Pharmacological blockade of the MaxiK channel attenuates experimental acute pancreatitis and associated lung injury in rats.
Increasing evidence has recently demonstrated that soluble heparan sulfate (HS), a degradation product of extracellular matrix produced by elastase, plays a key role in the aggravation of acute pancreatitis (AP) and associated lung injury. However little is known about the detailed mechanism underlying HS-induced inflammatory cascade. Our previous work has provided a valuable clue that a large-conductance K(+) channel (MaxiK) was involved in the HS-stimulated activation of murine macrophages. Here we attempted to ask whether pharmacological inhibition of the MaxiK channel will exert beneficial effects on the treatment of AP and secondary lung injury. The protective effects of paxilline, a specific blocker of MaxiK, on rats against sodium taurocholate induced AP were evaluated. Our data showed that paxilline substantially attenuated AP and resultant lung injury, mainly by limiting the burst of inflammatory responses, as proven by decreased plasma concentrations of tumor necrosis factor-α and macrophage inflammatory protein-2, together with unimpaired pancreatic enzyme activities in rats suffering from AP. Compared with the therapeutic administration, pre-treatment of paxilline showed superior potential to slow down the progress of AP. Furthermore, AP rats received paxilline exhibited improved histopathologic alterations both in the pancreas and the lungs, and even lower lung MPO activity. Taken together, our study provides evidence that MaxiK is involved in the spread of inflammatory responses and the following lung injury during the attack of AP, indicating that this ion channel is a promising candidate as a therapeutic target for AP.
Department of Pharmacy, Chengdu Military General Hospital, Chengdu, China. Electronic address: keanrjd@qq.com.
Jian-Dong
JD
Ren
Department of Stomatology, Chengdu Military General Hospital, Chengdu, China.
Yong-Jun
YJ
Xing
Department of Pharmacy, Chengdu Military General Hospital, Chengdu, China. Electronic address: fan_kai_hua@163.com.
Kai-Hua
KH
Fan
Department of Pharmacy, Chengdu Military General Hospital, Chengdu, China.
Bo-Tao
BT
Yu
Department of Pharmacy, Chengdu Military General Hospital, Chengdu, China.
Wei-Hua
WH
Jin
Department of Pharmacy, Chengdu Military General Hospital, Chengdu, China.
Yan
Y
Jiang
Department of Pharmacy, Chengdu Military General Hospital, Chengdu, China.
Li
L
Jing
Department of Pharmacy, Chengdu Military General Hospital, Chengdu, China.
Xue-Chai
XC
Wu
Department of Pharmacy, Chengdu Military General Hospital, Chengdu, China.
Shi-Hua
SH
Wang
Department of Pharmacy, Chengdu Military General Hospital, Chengdu, China.
Juan
J
Wu
Department of Pharmacy, Chengdu Military General Hospital, Chengdu, China.
Hua
H
Chen
D000818:Animals; D054426:Chemokine CXCL2 / Q000097:blood; D018450:Disease Progression; D006801:Humans; D051036:Large-Conductance Calcium-Activated Potassium Channels / Q000037:antagonists & inhibitors; D008099:Liver / Q000187:drug effects* / Q000473:pathology; D008168:Lung / Q000187:drug effects / Q000473:pathology; D055370:Lung Injury / Q000139:chemically induced / Q000150:complications / Q000188:drug therapy*; D008264:Macrophages / Q000187:drug effects* / Q000276:immunology; D008297:Male; D051379:Mice; D023421:Models, Animal; D019283:Pancreatitis, Acute Necrotizing / Q000139:chemically induced / Q000150:complications / Q000188:drug therapy*; D051419:Paxillin / Q000008:administration & dosage* / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D013656:Taurocholic Acid / Q000008:administration & dosage; D014409:Tumor Necrosis Factor-alpha / Q000097:blood
D054426:Chemokine CXCL2; D051036:Large-Conductance Calcium-Activated Potassium Channels; D051419:Paxillin; D014409:Tumor Necrosis Factor-alpha; D013656:Taurocholic Acid
Acute pancreatitis; Heparan sulfate; Lung injury; MaxiK; Paxilline; Toll like receptor 4