Caspase-1 inhibitor prevents neurogenic pulmonary edema after subarachnoid hemorrhage in mice.
OBJECTIVE
We examined the effects of a caspase-1 inhibitor, N-Ac-Tyr-Val-Ala-Asp-chloromethyl ketone (Ac-YVAD-CMK), on neurogenic pulmonary edema in the endovascular perforation model of subarachnoid hemorrhage (SAH) in mice.


METHODS
Ninety-seven mice were assigned to sham, SAH+vehicle, SAH+Ac-YVAD-CMK (6 or 10 mg/kg), and SAH+Z-Val-Ala-Asp-fluoromethylketone (Z-VAD-FMK, 6 mg/kg) groups. Drugs were intraperitoneally injected 1 hour post-SAH. Pulmonary edema measurements, Western blot for interleukin-1beta, interleukin-18, myeloperoxidase, matrix metalloproteinase (MMP)-2, MMP-9, cleaved caspase-3 and zona occludens-1, MMP zymography, terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling staining, and immunostaining were performed on the lung at 24 hours post-SAH.


RESULTS
Ten- but not 6-mg/kg of Ac-YVAD-CMK significantly inhibited a post-SAH increase in the activation of interleukin-1beta and caspase-3 and the number of terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling-positive pulmonary endothelial cells, preventing neurogenic pulmonary edema. Another antiapoptotic drug, Z-VAD-FMK, also reduced neurogenic pulmonary edema. SAH did not change interleukin-18, myeloperoxidase, MMP-2, MMP-9, zona occludens-1 levels, or MMP activity.


CONCLUSIONS
We report for the first time that Ac-YVAD-CMK prevents lung cell apoptosis and neurogenic pulmonary edema after SAH in mice.
Suzuki
Hidenori
H
Sozen
Takumi
T
Hasegawa
Yu
Y
Chen
Wanqiu
W
Zhang
John H
JH
D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D015415:Biomarkers; D020170:Caspase 1 / Q000378:metabolism; D061945:Caspase Inhibitors; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D020287:In Situ Nick-End Labeling; D007274:Injections, Intraperitoneal; D053583:Interleukin-1beta / Q000187:drug effects / Q000378:metabolism; D008168:Lung / Q000187:drug effects / Q000294:innervation / Q000503:physiopathology; D051379:Mice; D011654:Pulmonary Edema / Q000188:drug therapy* / Q000209:etiology* / Q000503:physiopathology; D013345:Subarachnoid Hemorrhage / Q000150:complications*; D016896:Treatment Outcome
D000590:Amino Acid Chloromethyl Ketones; D015415:Biomarkers; D061945:Caspase Inhibitors; D015853:Cysteine Proteinase Inhibitors; D053583:Interleukin-1beta; C098738:N-acetyl-tyrosyl-valyl-alanyl-aspartyl chloromethyl ketone; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; D020170:Caspase 1