Sildenafil Blunts Lung Inflammation and Oxidative Stress in a Rat Model of Cholestasis

Background: Cholestasis is a multifaceted disease that influences not only the function of the liver but also affects many other organs. In this context, cholestasis-induced lung injury is a significant clinical complication. Unfortunately, there is no precise therapeutic option against cholestasis-associated lung injury. It has been revealed that oxidative stress and inflammatory response play a role in cholestasis-induced pulmonary damage. Sildenafil is a phosphodiesterase enzyme inhibitor used in the management of erectile dysfunction. Meanwhile, several experiments revealed the effects of sildenafil on oxidative stress and inflammation. This study aimed to evaluate the effect of sildenafil on cholestasis-induced oxidative stress and inflammation in cholestasis-induced lung injury. Methods: Rats underwent bile duct ligation (BDL) to induce cholestasis. Bronchoalveolar lavage fluid (BALF) levels of inflammatory cells, cytokine, and immunoglobulin were monitored at (3, 7, and 14 days after BDL surgery). Moreover, lung tissue histopathological alterations and biomarkers of oxidative stress were evaluated. Results: A significant increase in BALF inflammatory cells, TNF-α, and immunoglobulin G (IgG) was evident in BDL animals. Moreover, the infiltration of inflammatory cells, vascular congestion, and hemorrhage were detected in the lung of BDL rats. Increased markers of oxidative stress were also evident in the lung of BDL animals. Sildenafil (10 and 20 mg/kg) significantly blunted inflammatory response, oxidative stress, and histopathological alterations in the lung of cholestatic animals. Conclusion: The effects of sildenafil on inflammatory response and oxidative stress biomarkers seems to play a crucial role in its protective properties in the lung of cholestatic animals

Dexamethasone Blunts Lung Inflammation in Cholestatic Mice

Cholestasis/cirrhosis is a multifaceted clinical complication that influences many organs, including the liver, kidney, heart, skeletal muscle, and lung. Cirrhosis-associated lung injury could lead to severe and lethal consequences, including acute respiratory syndrome and patient dearth. Unfortunately, there is no specific pharmacological intervention to manage cholestasis-induced lung injury. It has been revealed that severe inflammation and its associated complications, such as oxidative stress, are involved in the pathogenesis of cholestasis-associated pulmonary damage. The current study was designed to evaluate the role of dexamethasone (DXM) on lung inflammation in cholestatic mice. For this purpose, bile duct ligated (BDL) mice received DXM (1 and 2.5 mg/kg, i.p, 2 times/week) for 14 days. On day 15, the bronchoalveolar lavage fluid (BALF) was prepared. Several markers, including inflammatory cell infiltration, TNF-α, and IgG, were assessed in the BALF of BDL animals. Significant infiltration of inflammatory cells along with increased TNF-α and IgG were detected in the BALF of BDL mice (14 days after surgery). Moreover, significant ROS formation, glutathione depletion, lipid peroxidation, and protein carbonylation were evident in the lung tissue of the BDL group. It was found that DXM (1 and 2.5 mg/kg) significantly blunted inflammation and oxidative stress in the lung of cholestatic mice. Moreover, lung tissue histopathological changes, including inflammatory cell infiltration, were significantly mitigated in DXM-treated mice. These data offer the potential therapeutic effects of DXM against cholestasis-related complications. Therefore, patients with cholestasis-induced lung injury might benefit from repurposing DXM in clinical settings

Thiol-reducing agents abate cholestasis-induced lung inflammation, oxidative stress, and histopathological alterations

Cholestasis is not only influences the hepatic function but also damages many other organs. Lung injury is a critical secondary organ damage associated with cholestasis/cirrhosis. Pulmonary histopathological alterations, respiratory distress, and hypoxia are related to cholestasis/cirrhosis-induced lung injury. It has been found that oxidative stress plays a crucial role in this complication. The current study was designed to investigate the effect of N-acetyl cysteine (NAC) and dithiothreitol (DTT) as thiol-reducing and antioxidant agents against cholestasis-induced lung injury. Bile duct ligated (BDL) rats were monitored for the presence of inflammatory cells, TNF-α, and IgG levels in their broncho-alveolar fluid (BALF) at scheduled time intervals (3, 7, 14, and 28 days post-BDL surgery). These markers reached their highest level in the BALF of BDL rats on day 28 after the surgery. Therefore, in another set of experiments, the BDL animals were treated with NAC (100 and 300 mg/kg/day, i.p, for 28 consecutive days) and DTT (10 and 20 mg/kg/day, i.p, for 28 consecutive days). Meanwhile, a significant increase in the levels of TNF-α and IgG was detected in the BALF of BDL rats. The BALF level of neutrophils, monocytes, and lymphocytes was also significantly increased in cholestatic animals. A significant increase in lung tissue biomarkers of oxidative stress was detected in the BDL rats. It was found that NAC and DTT could significantly blunt pulmonary damage induced by cholestasis. The effects of these agents on oxidative stress biomarkers and inflammatory response seem to play a pivotal role in their mechanisms of protective properties

Taurine mitigates the development of pulmonary inflammation, oxidative stress, and histopathological alterations in a rat model of bile duct ligation

Abstract Lung injury is a significant complication associated with cholestasis/cirrhosis. This problem significantly increases the risk of cirrhosis-related morbidity and mortality. Hence, finding effective therapeutic options in this field has significant clinical value. Severe inflammation and oxidative stress are involved in the mechanism of cirrhosis-induced lung injury. Taurine (TAU) is an abundant amino acid with substantial anti-inflammatory and antioxidative properties. The current study was designed to evaluate the role of TAU in cholestasis-related lung injury. For this purpose, bile duct ligated (BDL) rats were treated with TAU (0.5 and 1% w: v in drinking water). Significant increases in the broncho-alveolar lavage fluid (BALF) level of inflammatory cells (lymphocytes, neutrophils, basophils, monocytes, and eosinophils), increased IgG, and TNF-α were detected in the BDL animals (14 and 28 days after the BDL surgery). Alveolar congestion, hemorrhage, and fibrosis were the dominant pulmonary histopathological changes in the BDL group. Significant increases in the pulmonary tissue biomarkers of oxidative stress, including reactive oxygen species formation, lipid peroxidation, increased oxidized glutathione levels, and decreased reduced glutathione, were also detected in the BDL rats. Moreover, significant myeloperoxidase activity and nitric oxide levels were seen in the lung of BDL rats. It was found that TAU significantly blunted inflammation, alleviated oxidative stress, and mitigated lung histopathological changes in BDL animals. These data suggest TAU as a potential protective agent against cholestasis/cirrhosis-related lung injury