title: 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.affiliation: Departments of Drug Science and Technology, University of Turin, Turin, Italy (A.C.R., E.V.); Department of Neuroscience, Psychiatry, and Drug Research, Section of Pharmacology (L.L., C.L., E.M.), and Experimental and Clinical Medicine (A.P.), University of Florence, Florence, Italy; Janssen Research & Development, L.L.C., San Diego, California (R.L.T.); and Heinrich-Heine Düsseldorf University, Institute of Medicinal Chemistry, Düsseldorf, Germany (H.S.).
authors.forename: Arianna Carolina
authors.initials: AC
authors.lastname: Rosa
authors.affiliation: Departments of Drug Science and Technology, University of Turin, Turin, Italy (A.C.R., E.V.); Department of Neuroscience, Psychiatry, and Drug Research, Section of Pharmacology (L.L., C.L., E.M.), and Experimental and Clinical Medicine (A.P.), University of Florence, Florence, Italy; Janssen Research & Development, L.L.C., San Diego, California (R.L.T.); and Heinrich-Heine Düsseldorf University, Institute of Medicinal Chemistry, Düsseldorf, Germany (H.S.).
authors.forename: Alessandro
authors.initials: A
authors.lastname: Pini
authors.affiliation: Departments of Drug Science and Technology, University of Turin, Turin, Italy (A.C.R., E.V.); Department of Neuroscience, Psychiatry, and Drug Research, Section of Pharmacology (L.L., C.L., E.M.), and Experimental and Clinical Medicine (A.P.), University of Florence, Florence, Italy; Janssen Research & Development, L.L.C., San Diego, California (R.L.T.); and Heinrich-Heine Düsseldorf University, Institute of Medicinal Chemistry, Düsseldorf, Germany (H.S.).
authors.forename: Laura
authors.initials: L
authors.lastname: Lucarini
authors.affiliation: Departments of Drug Science and Technology, University of Turin, Turin, Italy (A.C.R., E.V.); Department of Neuroscience, Psychiatry, and Drug Research, Section of Pharmacology (L.L., C.L., E.M.), and Experimental and Clinical Medicine (A.P.), University of Florence, Florence, Italy; Janssen Research & Development, L.L.C., San Diego, California (R.L.T.); and Heinrich-Heine Düsseldorf University, Institute of Medicinal Chemistry, Düsseldorf, Germany (H.S.).
authors.forename: Cecilia
authors.initials: C
authors.lastname: Lanzi
authors.affiliation: Departments of Drug Science and Technology, University of Turin, Turin, Italy (A.C.R., E.V.); Department of Neuroscience, Psychiatry, and Drug Research, Section of Pharmacology (L.L., C.L., E.M.), and Experimental and Clinical Medicine (A.P.), University of Florence, Florence, Italy; Janssen Research & Development, L.L.C., San Diego, California (R.L.T.); and Heinrich-Heine Düsseldorf University, Institute of Medicinal Chemistry, Düsseldorf, Germany (H.S.).
authors.forename: Eleonora
authors.initials: E
authors.lastname: Veglia
authors.affiliation: Departments of Drug Science and Technology, University of Turin, Turin, Italy (A.C.R., E.V.); Department of Neuroscience, Psychiatry, and Drug Research, Section of Pharmacology (L.L., C.L., E.M.), and Experimental and Clinical Medicine (A.P.), University of Florence, Florence, Italy; Janssen Research & Development, L.L.C., San Diego, California (R.L.T.); and Heinrich-Heine Düsseldorf University, Institute of Medicinal Chemistry, Düsseldorf, Germany (H.S.).
authors.forename: Robin L
authors.initials: RL
authors.lastname: Thurmond
authors.affiliation: Departments of Drug Science and Technology, University of Turin, Turin, Italy (A.C.R., E.V.); Department of Neuroscience, Psychiatry, and Drug Research, Section of Pharmacology (L.L., C.L., E.M.), and Experimental and Clinical Medicine (A.P.), University of Florence, Florence, Italy; Janssen Research & Development, L.L.C., San Diego, California (R.L.T.); and Heinrich-Heine Düsseldorf University, Institute of Medicinal Chemistry, Düsseldorf, Germany (H.S.).
authors.forename: Holger
authors.initials: H
authors.lastname: Stark
authors.affiliation: Departments of Drug Science and Technology, University of Turin, Turin, Italy (A.C.R., E.V.); Department of Neuroscience, Psychiatry, and Drug Research, Section of Pharmacology (L.L., C.L., E.M.), and Experimental and Clinical Medicine (A.P.), University of Florence, Florence, Italy; Janssen Research & Development, L.L.C., San Diego, California (R.L.T.); and Heinrich-Heine Düsseldorf University, Institute of Medicinal Chemistry, Düsseldorf, Germany (H.S.) emanuela.masini@unifi.it.
authors.forename: Emanuela
authors.initials: E
authors.lastname: Masini
mesh_terms: D000080242:8-Hydroxy-2'-Deoxyguanosine; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D001761:Bleomycin / Q000009:adverse effects*; D003094:Collagen / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000378:metabolism; D003849:Deoxyguanosine / Q000031:analogs & derivatives / Q000378:metabolism; D004195:Disease Models, Animal; D020397:Goblet Cells / Q000378:metabolism / Q000473:pathology; D007211:Indoles / Q000494:pharmacology*; D008168:Lung / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051379:Mice; D009130:Muscle, Smooth / Q000473:pathology; D009288:Naproxen / Q000494:pharmacology*; D018384:Oxidative Stress / Q000187:drug effects; D009195:Peroxidase / Q000378:metabolism; D010879:Piperazines / Q000494:pharmacology*; D011014:Pneumonia / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D017392:Thiobarbituric Acid Reactive Substances / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: D000893:Anti-Inflammatory Agents; D007211:Indoles; D010879:Piperazines; D017392:Thiobarbituric Acid Reactive Substances; D016212:Transforming Growth Factor beta; D001761:Bleomycin; C484309:1-((5-chloro-1H-indol-2-yl)carbonyl)-4-methylpiperazine; D009288:Naproxen; D000080242:8-Hydroxy-2'-Deoxyguanosine; D003094:Collagen; D009195:Peroxidase; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; D003849:Deoxyguanosine