Fatty Acid Amide Hydrolase (FAAH) Inhibition Plays a Key Role in Counteracting Acute Lung Injury.

Tiziana Genovese,Roberta Fusco,Enrico Gugliandolo,Daniela Impellizzeri,Salvatore Cuzzocrea,Rosanna Di Paola,Ramona D’Amico,Rosalia Crupi,Alessio Filippo Peritore,Rosalba Siracusa,Andrea Duranti,Marika Cordaro

doi:10.3390/ijms23052781

Abstract

Acute lung injury (ALI) is a group of lung illnesses characterized by severe inflammation, with no treatment. The fatty acid amide hydrolase (FAAH) enzyme is an integral membrane protein responsible for the hydrolysis of the main endocannabinoids, such as anandamide (AEA). In pre-clinical pain and inflammation models, increasing the endogenous levels of AEA and other bioactive fatty acid amides (FAAs) via genetic deletion or the pharmacological inhibition of FAAH produces many analgesic benefits in several different experimental models. To date, nobody has investigated the role of FAAH inhibition on an ALI mouse model. Mice were subjected to a carrageenan injection and treated orally 1 h after with the FAAH inhibitor URB878 dissolved in a vehicle consisting of 10% PEG-400, 10% Tween-80 and 80% saline at different doses: The inhibition of FAAH activity was able to counteract not only the CAR-induced histological alteration, but also the cascade of related inflammatory events. URB878 clears the way for further studies based on FAAH inhibition in acute lung pathologies.

Highlights

Acute lung injury (ALI) or its more severe form acute respiratory distress syndrome (ARDS) is a group of lung illnesses characterized by a severe inflammatory process that causes severe hypoxia, hypercapnia, diffuse infiltration, and poor pulmonary compliance [1].The inflammatory process causes alveolar and interstitial edema, impaired alveolar fluid clearance, reduction in surfactant synthesis and function, and lung fibrosis, depending on whether it starts from the alveolar or microvascular side
Systemic inflammation is triggered by the release of inflammatory mediators from injured lung tissue, and it can lead to multiple organ failure, which is the leading cause of mortality in ARDS patients
By Western blots, immunohistochemistry and nitrite/nitrate analyses, we investigated the effects of fatty acid amide hydrolase (FAAH) inhibition on nitrosative stress

Summary

Introduction

Acute lung injury (ALI) or its more severe form acute respiratory distress syndrome (ARDS) is a group of lung illnesses characterized by a severe inflammatory process that causes severe hypoxia, hypercapnia, diffuse infiltration, and poor pulmonary compliance [1]. The inflammatory process causes alveolar and interstitial edema, impaired alveolar fluid clearance, reduction in surfactant synthesis and function, and lung fibrosis, depending on whether it starts from the alveolar or microvascular side. The persistence of inflammatory mediators (mainly of neutrophilic origin) in the bronchoalveolar lavage prevents the resolution of the inflammatory process in the lungs [2]. Systemic inflammation is triggered by the release of inflammatory mediators from injured lung tissue, and it can lead to multiple organ failure, which is the leading cause of mortality in ARDS patients.

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