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 H 4 receptor (H 4 R), 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 H 4 R 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-29-deoxyguanosine production. Lung fibrosis was inhibited, as demonstrated by the reduction of tissue levels of transforming growth factor-b, 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.

Enigmatic Histamine Receptor H4 for Potential Treatment of Multiple Inflammatory, Autoimmune, and Related Diseases

“…Extensive studies have provided evidence detailing the functional profile of H 4 R in eosinophil biology [70] and in the chemotaxis and differentiation of other immune cell types. In experiments carried out on animal models of inflammation of the airways, it was observed that in mice lacking the H 4 R gene, there was a significant reduction in the allergic reaction caused by the administration of a chicken protein-ovalbumin [71]. Chemotaxis of eosinophils was shown to be blocked by H 4 R selective antagonists (JNJ7777120, JNJ39758979, or JNJ10191584) in animal asthma models due to priming and T cell activation [51,72] while induced by histamine and selective H 4 R agonists (e.g., 4-methylhistamine) [72].…”

Histamine and diabetic nephropathy: an up-to-date overview

“…However, recent data suggest that antihistamine anti-H 4 R compounds can be used to regulate TGF-β1 release and effects. Indeed, in vivo studies carried out on a model of bleomycin-induced lung fibrosis clearly demonstrate that H 4 R antagonism counteracts fibrosis establishment by acting on TGF-ß production (94,95). TGF-β, in turn, modulates the fibrotic process by impacting upon downstream signalling.…”

“…(the H 4 R antagonist prototype) has been sustained by a reduction in Smad 3 phosphorylation and, consequently, Smad3/Smad4 complex formation (94). The Smad family is one of the most-commonly studied pathways and is closely involved with TGF-β1.…”

Histamine H 4 receptor antagonism prevents the progression of diabetic nephropathy in male DBA2/J mice

“…Inhibiting the induction of pro-inflammatory and pro-fibrotic mediators have already been demonstrated to have renoprotective effects [47]. H4R blockade has been reported to exert anti-fibrotic effects through the reduction in transforming growth factor (TGF)-ß production and pro-inflammatory events in a model of lung fibrosis [48,49].…”