title: Critical role of serpinB1 in regulating inflammatory responses in pulmonary influenza infection.
abstract: BACKGROUND
  Excessive inflammatory host response increases morbidity and mortality associated with seasonal respiratory influenza, and highly pathogenic virus strains are characterized by massive infiltration of monocytes and/or macrophages that produce a storm of injurious cytokines.
  
  
  METHODS
  Here, we examined the role in respiratory influenza of serpinB1, an endogenous inhibitor of the serine proteases elastase, cathepsin G, and proteinase-3, increasingly recognized as regulators of inflammation.
  
  
  RESULTS
  After challenge with high-dose surfactant protein-D (SP-D)-sensitive influenza A/Philadelphia/82 (H3N2), serpinB1(-/-) mice died earlier and in greater numbers than did wild-type mice. Sublethally infected animals suffered increased morbidity, delayed resolution of epithelial injury, and increased immune cell death. Viral clearance and SP-D/SP-A upregulation were unimpaired and so were early virus-induced cytokine and chemokine burst and influx of large numbers of neutrophils and monocytes. Whereas initial cytokines and chemokines rapidly cleared in wild-type mice, TNF-α, IL-6, KC/CXCL1, G-CSF, IL-17A, and MCP-1/CCL2 remained elevated in serpinB1(-/-) mice. Monocyte-derived cells were the dominant immune cells in influenza-infected lungs, and those from serpinB1(-/-) mice produced excessive IL-6 and TNF-α when tested ex vivo. Pulmonary γδ T-cells that produced IL-17A were also increased.
  
  
  CONCLUSIONS
  Because viral clearance was unimpaired, the study highlights the critical role of serpinB1 in mitigating inflammation and restricting pro-inflammatory cytokine production in influenza infection.
authors.affiliation: Immune Disease Institute and Program in Cellular and Molecular Medicine at Children's Hospital and Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Dapeng
authors.initials: D
authors.lastname: Gong
authors.forename: Kalamo
authors.initials: K
authors.lastname: Farley
authors.forename: Mitchell
authors.initials: M
authors.lastname: White
authors.forename: Kevan L
authors.initials: KL
authors.lastname: Hartshorn
authors.forename: Charaf
authors.initials: C
authors.lastname: Benarafa
authors.forename: Eileen
authors.initials: E
authors.lastname: Remold-O'Donnell
mesh_terms: D000818:Animals; D016923:Cell Death; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation / Q000502:physiology; D007249:Inflammation / Q000378:metabolism* / Q000473:pathology; D053122:Influenza A Virus, H3N2 Subtype; D008168:Lung / Q000473:pathology*; D008171:Lung Diseases / Q000473:pathology / Q000821:virology*; D051379:Mice; D018345:Mice, Knockout; D009976:Orthomyxoviridae Infections / Q000276:immunology / Q000473:pathology*; D015843:Serpins / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors
chemical_list: D016207:Cytokines; C522950:Serpinb1a protein, mouse; D015843:Serpins