Inhibition of neutrophil exocytosis ameliorates acute lung injury in rats.
Exocytosis of neutrophil granules contributes to acute lung injury (ALI) induced by infection or inflammation, suggesting that inhibition of neutrophil exocytosis in vivo could be a viable therapeutic strategy. This study was conducted to determine the effect of a cell-permeable fusion protein that inhibits neutrophil exocytosis (TAT-SNAP-23) on ALI using an immune complex deposition model in rats. The effect of inhibition of neutrophil exocytosis by intravenous administration of TAT-SNAP-23 on ALI was assessed by albumin leakage, neutrophil infiltration, lung histology, and proteomic analysis of bronchoalveolar lavage fluid (BALF). Administration of TAT-SNAP-23, but not TAT-control, significantly reduced albumin leakage, total protein levels in the BALF, and intra-alveolar edema and hemorrhage. Evidence that TAT-SNAP-23 inhibits neutrophil exocytosis included a reduction in plasma membrane CD18 expression by BALF neutrophils and a decrease in neutrophil granule proteins in BALF. Similar degree of neutrophil accumulation in the lungs and/or BALF suggests that TAT-SNAP-23 did not alter vascular endothelial cell function. Proteomic analysis of BALF revealed that components of the complement and coagulation pathways were significantly reduced in BALF from TAT-SNAP-23-treated animals. Our results indicate that administration of a TAT-fusion protein that inhibits neutrophil exocytosis reduces in vivo ALI. Targeting neutrophil exocytosis is a potential therapeutic strategy to ameliorate ALI.
Department of Medicine, University of Louisville, Louisville, KY, USA. silvia.uriarte@louisville.edu
Silvia M
SM
Uriarte
Madhavi J
MJ
Rane
Michael L
ML
Merchant
Shunying
S
Jin
Alex B
AB
Lentsch
Richard A
RA
Ward
Kenneth R
KR
McLeish
D055371:Acute Lung Injury / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry / Q000166:cytology; D018821:CD18 Antigens / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical / Q000379:methods; D005089:Exocytosis / Q000187:drug effects*; D015696:Gene Products, tat / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D008297:Male; D020556:Neutrophil Infiltration / Q000187:drug effects; D009504:Neutrophils / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D040901:Proteomics / Q000379:methods; D051381:Rats; D020318:Rats, Long-Evans; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D050600:SNARE Proteins / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*
D018821:CD18 Antigens; D015696:Gene Products, tat; D011993:Recombinant Fusion Proteins; D050600:SNARE Proteins; C582513:TAT-SNAP-23 fusion protein