Dysregulated Renin-AngioteNsin System Contributes to acute Lung Injury Caused by Hind-limb Ischemia-Reperfusion in Mice

Abstract

The mechanism of acute lung injury (ALI) following limb ischemia-reperfusion (LIR) is not yet clear. We speculate that the unbalanced expression of angiotensin-converting enzymes (ACE and ACE2) and angiotensins [Ang II and Ang-(1-7)] in the renin-angiotensin system (RAS) is a major cause of ALI. To prove this hypothesis, pathological changes, lung edema, and permeability of wild-type mice at different time points within 12 h of reperfusion after 2 h of hind-limb ischemia were first detected by morphological method, measurements of wet-to-dry weight ratio, and bronchoalveolar lavage fluid. Meanwhile, the changes of lung ACE/ACE2 mRNA and protein expression were surveyed by the methods of real-time reverse transcription-polymerase chain reaction, Western blotting, and immunohistochemistry. Angiotensin II/Ang-(1-7) levels in the blood serum and lung tissue were measured by enzyme-linked immunosorbent assay. Then the effects of ACE2 gene insertion and deletion on the previously mentioned parameters were investigated in the mice being exposed to hind-limb 2-h ischemia and 4-h reperfusion. The results revealed that lung injuries in the wild-type mice were gradually aggravated, and the expression of ACE in lung tissue was progressively increased, whereas that of ACE2 decreased within 12 h after LIR. Unexpectedly, both Ang II and Ang-(1-7) in the lung tissue were obviously increased after LIR, showing Ang-(1-7) higher than Ang II in the early stage of reperfusion but lower than Ang II at the late stage of reperfusion. Unlike local Ang II/Ang-(1-7) changes, circulating Ang-(1-7) became greatly descending, and Ang II was markedly ascending from the start of reperfusion, corresponding to local ACE/ACE2 unbalanced expression. ACE2 transgenosis improved the imbalance of ACE/ACE2 and Ang II/Ang-(1-7) expression and alleviated lung injuries, whereas ACE2 knockout further aggravated the imbalance of ACE/ACE2 and Ang II/Ang-(1-7) expression and made lung injuries more serious in the post-LIR mice. The results indicate that the dysregulation of local and circulating RAS with increased expression of ACE/Ang II and decreased expression of ACE2/Ang-(1-7) contribute to ALI caused by LIR in mice. Maintaining RAS homeostasis through upregulating ACE2 expression may lessen lung injury, which provides a new idea for the treatment of posttraumatic ALI.

Curcumin and dexmedetomidine prevents oxidative stress and renal injury in hind limb ischemia/reperfusion injury in a rat model

“…24 This cellular dysfunction and disintegrity might play a role in the etiopathology of remote organ damage including liver, kidney and lung in lower limb ischemia-reperfusion injury. [3][4][5]16 The kidneys are particularly involved in the remote alteration phenomenon following skeletal muscle ischemia-reperfusion injuries. 23 Although a diversity of mechanisms exist, oxidative stress, inflammatory response, and the apoptosis are believed to be the primary causes.…”

“…In addition, several animal studies showed that hind limb I/R injury affected several organs, including the kidneys, liver and lungs. [3][4][5] The highly selective and potent a2-adrenergic agonist dexmedetomidine (DXM) is an effective sedative, anxiolytic, and analgesic agent 6 with protective effects against I/R injury in several organs, including the heart, 7 brain, 8 and kidneys, 9 probably due to the antioxidant and anti-inflammatory properties of the compound. [10][11][12] Curcumin (CUR) has a long history of therapeutic use in Indian and Chinese medicine and has several pharmacological properties, including antioxidant, anti-inflammatory, antiviral, antimicrobial, antifungal, as well as anticancer activities.…”

Captopril pretreatment protects the lung against severe acute pancreatitis induced injury via inhibiting angiotensin II production and suppressing Rho/ROCK pathway

“…RAS, which is vital in the regulation of blood pressure, electrolytes, and total body volume, is closely related to lung injury [7]. Studies have shown that Ang II as an important component of RAS is involved in the pathogenesis of lung injury in different models, and most actions of Ang II are related to the AT1 receptor.…”

Degradation of Lung Protective Angiotensin Converting Enzyme-2 by Meconium in Human Alveolar Epithelial Cells: A Potential Pathogenic Mechanism in Meconium Aspiration Syndrome

“…RAS is thought to be a systemic cascade and plays an important role in fluid balance and blood pressure regulation [5]. However, many studies support the pivotal role of tissue specific RAS in injury and repair [6][7][8][9][10][11]. A subset of these studies supports the existence of an intrinsic angiotensin system in lung alveolar epithelial cells (AECs) and demonstrates that activation of this local angiotensin system plays a major role in lung injury [12].…”