title: Airway proteins involved in bacterial clearance susceptible to cathepsin G proteolysis.
abstract: Serine proteases released from neutrophils are central to the pathogenesis of cystic fibrosis lung disease and are considered to be obvious therapeutic targets. Neutrophil elastase digests key opsonins present in the lung and disrupts phagocytosis, allowing bacteria to persist despite established pulmonary inflammation. We have found that cathepsin G, an abundant serine protease found in human and murine neutrophils, has other roles in the development of suppurative lung diseases. Murine models of endobronchial inflammation indicate that cathepsin G inhibits airway defences and interferes with the host's ability to clear Pseudomonas aeruginosa from the lung with effects distinct from neutrophil elastase. We hypothesise that differences in bacterial killing are due to defects in innate defences created by proteolysis. Protein profiles of bronchoalveolar lavage of infected wild-type and cathepsin G-deficient mice were compared using two-dimensional polyacrylamide gel electrophoresis and tandem mass spectrometry. Four proteins in bronchoalveolar lavage were cleaved by cathepsin G. Serum amyloid P component leaked into the lung during acute infection and was digested by cathepsin G. Its cleavage products had greater binding to lipopolysaccharide and interfered with phagocytosis. These results indicate that cleaved serum amyloid P component acts as an anti-opsonin and interferes with bacterial clearance from the lung.
authors.affiliation: Division of Paediatric Allergy and Pulmonary Medicine, Dept of Paediatrics, Washington University School of Medicine, 660 South Euclid Avenue, Mailbox 8116, St Louis, MO 63110, USA.
authors.forename: M M
authors.initials: MM
authors.lastname: Farberman
authors.forename: K T
authors.initials: KT
authors.lastname: Akers
authors.forename: J P
authors.initials: JP
authors.lastname: Malone
authors.forename: P
authors.initials: P
authors.lastname: Erdman-Gilmore
authors.forename: R R
authors.initials: RR
authors.lastname: Townsend
authors.forename: T
authors.initials: T
authors.lastname: Ferkol
mesh_terms: D000818:Animals; D001980:Bronchi / Q000382:microbiology; D018893:Bronchoalveolar Lavage; D056649:Cathepsin G / Q000737:chemistry* / Q000378:metabolism; D015180:Electrophoresis, Gel, Two-Dimensional / Q000379:methods; D018922:HL-60 Cells; D006801:Humans; D008168:Lung / Q000382:microbiology / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D009504:Neutrophils / Q000378:metabolism; D009895:Opsonin Proteins / Q000737:chemistry; D010587:Phagocytosis; D000683:Serum Amyloid P-Component / Q000096:biosynthesis; D053719:Tandem Mass Spectrometry / Q000379:methods
chemical_list: D009895:Opsonin Proteins; D000683:Serum Amyloid P-Component; D056649:Cathepsin G
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