title: TAT-SNAP-23 treatment inhibits the priming of neutrophil functions contributing to shock and/or sepsis-induced extra-pulmonary acute lung injury.
abstract: Respiratory burst function of neutrophils is thought to play a pivotal role in the development of pathologies such as indirect (extra-pulmonary) acute lung injury (iALI), as well as sepsis. The current study was conducted to determine the effect of an HIV transactivator of transcription (TAT)-fusion protein containing a soluble N-ethylmaleimide-sensitive factor attachment protein receptor domain from synaptosome-associated protein-23 (SNAP-23) on the shock/sepsis- and sepsis-enhanced neutrophil burst capacity using the clinical relevant two-hit iALI mouse model and the classical cecal ligation and puncture (CLP) septic model. TAT-SNAP-23 significantly decreased the blood neutrophil respiratory burst in vitro, and also in vivo in CLP and hemorrhaged mice. We found that the neutrophil influx to the lung tissue, as measured by myeloperoxidase levels and neutrophil-specific esterase(+) cells, was also decreased in the TAT-SNAP-23-treated group. Consistent with this, treatment of TAT-SNAP-23 significantly reduced the disruption of lung tissue architecture and protein concentration of bronchoalveolar lavage fluid in iALI mice compared with vehicle-treated iALI mice. In addition, although TAT-SNAP-23 did not alter the extent of local cytokine/chemokine expression, the in vitro migration capacity of neutrophils was blunted from septic and hemorrhagic mice. These data support our hypothesis that TAT-SNAP-23 reduces neutrophil dysfunction in iALI and sepsis by inhibiting neutrophil respiratory burst.
authors.affiliation: Department of Emergency Medicine and Critical Care, Shanghai East Hospital, Tong Ji University, Shanghai, PR China.
authors.forename: Jianwen
authors.initials: J
authors.lastname: Bai
authors.affiliation: Department of Emergency Medicine and Critical Care, Shanghai East Hospital, Tong Ji University, Shanghai, PR China.
authors.forename: Lunxian
authors.initials: L
authors.lastname: Tang
authors.affiliation: Department of Surgery, Division of Surgical Research, the Alpert School of Medicine at Brown University/Rhode Island Hospital, Providence, RI, USA.
authors.forename: Joanne
authors.initials: J
authors.lastname: Lomas-Neira
authors.affiliation: Department of Surgery, Division of Surgical Research, the Alpert School of Medicine at Brown University/Rhode Island Hospital, Providence, RI, USA.
authors.forename: Yaping
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Medicine, University of Louisville, Louisville, KY, USA Robley Rx VAMC, Louisville, KY, USA.
authors.forename: Kenneth R
authors.initials: KR
authors.lastname: McLeish
authors.affiliation: Department of Medicine, University of Louisville, Louisville, KY, USA.
authors.forename: Silvia M
authors.initials: SM
authors.lastname: Uriarte
authors.affiliation: Department of Surgery, Division of Surgical Research, the Alpert School of Medicine at Brown University/Rhode Island Hospital, Providence, RI, USA.
authors.forename: Chun-Shiang
authors.initials: CS
authors.lastname: Chung
authors.affiliation: Department of Surgery, Division of Surgical Research, the Alpert School of Medicine at Brown University/Rhode Island Hospital, Providence, RI, USA aayala@lifespan.org.
authors.forename: Alfred
authors.initials: A
authors.lastname: Ayala
mesh_terms: D055371:Acute Lung Injury / Q000209:etiology* / Q000503:physiopathology; D000818:Animals; D001992:Bronchoalveolar Lavage Fluid; D002634:Chemotaxis, Leukocyte / Q000187:drug effects; D015696:Gene Products, tat / Q000494:pharmacology*; D006470:Hemorrhage / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D052066:N-Ethylmaleimide-Sensitive Proteins / Q000494:pharmacology; D009504:Neutrophils / Q000187:drug effects*; D009195:Peroxidase / Q000378:metabolism; D050766:Qb-SNARE Proteins / Q000494:pharmacology*; D050767:Qc-SNARE Proteins / Q000494:pharmacology*; D016897:Respiratory Burst / Q000187:drug effects; D018805:Sepsis / Q000150:complications* / Q000503:physiopathology; D012772:Shock, Septic / Q000150:complications* / Q000503:physiopathology
chemical_list: D015696:Gene Products, tat; D050766:Qb-SNARE Proteins; D050767:Qc-SNARE Proteins; C107017:Snap23 protein, mouse; D009195:Peroxidase; D052066:N-Ethylmaleimide-Sensitive Proteins
keywords: Neutrophil influx; migration; respiratory burst capacity