ABSTRACT
Title
Bleomycin-induced lung inflammation and fibrosis in mice: effect of cyclooxygenase inhibitor and histamine H4 receptor antagonist
Authors
A. Pini, T. Somma, G. Formicola , I. Pacileo, R.T. Thurmond2, D. Bani3, E.Masini
Departments of Preclinical and Clinical Pharmacology, and 3Istology, Anatomy and Forensic Medicine, University of Florence, Florence, Italy and 2Immunology, Johnson & Johnson Pharmaceutical Research & Development, LLC, San Diego, CA, USA
Departments of Preclinical and Clinical Pharmacology, and 3Istology, Anatomy and Forensic Medicine, University of Florence, Florence, Italy and 2Immunology, Johnson & Johnson Pharmaceutical Research & Development, LLC, San Diego, CA, USA
Abstract
Pulmonary fibrosis is a progressive and lethal lung disease characterized by a wide range of lung inflammation and abnormal remodeling of lung parenchyma. At the moment no cure exists for this disease.
The histamine H4R, widely expressed in cell of immune origins, plays an important role in inflammatory processes. We have previously demonstrated that an H4R antagonist and non steroid anti-inflammatory drugs (NSAIDs) decrease the inflammatory response in animal models of carrageenan-induced pleurisy.
The aim of the present investigation was to evaluate the antinflammatory and antifibrotic properties of a selective H4R antagonist, JNJ7777120 (JNJ) in a murine model of bleomycin-induced pulmonary fibrosis. In comparison to naproxen, a classic NSAID
Bleomycin (0.05 IU) was instilled intra-tracheally to C57BL/6 mice, which were then treated with a micro-osmotic pump with vehicle or with JNJ for 28 days (total dose 40 mg per Kg/bw). Airway resistance, an index of lung stiffness, was assayed and lung specimens were taken for the analysis of lung inflammation and fibrosis.
JNJ and naproxen prevented bleomycin-induced airway stiffness and accumulation of collagen and reduced the levels of the pro-fibrotic cytokine TGF-β, of the oxidative stress markers thiobarbituric acid reactive substances (TBARS) and of 8-hydroxy-2’-deoxyguanosine (8-OHdG). Moreover, JNJ also decreased myeloperoxidase activity, an index of leukocyte infiltration, and PGE2 production.
The result of this study indicates that JNJ displays antinflammatory and antifibrotic properties and may offer a new therapeutic option for the treatment of pulmonary fibrosis.
The histamine H4R, widely expressed in cell of immune origins, plays an important role in inflammatory processes. We have previously demonstrated that an H4R antagonist and non steroid anti-inflammatory drugs (NSAIDs) decrease the inflammatory response in animal models of carrageenan-induced pleurisy.
The aim of the present investigation was to evaluate the antinflammatory and antifibrotic properties of a selective H4R antagonist, JNJ7777120 (JNJ) in a murine model of bleomycin-induced pulmonary fibrosis. In comparison to naproxen, a classic NSAID
Bleomycin (0.05 IU) was instilled intra-tracheally to C57BL/6 mice, which were then treated with a micro-osmotic pump with vehicle or with JNJ for 28 days (total dose 40 mg per Kg/bw). Airway resistance, an index of lung stiffness, was assayed and lung specimens were taken for the analysis of lung inflammation and fibrosis.
JNJ and naproxen prevented bleomycin-induced airway stiffness and accumulation of collagen and reduced the levels of the pro-fibrotic cytokine TGF-β, of the oxidative stress markers thiobarbituric acid reactive substances (TBARS) and of 8-hydroxy-2’-deoxyguanosine (8-OHdG). Moreover, JNJ also decreased myeloperoxidase activity, an index of leukocyte infiltration, and PGE2 production.
The result of this study indicates that JNJ displays antinflammatory and antifibrotic properties and may offer a new therapeutic option for the treatment of pulmonary fibrosis.