Inhibition of hypoxia inducible factor-1α ameliorates lung injury induced by trauma and hemorrhagic shock in rats

Abstract

Aim: Ischemia/reperfusion is an initial triggering event that leads to gut-induced acute lung injury (ALI). In this study, we investigated whether hypoxia inducible factor-1α (HIF-1α) played a role in the pathogenesis of lung injury induced by trauma and hemorrhagic shock (T/HS). Methods: Male Wistar rats underwent laparotomy and hemorrhagic shock for 60 min. Sham-shock animals underwent laparotomy but without hemorrhagic shock. After resuscitation for 3 h, the rats were sacrificed. Morphologic changes of the lungs and intestines were examined. Bronchoalveolar lavage fluid (BALF) was collected. Lung water content, pulmonary myeloperoxidase (MPO) activity and the levels of malondialdehyde (MDA), nitrite/nitrate, TNF-α, IL-1β, and IL-6 in the lungs were measured. The gene expression of pulmonary HIF-1α and iNOS, and HIF-1α transcriptional activity in the lungs were also assessed. The apoptosis in the lungs was determined using TUNEL assay and cleaved caspase-3 expression. Results: Lung and intestinal injuries induced by T/HS were characterized by histological damages and a significant increase in lung water content. Compared to the sham-shock group, the BALF cell counts, the pulmonary MPO activity and the MDA, nitrite/nitrate, TNF-α, IL-1β, and IL-6 levels in the T/HS group were significantly increased. Acute lung injury was associated with a higher degree of pulmonary HIF-1α and iNOS expression as well as apoptosis in the lungs. Intratracheal delivery of HIF-1α inhibitor YC-1 (1 mg/kg) significantly attenuated lung injury, and reduced pulmonary HIF-1α and iNOS expression and HIF-1α transcriptional activity in the T/HS group. Conclusion: Local inhibition of HIF-1α by YC-1 alleviates the lung injury induced by T/HS. Our results provide novel insight into the pathogenesis of T/HS-induced ALI and a potential therapeutic application.

Repeated Administration of Ketamine can Induce Hippocampal Neurodegeneration and Long-Term Cognitive Impairment via the ROS/HIF-1a Pathway in Developing Rats

“…Ketamine was diluted in saline at a concentration of 7.5 mg/ml and was administered at 75 mg/kg body weight. YC-1 was dissolved in 1% DMSO and was administered at 1 mg/kg 10 min after ketamine [18]. L-carnitine was dissolved in saline and was administered at 300 mg/kg 10 min after ketamine [36].…”

“…In contrast, under hypoxic conditions, HIF-1α is stabilized and translocated to the nucleus, where it dimerizes with HIF-1β and activates the expression of target genes carrying hypoxia-response elements (HREs) within their promoter or enhancer elements [17]. HIF-1 thus acts as a master regulator of cellular hypoxia response, and it can directly regulate the expression of more than 70 genes in all cell types [18]. In addition to hypoxia, non-hypoxic stimuli, such as increased ROS generation, can also increase HIF-1α expression under normoxic conditions [19,20,21].…”

“…3-(5'-hydroxymethyl-2'-furyl)-1-benzyl indazole (YC-1) is an inhibitor of HIF-1α that is widely used as a pharmacological tool for studying the physiological and pathological properties and functions of HIF-1α [18,22,23]. In this study, we used YC-1, the antioxidant L-carnitine and the Ca 2+ channel blocker nimodipine to explore and dissect the involvement of calcium influx, ROS, and HIF-1α in ketamine-induced neurotoxicity in the developing brains of neonatal rats.…”

Modulatory effect of silymarin on pulmonary vascular dysfunction through HIF-1α-iNOS following rat lung ischemia-reperfusion injury

“…HIF-1α promotion of lung tissue cell injury may be associated with hypoxia; the mitochondria of I/R-conditioned cells produce large amounts of reactive oxygen species, in addition to the hydroxide produced during I/R (28). A previous study in a rat model of pulmonary hypertension reported increased HIF-1α expression in the pulmonary artery intima, raising the level of downstream iNOS expression; this resulted in the proliferation of vascular endothelial cells within the pulmonary artery intima and concomitant structural damage to the pulmonary vascular endothelium, thereby promoting angiogenesis and pulmonary vascular remodeling (29). This prior study indicated that, at the protein and gene level, HIF-1α and iNOS may contribute to hypoxia, causing lung I/R injury (4).…”

Inhibition of IκB Kinase Attenuates the Organ Injury and Dysfunction Associated with Hemorrhagic Shock

“…Most notably, the inhibition of IKK on resuscitation attenuated iNOS expression and NOx production. The reduction of the iNOS/NO pathway may contribute to the organ protection afforded by IKK16, because several strategies which reduce an excessive formation of NO also reduce organ injury (32)(33)(34)(35).…”