Abstract:
:Fasudil, a rock kinase inhibitor, can inhibit systemic inflammation and prevent paraquat (PQ)-induced acute lung injuries in rats; however, the mechanisms for these protective effects remain elusive. This study investigated how the Rho/ROCK signaling pathway enables fasudil to protect against acute lung injuries in PQ-treated rats. Wistar rats (n = 240) were pretreated with fasudil (10 and 30 mg/kg, i.p.) 1 h prior to PQ administration. When compared to rats with PQ-induced lung injuries, rats pretreated with fasudil had significantly fewer polymorphonuclear neutrophils and lower concentrations of protein, TNF-α, IL-1β, and IL-6 in their bronchoalveolar lavage fluid. Moreover, fasudil also reduced the Evans Blue content, wet-to-dry weight ratio, lung injury scores, and levels malondialdehyde and 8-hydroxy-2 deoxyguanosine, but increased superoxide dismutase activity in lung tissue. Furthermore, Rho, ROCK1 expression and the levels of phosphorylated MYPT-1 in lung tissues were drastically decreased in fasudil-treated rats, whereas ZO-1 protein expression was significantly increased (p < 0.05). We found that fasudil downregulated bax and activated caspase-3 mRNA expression but upregulated Bcl-2 mRNA expression. In vitro experiments showed that the levels of TNF-α, IL-1β, and IL-6 secreted by human pulmonary microvascular endothelial cells treated with PQ were attenuated by fasudil. Fasudil inhibited the upregulation Rho and ROCK protein expression and downregulation of ZO-1 protein expression in HPMVECs induced with PQ. Higher concentrations of fasudil produced greater affects than lower concentrations. Fasudil improved endothelial permeability and inhibited inflammation, oxidative stress, and cell apoptosis to alleviate acute lung injuries in PQ-treated rats. Fasudil exerted these therapeutic effects by inhibiting the Rho/ROCK signaling pathway.
journal_name
Inflammationjournal_title
Inflammationauthors
Zhang L,Li Q,Liu Z,Liu W,Zhao Mdoi
10.1007/s10753-018-0860-1subject
Has Abstractpub_date
2018-12-01 00:00:00pages
2171-2183issue
6eissn
0360-3997issn
1573-2576pii
10.1007/s10753-018-0860-1journal_volume
41pub_type
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