The neutrophil serine protease inhibitor serpinb1 preserves lung defense functions in Pseudomonas aeruginosa infection.
Neutrophil serine proteases (NSPs; elastase, cathepsin G, and proteinase-3) directly kill invading microbes. However, excess NSPs in the lungs play a central role in the pathology of inflammatory pulmonary disease. We show that serpinb1, an efficient inhibitor of the three NSPs, preserves cell and molecular components responsible for host defense against Pseudomonas aeruginosa. On infection, wild-type (WT) and serpinb1-deficient mice mount similar early responses, including robust production of cytokines and chemokines, recruitment of neutrophils, and initial containment of bacteria. However, serpinb1(-/-) mice have considerably increased mortality relative to WT mice in association with late-onset failed bacterial clearance. We found that serpinb1-deficient neutrophils recruited to the lungs have an intrinsic defect in survival accompanied by release of neutrophil protease activity, sustained inflammatory cytokine production, and proteolysis of the collectin surfactant protein-D (SP-D). Coadministration of recombinant SERPINB1 with the P. aeruginosa inoculum normalized bacterial clearance in serpinb1(-/-) mice. Thus, regulation of pulmonary innate immunity by serpinb1 is nonredundant and is required to protect two key components, the neutrophil and SP-D, from NSP damage during the host response to infection.
CBR Institute for Biomedical Research, Harvard Medical School, Boston, MA 02115, USA. benarafa@cbr.med.harvard.edu
Charaf
C
Benarafa
Gregory P
GP
Priebe
Eileen
E
Remold-O'Donnell
D000818:Animals; D007113:Immunity, Innate; D008070:Lipopolysaccharides / Q000378:metabolism; D008168:Lung / Q000276:immunology / Q000378:metabolism / Q000382:microbiology*; D008171:Lung Diseases / Q000382:microbiology; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008954:Models, Biological; D009504:Neutrophils / Q000378:metabolism / Q000382:microbiology; D009195:Peroxidase / Q000378:metabolism; D011552:Pseudomonas Infections / Q000378:metabolism* / Q000517:prevention & control*; D011550:Pseudomonas aeruginosa / Q000378:metabolism*; D015842:Serine Proteinase Inhibitors / Q000378:metabolism / Q000502:physiology*; D015843:Serpins / Q000096:biosynthesis / Q000502:physiology*
D008070:Lipopolysaccharides; D015842:Serine Proteinase Inhibitors; C522950:Serpinb1a protein, mouse; D015843:Serpins; D009195:Peroxidase