Prevention of bleomycin-induced lung inflammation and fibrosis in mice by naproxen and JNJ7777120 treatment.

Abstract

Pulmonary fibrosis, a progressive and lethal lung disease characterized by inflammation and accumulation of extracellular matrix components, is a major therapeutic challenge for which new therapeutic strategies are warranted. Cyclooxygenase (COX) inhibitors have been previously utilized to reduce inflammation. Histamine H4 receptor (H4R), largely expressed in hematopoietic cells, has been identified as a novel target for inflammatory and immune disorders. The aim of this study was to evaluate the effect of JNJ7777120 (1-[(5-chloro-1H-indol-2-yl)carbonyl]-4-methylpiperazine), a selective H4R antagonist, and naproxen, a well known nonsteroidal anti-inflammatory drug, and their combination in a murine model of bleomycin-induced fibrosis. Bleomycin (0.05 IU) was instilled intratracheally to C57BL/6 mice, which were then treated by micro-osmotic pump with vehicle, JNJ7777120 (40 mg/kg b.wt.), naproxen (21 mg/kg b.wt.), or a combination of both. Airway resistance to inflation, an index of lung stiffness, was assessed, and lung specimens were processed for inflammation, oxidative stress, and fibrosis markers. Both drugs alone were able to reduce the airway resistance to inflation induced by bleomycin and the inflammatory response by decreasing COX-2 and myeloperoxidase expression and activity and thiobarbituric acid-reactive substance and 8-hydroxy-2'-deoxyguanosine production. Lung fibrosis was inhibited, as demonstrated by the reduction of tissue levels of transforming growth factor-β, collagen deposition, relative goblet cell number, and smooth muscle layer thickness. Our results demonstrate that both JNJ7777120 and naproxen exert an anti-inflammatory and antifibrotic effect that is increased by their combination, which could be an effective therapeutic strategy in the treatment of pulmonary fibrosis.

• Authors: Arianna Carolina Rosa, Alessandro Pini, Laura Lucarini, Cecilia Lanzi, Eleonora Veglia, Robin L Thurmond, Holger Stark, Emanuela Masini
• Journal: The Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 351 Issue 2 Pg. 308-16 (Nov 2014) ISSN: 1521-0103 [Electronic] United States
• PMID: 25185215 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics.

Chemical References

• Anti-Inflammatory Agents
• Indoles
• Piperazines
• Thiobarbituric Acid Reactive Substances
• Transforming Growth Factor beta
• Bleomycin
• 1-((5-chloro-1H-indol-2-yl)carbonyl)-4-methylpiperazine
• Naproxen
• 8-Hydroxy-2'-Deoxyguanosine
• Collagen
• Peroxidase
• Ptgs2 protein, mouse
• Cyclooxygenase 2
• Deoxyguanosine

Topics

• 8-Hydroxy-2'-Deoxyguanosine
• Animals
• Anti-Inflammatory Agents (pharmacology)
• Bleomycin (adverse effects)
• Collagen (metabolism)
• Cyclooxygenase 2 (metabolism)
• Deoxyguanosine (analogs & derivatives, metabolism)
• Disease Models, Animal
• Goblet Cells (metabolism, pathology)
• Indoles (pharmacology)
• Lung (drug effects, metabolism, pathology)
• Mice
• Muscle, Smooth (pathology)
• Naproxen (pharmacology)
• Oxidative Stress (drug effects)
• Peroxidase (metabolism)
• Piperazines (pharmacology)
• Pneumonia (chemically induced, metabolism, pathology, prevention & control)
• Pulmonary Fibrosis (chemically induced, metabolism, pathology, prevention & control)
• Thiobarbituric Acid Reactive Substances (metabolism)
• Transforming Growth Factor beta (metabolism)