Abstract
We examined anti-inflammatory potency of hybrid peptide-PK20, composed of neurotensin (NT) and endomorphin-2 (EM-2) pharmacophores in a murine model of non-atopic asthma induced by skin sensitization with 2,4-dinitrofluorobenzene and intratracheal challenge of cognate hapten. Mice received intraperitoneally PK20, equimolar mixture of its structural elements (MIX), dexamethasone (DEX), or NaCl. Twenty-four hours following hapten challenge, the measurements of airway responsiveness to methacholine were taken. Bronchoalveolar lavage (BALF) and lungs were collected for further analyses. Treatment with PK20, similarly to dexamethasone, reduced infiltration of inflammatory cells, concentration of mouse mast cell protease, IL-1β, IL-12p40, IL-17A, CXCL1, RANTES in lungs and IL-1α, IL-2, IL-13, and TNF-α in BALF. Simple mixture of NT and EM-2 moieties was less potent. PK20, DEX, and MIX significantly decreased malondialdehyde level and secretory phospholipase 2 activity in lungs. Intensity of NF-κB immunoreactivity was diminished only after PK20 and DEX treatments. Neither PK20 nor mixture of its pharmacophores were as effective as DEX in alleviating airway hyperresponsiveness. PK20 effectively inhibited hapten-induced inflammation and mediator and signaling pathways in a manner seen with dexamethasone. Improved anti-inflammatory potency of the hybrid over the mixture of its moieties shows its preponderance and might pose a promising tool in modulating inflammation in asthma.
Highlights
Asthma is a chronic disease characterized by airway inflammation, remodeling, and bronchial hyperresponsiveness with usually reversible airflow limitation [1,2]
Compared with vehicle-sensitized/DNS-challenged group, DNFB-sensitized/DNS-challenged mice showed in bronchoalveolar lavage fluid (BALF) a significant increase in the infiltrate of total cells, which consisted of an augmented cell number of macrophages (94%), neutrophils (5%), and lymphocytes (0.8%)
In the murine model of non-atopic asthma, we demonstrated that the hybrid peptide engineered from IpnhtahremmacuorpinheormesodofelNoTf-naonnd-aEtoMp-i2c-absatshemd aa,nwaleogdsemmoanyssterravteedasthaapt tohteenhtyabnrtiid-ipnflepamtidmeaetnogryinaegeernedt afffroemctinpghaarmnuamcobpehroorfesinoflfamNmT-aatinodn mEMar-k2e-brsa,saedndaintaslpoogtsenmcayyissecrovmepaasraablpeottoentht eanefftie-icntfslammemdiaattoerdy agent affecting a number of inflammation markers, and its potency is comparable to the effects mediated by the dexamethasone
Summary
Asthma is a chronic disease characterized by airway inflammation, remodeling, and bronchial hyperresponsiveness with usually reversible airflow limitation [1,2]. According to the Global Asthma Report, the prevalence of asthma has increased lately, and over 334 million people worldwide have been reported to be affected [3]. Treatment of both controlled and severe uncontrolled asthma patients poses a substantial economic burden for developed and developing countries [4,5,6]. Inhaled bronchodilators and corticosteroids are currently used to improve asthma condition. Most of these medications produce unwanted adverse effects, resistance with long-term use, and unresponsiveness [7,8]. There is an urgent need to develop novel anti-inflammatory therapies for the treatment of asthma
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