Role of histamine H 4 receptor ligands in bleomycin-induced pulmonary fibrosis

Fibrosis of lung tissue is a disease where a chronic inflammatory process determines a pathological remodelling of lung parenchyma. The animal model obtained by intra-tracheal administration of bleomycin in C57BL/6 mice is one of the most validated murine model. Bleomycin stimulates oxidative stress and the production of pro-inflammatory mediators. Histamine H 4 R have recently been implicated in inflammation and immune diseases. This study was focused to investigate the effects of H 4 R ligands in the modulation of inflammation and in the reduction of lung fibrosis in C57BL/6 mice treated with bleomycin. C57BL/6 mice were treated with vehicle, JNJ7777120 (JNJ, selective H 4 R antagonist) or ST-1006 (partial H 4 R agonist), ST-994 (H 4 R neutral antagonist) and ST-1012 (inverse H 4 R agonist) at equimolar doses, released by micro-osmotic pumps for 21 days. Airway resistance to inflation was assayed and lung samples were processed to measure malondialdehyde (TBARS); 8-hydroxy-2⿲-deoxyguanosine (8OH d G); myeloperoxidase (MPO); COX-2 expression and activity as markers of oxidative stress and inflammation. Fibrosis and airway remodelling were evaluated throughout transforming growth factor-β (TGF-β), percentage of positive Goblet cells, smooth muscle layer thickness determination. Our results indicated that JNJ, ST-994 and ST-1012 decreased inflammation and oxidative stress markers, i.e. the number of infiltrating leukocytes evaluated as lung tissue MPO, COX-2 expression and activity, TBARS and 8OH d G production. They also reduced the level of TGF-β, a pro-fibrotic cytokine, collagen deposition, thickness of smooth muscle layer, Goblet cells hyperplasia; resulting in a decrease of airway functional impairment. The results here reported clearly demonstrated that H 4 R ligands have a beneficial effect in a model of lung fibrosis in the mouse, thus indicating that H 4 R antagonists or inverse agonists could be a novel therapeutic strategy for lung inflammatory diseases.