title: Role of histamine H4 receptor ligands in bleomycin-induced pulmonary fibrosis.
abstract: 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.
authors.affiliation: Departments of NEUROFARBA, Section of Pharmacology, University of Florence, Florence, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Lucarini
authors.affiliation: Departments of Experimental and Clinical Medicine, Section of Histology, University of Florence, Florence, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Pini
authors.affiliation: Departments of Drug Science and Technology, University of Turin, Turin, Italy.
authors.forename: Arianna Carolina
authors.initials: AC
authors.lastname: Rosa
authors.affiliation: Departments of NEUROFARBA, Section of Pharmacology, University of Florence, Florence, Italy.
authors.forename: Cecilia
authors.initials: C
authors.lastname: Lanzi
authors.affiliation: Departments of NEUROFARBA, Section of Pharmacology, University of Florence, Florence, Italy.
authors.forename: Mariaconcetta
authors.initials: M
authors.lastname: Durante
authors.affiliation: School of Biological & Biomedical Sciences, Durham University, Durham, UK.
authors.forename: Paul Louis
authors.initials: PL
authors.lastname: Chazot
authors.affiliation: Bioproject BIOTECH, 4, rue du Chesnay Beauregard 35760 Saint-Grégoire, France.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Krief
authors.affiliation: Institute of Pharmaceutical Chemistry, Johann-Wolfgang Goethe University, Frankfurt, Germany.
authors.forename: Annemarie
authors.initials: A
authors.lastname: Schreeb
authors.affiliation: Departments of Medicinal Chemistry, University of Dusseldorf, Dusseldorf, Germany.
authors.forename: Holger
authors.initials: H
authors.lastname: Stark
authors.affiliation: Departments of NEUROFARBA, Section of Pharmacology, University of Florence, Florence, Italy. Electronic address: emanuela.masini@unifi.it.
authors.forename: Emanuela
authors.initials: E
authors.lastname: Masini
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D015415:Biomarkers / Q000378:metabolism; D001761:Bleomycin; D003094:Collagen / Q000378:metabolism; D019610:Cytoprotection; D004195:Disease Models, Animal; D054333:Drug Partial Agonism; D020397:Goblet Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D006633:Histamine Antagonists / Q000494:pharmacology*; D006965:Hyperplasia; D007211:Indoles / Q000494:pharmacology*; D018836:Inflammation Mediators / Q000378:metabolism; D008024:Ligands; D008168:Lung / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D008297:Male; D008810:Mice, Inbred C57BL; D018384:Oxidative Stress / Q000187:drug effects; D010879:Piperazines / Q000494:pharmacology*; D011014:Pneumonia / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D011743:Pyrimidines / Q000494:pharmacology*; D000074040:Receptors, Histamine H4 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: D000893:Anti-Inflammatory Agents; D015415:Biomarkers; D006633:Histamine Antagonists; D007211:Indoles; D018836:Inflammation Mediators; D008024:Ligands; C000610568:N4-(2,6-dichlorobenzyl)-6-(4-methylpiperazin-1-yl)pyrimidine-2,4-diamine; D010879:Piperazines; D011743:Pyrimidines; D000074040:Receptors, Histamine H4; D016212:Transforming Growth Factor beta; D001761:Bleomycin; C484309:1-((5-chloro-1H-indol-2-yl)carbonyl)-4-methylpiperazine; D003094:Collagen
keywords: Bleomycin; Histamine H(4) ligands; Histamine H(4) receptors; Inflammation; Lung fibrosis; TGFβ