Therapeutic effects of caspase-1 inhibitors on acute lung injury in experimental severe acute pancreatitis.
OBJECTIVE
To assess the therapeutic effect of Caspase-1 inhibitors (ICE-I) on acute lung injury (ALI) in experimental severe acute pancreatitis (SAP).


METHODS
Forty-two SD rats were randomly divided into 3 groups: healthy controls (HC, n = 6); SAP-S group (n = 18); SAP-ICE-I group (n = 18). SAP was induced by retrograde infusion of 5% sodium taurocholate into the bile-pancreatic duct. HC rats underwent the same surgical procedures and duct cannulation without sodium taurocholate infusion. In SAP-S group, rats received the first intraperitoneal injection of isotonic saline 2 h after induction of acute pancreatitis and a repeated injection after 12 h. In SAP-ICE-I group, the rats were firstly given ICE inhibitors intraperitoneally 2 h after induction of pancreatitis. As in SAP-S group, the injection was repeated at 12 h. Serum IL-1beta was measured by ELISA. Intrapulmonary expression of Caspase-1, IL-1beta and IL-18 mRNA were detected by semi-quantitative RT-PCR. The wet/dry weight ratios and histopathological changes of the lungs were also evaluated.


RESULTS
Serum IL-1beta levels in SAP-S group were 276.77 +/- 44.92 pg/mL at 6 h, 308.99 +/- 34.95 pg/mL at 12 h, and 311.60 +/- 46.51 pg/mL at 18 h, which were increased significantly (P < 0.01, vs HC). In SAP-ICE-I group, those values were decreased significantly (P < 0.01, vs SAP-S). Intrapulmonary expression of Caspase-1, IL-1beta and IL-18 mRNA were observed in the HC group, while they were increased significantly in the SAP-S group (P < 0.01, vs HC). The expression of IL-1beta and IL-18 mRNA were decreased significantly in the SAP-ICE-I group (P < 0.01, vs SAP-S), whereas Caspase-1 mRNA expression had no significant difference (P > 0.05). The wet/dry weight ratios of the lungs in the SAP-S group were increased significantly (P < 0.05 at 6 h, P < 0.01 at 12 h and 18 h, vs HC) and they were decreased significantly in the SAP-ICE-I group (P < 0.05, vs SAP-S). Caspase-1 inhibitors ameliorated the severity of ALI in SAP.


CONCLUSIONS
Caspase-1 activation, and overproduction of IL-1beta and IL-18 play an important role in the course of ALI, and Caspase-1 inhibition is effective for the treatment of ALI in experimental SAP.
Zhang
Xiao-Hua
XH
Department of Gastroenterology, Jinling Hospital, Nanjing 210002, Jiangsu Province, China.
Zhu
Ren-Min
RM
Xu
Wen-An
WA
Wan
Hai-Jun
HJ
Lu
Heng
H
D000208:Acute Disease; D000818:Animals; D020170:Caspase 1 / Q000235:genetics; D061945:Caspase Inhibitors; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D020382:Interleukin-18 / Q000235:genetics; D053583:Interleukin-1beta / Q000097:blood / Q000235:genetics; D008168:Lung / Q000473:pathology; D008297:Male; D010195:Pancreatitis / Q000150:complications* / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D012128:Respiratory Distress Syndrome / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics
D061945:Caspase Inhibitors; D004791:Enzyme Inhibitors; D020382:Interleukin-18; D053583:Interleukin-1beta; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D020170:Caspase 1