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Airway biology
Linkage of neutrophil serine proteases and decreased surfactant protein-A (SP-A) levels in inflammatory lung disease
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  1. F Rubio1,
  2. J Cooley1,
  3. F J Accurso2,
  4. E Remold-O’Donnell1,3
  1. 1CBR Institute for Biomedical Research Inc, Harvard Medical School, Boston, Massachusetts, USA
  2. 2Department of Pediatrics, University of Colorado School of Medicine and The Children’s Hospital, Denver, Colorado, USA
  3. 3Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, USA
  1. Correspondence to:
    Dr E Remold-O’Donnell
    Center for Blood Research, 800 Huntington Avenue, Boston, MA 02115, USA; remoldcbr.med.harvard.edu

Abstract

Background: In patients with cystic fibrosis (CF) neutrophils are recruited in excess to the airways yet pathogens are not cleared and the patients suffer from chronic infections. Recent studies have shown a deficiency in airway fluids from patients with CF and other inflammatory pulmonary conditions of surfactant protein A (SP-A), a pattern recognition molecule that facilitates uptake of microbes by macrophages and neutrophils.

Methods: In vitro simulations were used to test the hypothesis that decreased SP-A levels in CF might be the result of degradation by neutrophil serine proteases.

Results: Very low levels of the neutrophil granule serine proteases cathepsin G, elastase, and proteinase-3 rapidly degraded pure SP-A when tested in buffered saline. The order of potency was cathepsin G>elastase>proteinase-3. The addition of cathepsin G or elastase to normal bronchoalveolar lavage (BAL) fluid caused a dose dependent degradation of endogenous native SP-A. Cathepsin G and elastase were present in the BAL fluid from many patients with CF. Simple incubation of protease positive BAL fluid from patients with CF caused a time dependent degradation of added SP-A or, where present, endogenous SP-A. The degradation of SP-A by protease(s) in BAL fluid of patients with CF was abrogated by diisopropylfluorophosphate and monocyte/neutrophil elastase inhibitor.

Conclusions: The findings strongly suggest that the neutrophil serine proteases cathepsin G and/or elastase and/or proteinase-3 contribute to degradation of SP-A and thereby diminish innate pulmonary antimicrobial defence.

  • inflammation
  • neutrophil serine proteases
  • cathepsin G
  • surfactant protein A
  • cystic fibrosis
  • BAL, bronchoalveolar lavage
  • CF, cystic fibrosis
  • CRD, carbohydrate recognition domain
  • DFP, diisopropyl fluorophosphate
  • MeOSuc, methoxysuccinyl
  • MNEI, monocyte/neutrophil elastase inhibitor
  • PVDF, polyvinyldine difluoride
  • SBzl, thiobenzyl ester
  • SP-A, surfactant protein-A
  • Suc, succinyl

https://doi.org/10.1136/thx.2003.014902

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    Footnotes

    • Funding: This work was supported by the Cystic Fibrosis Foundation, Mike McMorris Cystic Fibrosis Center, and NIH grants HL66548 and RR00069 General Clinical Research Centers Program of the NCRR as well as a student fellowship award to FR from the Office of Enrichment Programs at Harvard Medical School.