TY - JOUR
T1 - Mechanisms of toxic smoke inhalation and burn injury
T2 - Role of neutral endopeptidase and vascular leakage in mice
AU - Jacob, Sam
AU - Deyo, Donald J.
AU - Cox, Robert A.
AU - Traber, Daniel L.
AU - Herndon, David N.
AU - Hawkins, Hal K.
N1 - Funding Information:
This work was supported by a program project grant from NIH, # NIGMS PO1-GM66312 and a core facility grant from Shriners Hospitals for Children (Project #8460).
PY - 2009
Y1 - 2009
N2 - The effects of neutral endopeptidase (NEP) in acute inflammation in the lung were studied using a newly developed murine model of smoke and burn (SB) injury. C57BL/6 mice were pretreated with an i.v. dose of a specific NEP antagonist CGS-24592 (10 mg/Kg) 1 h prior to SB injury (n 58/group). Mice were anesthetized with i.p. ketamine/xylazine, intubated, and exposed to cooled cotton smoke (2 × 30 s). After s.c. injection of 1 ml 0.9% saline, each received a 40% total body surface area (TBSA) flame burn. Buprenorphene (2 mg/kg) was given i.p. and resuscitated by saline. Evans Blue dye (EB) was injected i.v. 15 min before sacrifice. Lung wet/dry weight ratio was measured. After vascular perfusion, lungs were analyzed for their levels of EB dye and myeloperoxidase (MPO). In mice pretreated with CGS-24592 followed by SB injury the EB levels were significantly higher (61%, p 0.043) than those with SB injury alone. There was a significant increase (144%, p 0.035) in EB dye in animals with SB injury alone as compared to shams. In mice pretreated with CGS-24592 prior to SB injury wet/dry weight ratios were significantly (27%, p 0.042) higher compared to animals with SB injury alone. CGS-24592 pretreatment also caused a significant increase in MPO (29%, p 0.026) as compared to mice with SB injury alone. In conclusion the current study indicates that specific NEP inhibitor CGS 24592 exacerbates the SB-induced lung injury and inflammation in mice.
AB - The effects of neutral endopeptidase (NEP) in acute inflammation in the lung were studied using a newly developed murine model of smoke and burn (SB) injury. C57BL/6 mice were pretreated with an i.v. dose of a specific NEP antagonist CGS-24592 (10 mg/Kg) 1 h prior to SB injury (n 58/group). Mice were anesthetized with i.p. ketamine/xylazine, intubated, and exposed to cooled cotton smoke (2 × 30 s). After s.c. injection of 1 ml 0.9% saline, each received a 40% total body surface area (TBSA) flame burn. Buprenorphene (2 mg/kg) was given i.p. and resuscitated by saline. Evans Blue dye (EB) was injected i.v. 15 min before sacrifice. Lung wet/dry weight ratio was measured. After vascular perfusion, lungs were analyzed for their levels of EB dye and myeloperoxidase (MPO). In mice pretreated with CGS-24592 followed by SB injury the EB levels were significantly higher (61%, p 0.043) than those with SB injury alone. There was a significant increase (144%, p 0.035) in EB dye in animals with SB injury alone as compared to shams. In mice pretreated with CGS-24592 prior to SB injury wet/dry weight ratios were significantly (27%, p 0.042) higher compared to animals with SB injury alone. CGS-24592 pretreatment also caused a significant increase in MPO (29%, p 0.026) as compared to mice with SB injury alone. In conclusion the current study indicates that specific NEP inhibitor CGS 24592 exacerbates the SB-induced lung injury and inflammation in mice.
KW - Acute lung injury
KW - NEP
KW - Neurogenic inflammation
KW - Neutral endopeptidase activity
KW - Plasma extravasation
KW - Vascular permeability
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U2 - 10.1080/15376510902725649
DO - 10.1080/15376510902725649
M3 - Article
C2 - 19727335
AN - SCOPUS:70350489858
SN - 1537-6516
VL - 19
SP - 191
EP - 196
JO - Toxicology Mechanisms and Methods
JF - Toxicology Mechanisms and Methods
IS - 3
ER -