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 H4R have recently been implicated in
inflammation and
immune diseases. This study was focused to investigate the effects of H4R
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 H4R antagonist) or
ST-1006 (partial H4R agonist), ST-994 (H4R neutral antagonist) and ST-1012 (inverse H4R agonist) at equimolar doses, released by micro-osmotic pumps for 21days. Airway resistance to inflation was assayed and lung samples were processed to measure
malondialdehyde (
TBARS);
8-hydroxy-2'-deoxyguanosine (
8OHdG);
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
8OHdG 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 H4R
ligands have a beneficial effect in a model of lung
fibrosis in the mouse, thus indicating that H4R antagonists or inverse agonists could be a novel therapeutic strategy for lung inflammatory diseases.