. Increased HGF correlated with increased albumin in lavage fluid from infected mice, and immunostaining failed to detect increased lung tissue expression of HGF in infected mice. These findings are consistent with trans-alveolar flux rather than local production as the source of increased HGF in lavage fluid. However, levels of intact HGF from infected mice, normalized for albumin concentration, were two-fold higher in Dppi(-/-) versus Dppi(+/+) lavage fluid, suggesting regulation by Dppi-activated proteases. Consistent with the presence of active HGF, increased expression of activated receptor c-Met was observed in infected tissues. These data suggest that HGF entering alveoli from the bloodstream during pneumonia compensates for destruction by Dppi-activated inflammatory proteases to allow HGF to contribute to epithelial repair.
Cardiovascular Research Institute, School of Medicine, University of California San Francisco, San Francisco, California, United States of America.
Wilfred W
WW
Raymond
Department of Medicine, School of Medicine, University of California San Francisco, San Francisco, California, United States of America.
Xiang
X
Xu
Cardiovascular Research Institute, School of Medicine, University of California San Francisco, San Francisco, California, United States of America.
Shilpa
S
Nimishakavi
Department of Anatomy, School of Medicine, University of California San Francisco, San Francisco, California, United States of America.
Catherine
C
Le
Cardiovascular Research Institute, School of Medicine, University of California San Francisco, San Francisco, California, United States of America; Department of Anatomy, School of Medicine, University of California San Francisco, San Francisco, California, United States of America.
Donald M
DM
McDonald
Cardiovascular Research Institute, School of Medicine, University of California San Francisco, San Francisco, California, United States of America; Department of Medicine, School of Medicine, University of California San Francisco, San Francisco, California, United States of America; Northern California Institute for Research and Education, San Francisco, California, United States of America; Veterans Affairs Medical Center, San Francisco, California, United States of America.
George H
GH
Caughey
D000818:Animals; D001992:Bronchoalveolar Lavage Fluid; D020789:Cathepsin C / Q000235:genetics; D004195:Disease Models, Animal; D015870:Gene Expression; D017228:Hepatocyte Growth Factor / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D019272:Leukocyte Elastase / Q000378:metabolism; D008168:Lung / Q000378:metabolism / Q000382:microbiology / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D045803:Mycoplasma pulmonis / Q000201:enzymology; D009928:Organ Specificity / Q000235:genetics; D010447:Peptide Hydrolases / Q000378:metabolism*; D011014:Pneumonia / Q000235:genetics / Q000378:metabolism* / Q000382:microbiology / Q000473:pathology; D011019:Pneumonia, Mycoplasma / Q000235:genetics / Q000378:metabolism / Q000382:microbiology / Q000473:pathology; D054730:Protein Interaction Domains and Motifs; D059748:Proteolysis; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics / Q000378:metabolism; D011650:Pulmonary Alveoli / Q000378:metabolism*; D012697:Serine Endopeptidases / Q000378:metabolism
D017228:Hepatocyte Growth Factor; D019859:Proto-Oncogene Proteins c-met; D010447:Peptide Hydrolases; D020789:Cathepsin C; C533919:Ctsc protein, mouse; D012697:Serine Endopeptidases; C066932:mast cell protease 4; D019272:Leukocyte Elastase