Abstract
Pulmonary fibrosis is a severe lung disease with progressive worsening of dyspnea, characterized by chronic inflammation and remodeling of lung parenchyma. Carbonic anhydrases are a family of zinc-metallo-enzymes that catalyze the reversible interconversion of carbon-dioxide and water to bicarbonate and protons. Carbonic Anhydrase Inhibitor (CAI) exhibited anti-inflammatory effects in animals with permanent-middle-cerebral artery occlusion, arthritis and neuropathic pain. The pharmacological profile of a new class of hybrid compounds constituted by a CAI connected to a Nonsteroidal-Anti-Inflammatory Drug (NSAID) was studied in the modulation of inflammation and fibrosis. In-vitro tests were performed to assess their effects on cyclo-oxygenase enzyme (COX)-1 and COX-2, namely inhibition of platelet aggregation and thromboxane B2 production in the human-platelet-rich plasma, and reduction of Prostaglandin-E2 production in lipopolysaccharide-treated-RAW-264.7 macrophage cell line. The activity of compound 3, one of the most active, was studied in a model of bleomycin-induced lung fibrosis in C57BL/6 mice. The hybrid compounds showed a higher potency in inhibiting PGE2 production, but not in modifying the platelet aggregation and the TXB2 production in comparison to the reference molecules, indicating an increased activity in COX-2 inhibition. In the in-vivo murine model, the compound 3 was more effective in decreasing inflammation, lung stiffness and oxidative stress in comparison to the reference drugs given alone or in association. In conclusion, these CAI-NSAID hybrid compounds are promising new anti-inflammatory drugs for the treatment of lung chronic inflammatory diseases.
Highlights
Pulmonary fibrosis (PF) is defined as specific form of progressive and chronic interstitial pneumonia with unknown etiology, characterized by progressive worsening of dyspnea and function of the lungs and it is characterized by a poor prognosis [1,2]
Nintedanib and pirfenidone have been recently approved as safe drugs for idiopathic pulmonary fibrosis (IPF) treatment by the European Medicines Agency and the Food and Drug Administration (FDA) [3,4]
All studied Carbonic Anhydrase Inhibitor (CAI)-Nonsteroidal-Anti-Inflammatory Drug (NSAID) hybrids 3–6 were evaluated for their inhibition against the cytosolic CA I and II and against the membrane-bound CA IX and CA XII isoforms
Summary
Pulmonary fibrosis (PF) is defined as specific form of progressive and chronic interstitial pneumonia with unknown etiology, characterized by progressive worsening of dyspnea and function of the lungs and it is characterized by a poor prognosis [1,2]. New therapeutic strategies are needed as alternative treatments when the available therapies are not effective or satisfactory [5,6] In this context are our efforts in finding new and promising therapeutic approaches for the management of such disease. We explored the pharmacological profile on a pulmonary fibrosis animal model of a new class of hybrid compounds, recently reported by some of us, constituted by a Carbonic Anhydrase Inhibitor connected to a Nonsteroidal Anti-Inflammatory Drug (CAI-NSAIDs) [7,8]. A relationship between hypoxia, CAs IX and XII over-expression, and ischemia has been highlighted [13] Such a concept was proved by means of Carbonic Anhydrase Inhibitors (CAIs) of the sulfonamide type which exhibited anti-inflammatory effects in rats with permanent middle cerebral artery occlusion (pMCAO) [13]. The neurological score of pMCAO in rats was dramatically reduced 24 h after occlusion and the properties of novel CAIs to improve the neurological functionalities after cerebral ischemic insult are shown [13]
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