Effect of dexmedetomidine on lung ischemia‑reperfusion injury

Abstract

Dexmedetomidine, a specific selective α2-adrenergic agonist, does not only have the characteristics of being a sedative and analgesic, but also exhibits a protective role in brain ischemia-reperfusion injury and inhibits the inflammation in animals with sepsis. The objective of the present study was to investigate whether dexmedetomidine is capable of attenuating rat pulmonary damage induced by ischemia-reperfusion injury, which is a type of acute sterile lung injury. Sprague-Dawley rats were randomly assigned into six groups: The sham-operated (sham) group, the lung ischemia-reperfusion (I/R) group, intravenous injection of dexmedetomidine 2.5 µg/kg/h (Dex2.5) or 5 µg/kg/h (Dex5) for 1 h prior to ischemia, combination of α2-adrenergic antagonist yohimbine prior to dexmedetomidine pre-treatment (Dex+Yoh) and pre-administration of yohimbine alone (Yoh) prior to ischemia. Lung injury was assessed by the histopathological changes, arterial blood gas, wet/dry (w/d) weight ratio and myeloperoxidase (MPO) activity of the lung. The concentration of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and monocyte chemoattractant protein-1 (MCP-1) in bronchoalveolar lavage fluid (BALF) was measured by an enzyme-linked immunosorbent assay. The expression of toll-like receptor-4 (TLR4) and myeloid differentiation factor 88 (MyD88) mRNA in the lung were determined by quantitative PCR, and phosphorylated levels of c-Jun N-terminal kinase (JNK) and extracellular signal-regulated kinase (ERK)1/2 were determined by western blotting. Pre-treatment with dexmedetomidine significantly reduced the lung injury, w/d weight ratio and MPO activity, and decreased the concentration of TNF-α, IL-6 and MCP-1 in BALF compared with the I/R group. The expression of TLR4 and MyD88 mRNA and the levels of phosphorylated JNK and ERK1/2 in the lung tissue were markedly downregulated by intravenous injection of dexmedetomidne for 1 h prior to lung I/R. The protective effects of dexmedetomidine on the lung were not completely reversed by the α2-adrenergic antagonist, yohimbine. Pre-treatment with dexmedetomidine is capable of reducing pulmonary damage and inhibiting sterile inflammation induced by lung I/R injury. TLR4/MyD88/mitogen-activated protein kinase (MAPK) signaling is involved in the protective mechanism of dexmedetomidine through α2-adrenoceptor independence.

Figure 1

Microscopic findings from the rat left lung tissues stained with hematoxylin and eosin (magnification, ×200). The (A) sham (B) I/R (C) Dex2.5 (D) Dex5 (E) Dex+Yoh and (F) Yoh groups. (G) The severity of lung injury was scored and the data are presented as the mean ± standard deviation. ^**P<0.01 vs. the sham group and ^##P<0.01 vs. the I/R group. Dex, dexmedetomidine; Dex 2.5, 2.5 μg/kg/h Dex; Dex 5, 5 μg/kg/h; Yoh, yohimbine; DexI/R, ischemia-reperfusion.

Figure 2

Ratio of (A) wet/dry weight and (B) MPO activity assays in lung tissues harvested from rats of the six groups. The data are presented as the mean ± standard deviation. ^*P<0.05 and ^**P<0.01 vs. the sham group; ^#P<0.05 and ^##P<0.01 vs. the I/R group. MPO, myeloperoxidase; Dex, dexmedetomidine; Dex 2.5, 2.5 μg/kg/h Dex; Dex 5, 5 μg/kg/h; Yoh, yohimbine; I/R, ischemia-reperfusion.

Figure 3

ELISA analysis of (A) TNF-α, (B) IL-6, and (C) MCP-1 expression in BALF. The data are presented as the mean ± standard deviation. ^*P<0.05 and ^**P<0.01 vs. the sham group. TNF-α, tumor necrosis factor α; IL-6, interleukin-6; MCP-1, monocyte chemoattractant protein-1; BALF, bronchoalveolar lavage fluid; ELISA, enzyme-linked immunosorbent assay; Dex, dexmedetomidine; Yoh, yohimbine; I/R, ischemia-reperfusion.

Figure 4

Expression of (A) TLR4 mRNA and (B) MyD88 mRNA in lung tissues harvested from rats of the six groups. The data are presented as the mean ± standard deviation. ^*P<0.05 and ^**P<0.01 vs. the sham group; ^#P<0.05 and ^##P<0.01 vs. the I/R group. TLR4, toll-like receptor-4; MyD88, myeloid differentiation factor 88; Dex, dexmedetomidine; Dex 2.5, 2.5 μg/kg/h Dex; Dex 5, 5 μg/kg/h; Yoh, yohimbine; I/R, ischemia-reperfusion.

Figure 5

Activation of mitogen-activated protein kinase in lung tissues harvested from rats of the six groups. (A) Western blot analysis of JNK and ERK activation; (B) quantification of the p-JNK/JNK in (A); (C) quantification of the p-ERK/ERK in (A). The data are presented as the mean ± standard deviation. ^*P<0.05 and ^**P<0.01 vs. the sham group; ^#P<0.05 and ^##P<0.01 vs. the I/R group. I/R, ischemia-reperfusion; Dex, dexmedetomidine; Dex 2.5, 2.5 μg/kg/h Dex; Dex 5, 5 μg/kg/h; Yoh, yohimbine; P-JNK, phosphorylated c-Jun N-terminal kinase; P-ERK, phosphorylated extracellular signal-regulated kinase.