Carbonic anhydrase inhibitor attenuates ischemia-reperfusion induced acute lung injury

Abstract

Ischemia-reperfusion (IR)-induced acute lung injury (ALI) is implicated in several clinical conditions including lung transplantation, cardiopulmonary bypass surgery, re-expansion of collapsed lung from pneumothorax or pleural effusion and etc. IR-induced ALI remains a challenge in the current treatment. Carbonic anhydrase has important physiological function and influences on transport of CO2. Some investigators suggest that CO2 influences lung injury. Therefore, carbonic anhydrase should have the role in ALI. This study was undertaken to define the effect of a carbonic anhydrase inhibitor, acetazolamide (AZA), in IR-induced ALI, that was conducted in a rat model of isolated-perfused lung with 30 minutes of ischemia and 90 minutes of reperfusion. The animals were divided into six groups (n = 6 per group): sham, sham + AZA 200 mg/kg body weight (BW), IR, IR + AZA 100 mg/kg BW, IR + AZA 200 mg/kg BW and IR+ AZA 400 mg/kg BW. IR caused significant pulmonary micro-vascular hyper-permeability, pulmonary edema, pulmonary hypertension, neutrophilic sequestration, and an increase in the expression of pro-inflammatory cytokines. Increases in carbonic anhydrase expression and perfusate pCO2 levels were noted, while decreased Na-K-ATPase expression was noted after IR. Administration of 200mg/kg BW and 400mg/kg BW AZA significantly suppressed the expression of pro-inflammatory cytokines (TNF-α, IL-1, IL-6 and IL-17) and attenuated IR-induced lung injury, represented by decreases in pulmonary hyper-permeability, pulmonary edema, pulmonary hypertension and neutrophilic sequestration. AZA attenuated IR-induced lung injury, associated with decreases in carbonic anhydrase expression and pCO2 levels, as well as restoration of Na-K-ATPase expression.

Lidocaine attenuates hypoxia/reoxygenation‑induced inflammation, apoptosis and ferroptosis in lung epithelial cells by regulating the p38 MAPK pathway

“…This is problematic, as significantly higher IL-8 levels may result in higher mortality rates following lung transplantation ( 42 ). Lan et al ( 39 ) and de Perrot et al ( 40 ) reported that elevated TNF-α and IL-6 levels contributed to organ IR injury. In the present study, the results of ELISA demonstrated that IL-6, IL-8 and TNF-α levels were markedly increased in A549 cells following H/R induction.…”

“…Inflammation serves an important role in the mechanism of LIRI ( 38 ), such that the regulation of inflammation has been revealed to effectively alleviate the disease ( 39 ). Previous studies have verified that IL-8 levels are markedly increased in lung tissue and systemic circulation after IR ( 40 , 41 ).…”

Dissecting the novel mechanism of reduning injection in treating Coronavirus Disease 2019 (COVID-19) based on network pharmacology and experimental verification

“…CAs are metalloenzymes that catalyze the hydration of carbon dioxide to bicarbonate and protons ( Supuran, 2011 ). Studies have found that the inhibition of CA2 and CA4 in the proximal convoluted tubule could reduce bicarbonate reabsorption and causes metabolic acidosis, thereby would leading to the suppression of pro-inflammatory activation ( Hudalla, et al, 2019 ; Lan, et al, 2017 ). CA inhibitors can be a base of anti-infectives ( Supuran, 2010 ).…”

Barriers and Advances in Kidney Preservation

“…Several promising avenues of research are emerging from the study of hibernating species [87], such as the use of H 2 S [88]. Other concepts include: the replacement of damaged mitochondria with healthy mitochondria at the onset of reperfusion by auto-transplantation in the heart [89]; the control of pH regulation through inhibition of carbonic anhydrase in lung transplantation, which impacts both pCO 2 levels, and Na-K-ATPase expression [90]; the sensitization of calcium channels in human hepatocytes for liver transplantation [91]; or the control of systemic iron load to protect against renal ischemia-reperfusion injury-associated sterile inflammation [92]. Finally, other drugs were recently studied: pharmacologic targeting of DHPS by N1-guanyl-1,7-diaminoheptane (GC7) or RNA interference–mediated inhibition of DHPS or DOHH induced tolerance to anoxia in immortalized mouse renal proximal cells [93].…”