A selective antagonist of histamine H₄ receptors prevents antigen‐induced airway inflammation and bronchoconstriction in guinea pigs: involvement of lipocortin‐1

Abstract

BACKGROUND AND PURPOSEAmong the pathogenic mechanisms of asthma, a role for oxidative/nitrosative stress has been well documented. Recent evidence suggests that histamine H4 receptors play a modulatory role in allergic inflammation. Here we report the effects of compound JNJ 7777120 (JNJ), a selective H4 receptor antagonist, on antigen-induced airway inflammation, paying special attention to its effects on lipocortin-1 (LC-1/annexin-A1), a 37 kDA anti-inflammatory protein that plays a key role in the production of inflammatory mediators. EXPERIMENTAL APPROACHOvalbumin (OA)-sensitized guinea pigs placed in a respiratory chamber were challenged with antigen. JNJ (5, 7.5 and 10 mg·kg −1 ) was given i.p. for 4 days before antigen challenge. Respiratory parameters were recorded. Bronchoalveolar lavage (BAL) fluid was collected and lung specimens taken for further analyses 1 h after antigen challenge. In BAL fluid, levels of LC-1, PGD2, LTB4 and TNF-α were measured. In lung tissue samples, myeloperoxidase, caspase-3 and Mn-superoxide dismutase activities and 8-hydroxy-2-deoxyguanosine levels were measured. KEY RESULTSOA challenge decreased LC-1 levels in BAL fluid, induced cough, dyspnoea and bronchoconstriction and increased PGD2, LTB4 and TNF-α levels in lung tissue. Treatment with JNJ dose-dependently increased levels of LC-1, reduced respiratory abnormalities and lowered levels of PGD2, LTB4 and TNF-α in BAL fluid. CONCLUSIONS AND IMPLICATIONSAntigen-induced asthma-like reactions in guinea pigs decreased levels of LC-1 and increased TNF-α and eicosanoid production. JNJ pretreatment reduced allergic asthmatic responses and airway inflammation, an effect associated with LC-1 up-regulation. LINKED ARTICLES

The histamine H4 receptor: from orphan to the clinic

“…Improvement in lung function has also been shown upon treatment with an H 4 R antagonist and in H 4 R-deficient mice ( Cowden et al, 2010a ; Hartwig et al, 2014 ). Similar effects have been reported in a guinea pig model, where JNJ 7777120 improved lung function, reduced inflammation, eosinophilia, and inflammatory mediator production in the lung after allergen challenge ( Somma et al, 2013 ). All of these data point to a therapeutic potential for H 4 R antagonist for the treatment of asthma.…”

Poly(ADP‐ribose) polymerase inhibition with HYDAMTIQ reduces allergen‐induced asthma‐like reaction, bronchial hyper‐reactivity and airway remodelling

“…It also reduced intrapulmonary bronchial obstruction, alveolar changes, smooth muscle hyperplasia and lung infiltration of eosinophils or other inflammatory cells. The asthma model we used is generally considered a suitable model to evaluate agents and tools that may be helpful for the clinical treatment of this disease [38] and it has been in use in our laboratory for several years [6,13,25,26,28,[39][40][41][42]. The molecular mechanisms linking PARP inhibition to the reduced signs of asthma-like reaction and the attenuation of the airway inflammatory and remodelling events after OVA-challenge have not been clarified in details.…”

International Union of Basic and Clinical Pharmacology. XCVIII. Histamine Receptors

“…In mouse models of asthma, H 4 receptor antagonists reduced eosinophilia and Th2 responses (Dunford et al, 2006;Deml et al, 2009;Cowden et al, 2010a;Somma et al, 2013). However, the story may not be as straightforward as it first appeared, because a locally administered H 4 R/H 2 receptor agonist was protective in another mouse asthma study and these effects may have been mediated via enhanced recruitment of regulatory T cells via the H 4 receptor (Morgan et al, 2007).…”