title: Hemokinin-1 is an important mediator of endotoxin-induced acute airway inflammation in the mouse.
abstract: OBJECTIVE
  Hemokinin-1, the newest tachykinin encoded by the preprotachykinin C (Tac4) gene, is predominatly produced by immune cells. Similarly to substance P, it has the greatest affinity to the tachykinin NK1 receptor, but has different binding site and signaling mechanisms. Furthermore, several recent data indicate the existence of a not yet identified own receptor and divergent non-NK1-mediated actions. Since there is no information on its functions in the airways, we investigated its role in endotoxin-induced pulmonary inflammation.
  
  
  METHODS
  Acute pneumonitis was induced in Tac4 gene-deleted (Tac4(-/-)) mice compared to C57Bl/6 wildtypes by intranasal E. coli lipopolysaccharide (LPS). Airway responsiveness to inhaled carbachol was measured with unrestrained whole body plethysmography 24h later. Semiquantitative histopathological scoring was performed; reactive oxygen species (ROS) production was measured with luminol bioluminescence, myeloperoxidase activity with spectrophotometry, and inflammatory cytokines with Luminex.
  
  
  RESULTS
  All inflammatory parameters, such as histopathological alterations (perivascular edema, neutrophil/macrophage accumulation, goblet cell hyperplasia), myeloperoxidase activity, ROS production, as well as interleukin-1beta, interleukin-6, tumor necrosis factor alpha, monocyte chemoattractant protein-1 and keratinocyte chemoattractant concentrations were significantly diminished in the lung of Tac4(-/-) mice. However, bronchial hyperreactivity similarly developed in both groups. Interestingly, in LPS-treated Tac4(-/-) mouse lungs, bronchus-associated, large, follicle-like lymphoid structures developed.
  
  
  CONCLUSIONS
  We provide the first evidence that hemokinin-1 plays a crucial pro-inflammatory role in the lung by increasing inflammatory cell activities, and might also be a specific regulator of lymphocyte functions.
authors.affiliation: Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, University of Pécs, Pécs, Hungary; Szentágothai Research Centre, University of Pécs, Pécs, Hungary.
authors.forename: Zsófia
authors.initials: Z
authors.lastname: Hajna
authors.affiliation: Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, University of Pécs, Pécs, Hungary; Szentágothai Research Centre, University of Pécs, Pécs, Hungary.
authors.forename: Éva
authors.initials: É
authors.lastname: Borbély
authors.affiliation: Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, University of Pécs, Pécs, Hungary; Szentágothai Research Centre, University of Pécs, Pécs, Hungary.
authors.forename: Ágnes
authors.initials: Á
authors.lastname: Kemény
authors.affiliation: Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, University of Pécs, Pécs, Hungary; Szentágothai Research Centre, University of Pécs, Pécs, Hungary.
authors.forename: Bálint
authors.initials: B
authors.lastname: Botz
authors.affiliation: Department of Pathology, Faculty of Medicine, University of Pécs, Pécs, Hungary.
authors.forename: László
authors.initials: L
authors.lastname: Kereskai
authors.affiliation: Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, University of Pécs, Pécs, Hungary; PharmInVivo Ltd, Pécs, Hungary.
authors.forename: János
authors.initials: J
authors.lastname: Szolcsányi
authors.affiliation: Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, University of Pécs, Pécs, Hungary; Szentágothai Research Centre, University of Pécs, Pécs, Hungary; PharmInVivo Ltd, Pécs, Hungary.
authors.forename: Erika
authors.initials: E
authors.lastname: Pintér
authors.affiliation: Ontario Cancer Institute, University Health Network, Toronto, Canada.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Paige
authors.affiliation: Ontario Cancer Institute, University Health Network, Toronto, Canada.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Berger
authors.affiliation: Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, University of Pécs, Pécs, Hungary; Szentágothai Research Centre, University of Pécs, Pécs, Hungary; PharmInVivo Ltd, Pécs, Hungary; MTA-PTE NAP B Pain Research Group. Electronic address: zsuzsanna.helyes@aok.pte.hu.
authors.forename: Zsuzsanna
authors.initials: Z
authors.lastname: Helyes
mesh_terms: D000208:Acute Disease; D000818:Animals; D016207:Cytokines / Q000378:metabolism; D005260:Female; D008070:Lipopolysaccharides; D008168:Lung / Q000187:drug effects / Q000276:immunology / Q000503:physiopathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018384:Oxidative Stress; D011014:Pneumonia / Q000139:chemically induced / Q000276:immunology / Q000503:physiopathology*; D011498:Protein Precursors / Q000187:drug effects / Q000276:immunology / Q000502:physiology*; D015320:Tachykinins / Q000187:drug effects / Q000276:immunology / Q000502:physiology*
chemical_list: D016207:Cytokines; D008070:Lipopolysaccharides; D011498:Protein Precursors; C423233:Tac4 protein, mouse; D015320:Tachykinins
keywords: Acute pneumonitis; Luminescence imaging; Reactive oxygen species; Tachykinin