The Roles of Autophagy in Acute Lung Injury Induced by Myocardial Ischemia Reperfusion in Diabetic Rats

Abstract

Patients with diabetes are vulnerable to myocardial ischemia reperfusion (IR) injury, which may also induce acute lung injury (ALI) due to overaccumulation of reactive oxygen species (ROS) and inflammation cytokine in circulation. Despite autophagy plays a significant role in diabetes and pulmonary IR injury, the role of autophagy in ALI secondary to myocardial IR in diabetes remains largely elusive. We aimed to investigate pulmonary autophagy status and its roles in oxidative stress and inflammation reaction in lung tissues from diabetic rats subjected to myocardial IR. Control or diabetic rats were either treated with or without autophagy inducer rapamycin (Rap) or autophagy inhibitor 3-methyladenine (3-MA) before myocardial IR, which was achieved by occluding the left anterior descending coronary artery for 30 min and followed by reperfusion for 120 min. Diabetic rats subjected to myocardial IR showed more serious ALI with higher lung injury score and WET/DRY ratio and lower PaO2 as compared with control rats, accompanied with impaired autophagy indicated by reduced LC-3II/LC-3I ratio and Beclin-1 expression, decreased superoxide dismutase (SOD) activity, and increased 15-F2t-Isoprostane formation in lung tissues, as well as increased levels of leukocyte count and proinflammatory cytokines in BAL fluid. Improving autophagy with Rap significantly attenuated all these changes, but the autophagy inhibitor 3-MA exhibited adverse or opposite effects as Rap. In conclusion, diabetic lungs are more vulnerable to myocardial IR, which are involved in impaired autophagy. Improving autophagy could attenuate ALI induced by myocardial IR in diabetic rats, possibly through inhibiting inflammatory reaction and oxidative stress.

Delayed treatment with an autophagy inhibitor 3-MA alleviates the progression of hyperuricemic nephropathy

“…Autophagy inhibition by 3-MA with dosage of 15 mg/kg/d i.p. is consistent with studies in the rat models 60,61 . The sham group was injected with an equal volume of saline as a control.…”

Inhibition of HDAC3 Ameliorates Cerebral Ischemia Reperfusion Injury in Diabetic Mice In Vivo and In Vitro

“…When the stress stimuli remain unresolved, continued autophagy activation progresses to autophagy defect which is associated with the development of metabolic syndrome, lipid abnormalities, and diabetes [40]. Evidence from our group [26, 45], as well as others [44, 46], have demonstrated that autophagy is inhibited in diabetic state. Autophagy also plays an important role in the pathogenesis of cerebral I/R injury [47].…”

Oxymatrine exerts a protective effect in myocardial ischemia/reperfusion‑induced acute lung injury by inhibiting autophagy in diabetic rats

“…Light microscopic examination was conducted to determine the following: i) Pulmonary interstitial edema; ii) airway epithelial injury; iii) the degree of hyalinization; and vi) the lung injury score. The criteria for the lung injury score was membrane formation, neutrophil infiltration and alveolar hemorrhage (7,19). The indices were graded as follows: i) normal=0'; ii) minimal change=1'; iii) mild change=2'; iv) moderate change=3'; and v) severe change=4'.…”

“…Several studies have also demonstrated the subclinical significance of the diabetic lung, and that patients with diabetes are prone to severe respiratory disorders in the event of acute or chronic lung and/or cardiac disease (2,5). Further clinical and experimental data have indicated that inflammatory responses and metabolic abnormalities in diabetes aggravate the acute lung injury (ali) via autophagy (6,7). Myocardial infarction is considered to be one of the more common complications underlying diabetes-associated mortality.…”