title: Histamine H4 receptor antagonism diminishes existing airway inflammation and dysfunction via modulation of Th2 cytokines.
abstract: BACKGROUND
  Airway remodeling and dysfunction are characteristic features of asthma thought to be caused by aberrant production of Th2 cytokines. Histamine H4 receptor (H4R) perturbation has previously been shown to modify acute inflammation and Th2 cytokine production in a murine model of asthma. We examined the ability of H4R antagonists to therapeutically modify the effects of Th2 cytokine production such as goblet cell hyperplasia (GCH), and collagen deposition in a sub-chronic model of asthma. In addition, effects on Th2 mediated lung dysfunction were also determined.
  
  
  METHODS
  Mice were sensitized to ovalbumin (OVA) followed by repeated airway challenge with OVA. After inflammation was established mice were dosed with the H4R antagonist, JNJ 7777120, or anti-IL-13 antibody for comparison. Airway hyperreactivity (AHR) was measured, lungs lavaged and tissues collected for analysis.
  
  
  RESULTS
  Therapeutic H4R antagonism inhibited T cell infiltration in to the lung and decreased Th2 cytokines IL-13 and IL-5. IL-13 dependent remodeling parameters such as GCH and lung collagen were reduced. Intervention with H4R antagonist also improved measures of central and peripheral airway dysfunction.
  
  
  CONCLUSIONS
  These data demonstrate that therapeutic H4R antagonism can significantly ameliorate allergen induced, Th2 cytokine driven pathologies such as lung remodeling and airway dysfunction. The ability of H4R antagonists to affect these key manifestations of asthma suggests their potential as novel human therapeutics.
authors.affiliation: Immunology, Johnson & Johnson Pharmaceutical Research & Development, LLC San Diego, California, USA.
authors.forename: Jeffery M
authors.initials: JM
authors.lastname: Cowden
authors.forename: Jason P
authors.initials: JP
authors.lastname: Riley
authors.forename: Jing Ying
authors.initials: JY
authors.lastname: Ma
authors.forename: Robin L
authors.initials: RL
authors.lastname: Thurmond
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Dunford
mesh_terms: D056151:Airway Remodeling / Q000187:drug effects; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D000906:Antibodies / Q000494:pharmacology; D001249:Asthma / Q000188:drug therapy* / Q000276:immunology / Q000503:physiopathology; D016535:Bronchial Hyperreactivity / Q000188:drug therapy* / Q000276:immunology / Q000503:physiopathology; D001985:Bronchial Provocation Tests; D003094:Collagen / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005260:Female; D020397:Goblet Cells / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D006633:Histamine Antagonists / Q000494:pharmacology*; D006965:Hyperplasia; D007211:Indoles / Q000494:pharmacology*; D018836:Inflammation Mediators / Q000378:metabolism*; D018793:Interleukin-13 / Q000037:antagonists & inhibitors / Q000378:metabolism; D015848:Interleukin-5 / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D010047:Ovalbumin; D010879:Piperazines / Q000494:pharmacology*; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011968:Receptors, Histamine / Q000378:metabolism; D000074040:Receptors, Histamine H4; D018418:Th2 Cells / Q000187:drug effects* / Q000276:immunology
chemical_list: D000893:Anti-Inflammatory Agents; D000906:Antibodies; D006633:Histamine Antagonists; C498829:Hrh4 protein, mouse; D007211:Indoles; D018836:Inflammation Mediators; D018793:Interleukin-13; D015848:Interleukin-5; D010879:Piperazines; D043562:Receptors, G-Protein-Coupled; D011968:Receptors, Histamine; D000074040:Receptors, Histamine H4; C484309:1-((5-chloro-1H-indol-2-yl)carbonyl)-4-methylpiperazine; D010047:Ovalbumin; D003094:Collagen