Abstract
Proton pump inhibitors (PPIs) are well-known antacid drugs developed to treat gastric disorders. Emerging studies demonstrate that PPIs possess biological activities that extend beyond inhibition of H+/K+ ATPase (proton pumps) expressed in parietal cells of the stomach. Some of the extra-gastric activities of PPIs include modulation of epithelial, endothelial, and immune cell functions. Recently, we reported that PPIs suppress the expression of several proinflammatory and profibrotic molecules, as well as enhance antioxidant mechanisms in order to favorably regulate lung inflammation and fibrosis in an animal model of bleomycin-induced lung injury. In addition, several retrospective clinical studies report that the use of PPIs is associated with beneficial outcomes in chronic lung diseases including idiopathic pulmonary fibrosis (IPF) and chronic obstructive pulmonary disease (COPD). Based on these preclinical and clinical observations, we hypothesized that PPIs ameliorate smoke-induced lung injury. Accordingly, we evaluated the pharmacological efficacy of the PPI esomeprazole in a mouse model of cotton smoke-induced lung injury. The animals were exposed to cotton smoke for 3-weeks in the presence or absence of esomeprazole treatment. We found that therapeutic administration of esomeprazole significantly inhibited the progression of fibrosis throughout the lungs of the animals in this group compared to controls. In addition, esomeprazole also reduced circulating markers of inflammation and fibrosis. Overall, our work extends the emerging anti-inflammatory and antifibrotic potential of PPIs and their role in modulation of chronic lung diseases.
Highlights
For nearly 30 years, the field of gastroenterology has been substantially impacted by the development and progressive use of proton pump inhibitors (PPIs) for the treatment of disorders characterized by overproduction of gastric acid including gastroesophageal reflux disease (GERD)
Several studies have demonstrated that the dimethylarginine dimethylaminohydrolase (DDAH)/inducible nitric oxide synthase (iNOS) pathway is pathologically involved in a number of pulmonary disorders including asthma (Trifilieff et al, 2000; Batra et al, 2007), idiopathic pulmonary fibrosis (IPF) (Pullamsetti et al, 2011), and chronic obstructive pulmonary disease (COPD) (Seimetz et al, 2011)
Using a murine model of bleomycin-induced lung injury, Pullamsetti et al (2011) showed that overexpression of DDAH plays a pathological role in lung inflammation and fibrosis at preclinical and clinical levels
Summary
For nearly 30 years, the field of gastroenterology has been substantially impacted by the development and progressive use of proton pump inhibitors (PPIs) for the treatment of disorders characterized by overproduction of gastric acid including gastroesophageal reflux disease (GERD). In vitro, in vivo and retrospective clinical data has been emerging to suggest additional clinical utility of the PPIs in non-gastric diseases including cancer (Goh et al, 2014; Canitano et al, 2016; Fais, 2016), idiopathic pulmonary fibrosis (IPF; Raghu et al, 2006; Lee et al, 2011; Ghebremariam et al, 2015a), and chronic obstructive pulmonary disease (COPD; Sasaki et al, 2011). One aspect of PPIs that might be responsible for their pleiotropic pharmacological effect is the incorporation of a benzimidazole scaffold into their structure (Shin et al, 2004). Medicinal chemists and drug developers consider small molecules with benzimidazole cores as “privileged” in that the scaffold is able to simultaneously target several biological molecules (Bansal and Silakari, 2012; Gaba et al, 2014; Kaur et al, 2014). About 25% of the 100 best-selling drugs incorporate a benzimidazole moiety (Khokra and Choudhary, 2011)
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