title: Human neutrophil elastase degrades SPLUNC1 and impairs airway epithelial defense against bacteria.
abstract: BACKGROUND
  Acute exacerbations of chronic obstructive pulmonary disease (AECOPD) are a significant cause of mortality of COPD patients, and pose a huge burden on healthcare. One of the major causes of AECOPD is airway bacterial (e.g. nontypeable Haemophilus influenzae [NTHi]) infection. However, the mechanisms underlying bacterial infections during AECOPD remain poorly understood. As neutrophilic inflammation including increased release of human neutrophil elastase (HNE) is a salient feature of AECOPD, we hypothesized that HNE impairs airway epithelial defense against NTHi by degrading airway epithelial host defense proteins such as short palate, lung, and nasal epithelium clone 1 (SPLUNC1).
  
  
  RESULTS
  Recombinant human SPLUNC1 protein was incubated with HNE to confirm SPLUNC1 degradation by HNE. To determine if HNE-mediated impairment of host defense against NTHi was SPLUNC1-dependent, SPLUNC1 protein was added to HNE-treated primary normal human airway epithelial cells. The in vivo function of SPLUNC1 in NTHi defense was investigated by infecting SPLUNC1 knockout and wild-type mice intranasally with NTHi. We found that: (1) HNE directly increased NTHi load in human airway epithelial cells; (2) HNE degraded human SPLUNC1 protein; (3) Recombinant SPLUNC1 protein reduced NTHi levels in HNE-treated human airway epithelial cells; (4) NTHi levels in lungs of SPLUNC1 knockout mice were increased compared to wild-type mice; and (5) SPLUNC1 was reduced in lungs of COPD patients.
  
  
  CONCLUSIONS
  Our findings suggest that SPLUNC1 degradation by neutrophil elastase may increase airway susceptibility to bacterial infections. SPLUNC1 therapy likely attenuates bacterial infections during AECOPD.
authors.affiliation: Department of Medicine, National Jewish Health, Denver, Colorado, United States of America.
authors.forename: Di
authors.initials: D
authors.lastname: Jiang
authors.forename: Sally E
authors.initials: SE
authors.lastname: Wenzel
authors.forename: Qun
authors.initials: Q
authors.lastname: Wu
authors.forename: Russell P
authors.initials: RP
authors.lastname: Bowler
authors.forename: Christina
authors.initials: C
authors.lastname: Schnell
authors.forename: Hong Wei
authors.initials: HW
authors.lastname: Chu
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D004847:Epithelial Cells / Q000187:drug effects / Q000276:immunology / Q000382:microbiology; D006023:Glycoproteins / Q000276:immunology / Q000378:metabolism* / Q000494:pharmacology; D006192:Haemophilus Infections / Q000276:immunology* / Q000378:metabolism / Q000382:microbiology / Q000473:pathology; D006193:Haemophilus influenzae / Q000187:drug effects / Q000254:growth & development; D006801:Humans; D019272:Leukocyte Elastase / Q000378:metabolism*; D008168:Lung / Q000276:immunology* / Q000382:microbiology / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D020556:Neutrophil Infiltration / Q000276:immunology*; D010750:Phosphoproteins / Q000276:immunology / Q000378:metabolism* / Q000494:pharmacology; D059748:Proteolysis; D029424:Pulmonary Disease, Chronic Obstructive / Q000276:immunology* / Q000378:metabolism / Q000382:microbiology / Q000473:pathology; D011994:Recombinant Proteins / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology; D020545:Respiratory Mucosa / Q000276:immunology / Q000382:microbiology / Q000473:pathology
chemical_list: C485599:BPIFA1 protein, human; D006023:Glycoproteins; D010750:Phosphoproteins; D011994:Recombinant Proteins; D019272:Leukocyte Elastase