The Role of Peptides in Asthma-Obesity Phenotype.

The co-occurrence of asthma and obesity is becoming an increasingly common health problem. It became clear that both diseases are closely related, since overweight/obesity are associated with an increased risk of asthma development, and more than half of the subjects with severe or difficult-to-treat asthma are obese. Currently, there are no specific guidelines for the treatment of this group of patients. The mechanisms involved in the asthma-obesity phenotype include low-grade chronic inflammation and changes in pulmonary physiology. However, genetic predispositions, gender differences, comorbid conditions, and gut microbiota also seem to be important. Regulatory peptides affect many processes related to the functioning of the respiratory tract and adipose tissue. Adipokines such as leptin, adiponectin, resistin, and the less studied omentin, chemerin, and visfatin, as well as the gastrointestinal hormones ghrelin, cholecystokinin, glucagon-like peptide-1, and neuropeptides, including substance P or neuropeptide Y, can play a significant role in asthma with obesity. The aim of this article is to provide a concise review of the contribution of particular peptides in inflammatory reactions, obesity, asthma, and a combination of both diseases, as well as emphasize their potential role in the effective treatment of the asthma-obesity phenotype in the future.

Contribution of opioid and neurotensin receptors in the anti-inflammatory activity of PK20 hybrid compound in murine airways.

PK20 is an anti-inflammatory hybrid compound, composed of an endomorphin-2-like and neurotensin-like fragments. The aim of the present study is to assess the contribution of particular pharmacophores to the activity of the hybrid tested. For this purpose, airway hyperresponsiveness, accumulation of inflammatory cells in bronchoalveolar lavage fluid (BALF), concentration of mouse mast cell protease, malondialdehyde and secretory phospholipase 2 activity in lung tissue, as well as production of pro-inflammatory cytokines in BALF and lung were determined by using murine model of non-atopic asthma. Blocking either neurotensin receptors or mu opioid receptors did not alter the potential of PK20 in reducing airway hyperresponsiveness. In studies of inflammatory cells, the beneficial effect of the entire peptide occurs to be mediated by the stimulation of neurotensin receptors. However, regarding cytokine and biochemical assays, pretreatment with both receptor antagonists resulted in a different effect on its activity depending on the parameter studied. To conclude, the activation of both the opioid and neurotensin receptors seems to be necessary to induce the full anti-inflammatory activity of the hybrid compound.

Inhalations with Brine Solution from the 'Wieliczka' Salt Mine Diminish Airway Hyperreactivity and Inflammation in a Murine Model of Non-Atopic Asthma.

Inhalations with brine solutions are old but underestimated add-ons to pharmacological treatments of inflammatory lung diseases. Although widely used, not all features underlying their action on the respiratory system have been explored. The aim of the present study was to elucidate the mechanism of the beneficial action of inhalations of brine solution from the 'Wieliczka' Salt Mine, a Polish health resort, in a murine model of non-atopic asthma. Asthma was induced in BALB/c mice by skin sensitization with dinitrofluorobenzene followed by an intratracheal challenge of cognate hapten. All animals underwent 12 inhalation sessions with brine solution, pure water or physiological saline. Control mice were not inhaled. We found that brine inhalations reduced, as compared to non-inhaled mice, the typical asthma-related symptoms, like airway hyperreactivity (AHR), the infiltration of pro-inflammatory cells into the bronchial tree, and the inflammation of the airways at the level of pro-inflammatory cytokines IL-1α, IL-1ß and IL-6. The level of the anti-inflammatory IL-10 was elevated in brine-inhaled mice. Inhalations with pure water increased AHR, whereas saline had no influence, either on AHR or cytokine concentrations. These observations indicate that inhalations with a brine solution from the 'Wieliczka' Salt Mine diminish the asthma-related symptoms, mostly by reducing the inflammatory status and by decreasing AHR.

Endomorphin-2- and Neurotensin- Based Chimeric Peptide Attenuates Airway Inflammation in Mouse Model of Nonallergic Asthma.

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-1ß, 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.

Beneficial Effects of Neurotensin in Murine Model of Hapten-Induced Asthma.

Neurotensin (NT) demonstrates ambiguous activity on inflammatory processes. The present study was undertaken to test the potential anti-inflammatory activity of NT in a murine model of non-atopic asthma and to establish the contribution of NTR1 receptors. Asthma was induced in BALB/c mice by skin sensitization with dinitrofluorobenzene followed by intratracheal hapten provocation. The mice were treated intraperitoneally with NT, SR 142948 (NTR1 receptor antagonist) + NT or NaCl. Twenty-four hours after the challenge, airway responsiveness to nebulized methacholine was measured. Bronchoalveolar lavage fluid (BALF) and lungs were collected for biochemical and immunohistological analysis. NT alleviated airway hyperreactivity and reduced the number of inflammatory cells in BALF. These beneficial effects were inhibited by pretreatment with the NTR1 antagonist. Additionally, NT reduced levels of IL-13 and TNF-α in BALF and IL-17A, IL12p40, RANTES, mouse mast cell protease and malondialdehyde in lung homogenates. SR 142948 reverted only a post-NT TNF-α decrease. NT exhibited anti-inflammatory activity in the hapten-induced asthma. Reduced leukocyte accumulation and airway hyperresponsiveness indicate that this beneficial NT action is mediated through NTR1 receptors. A lack of effect by the NTR1 blockade on mast cell activation, oxidative stress marker and pro-inflammatory cytokine production suggests that other pathways can be involved, which requires further research.

Murine models of hapten-induced asthma.

Asthma is a chronic inflammatory disorder of the respiratory tract that is characterized by reversible airflow obstruction and airway hyperresponsiveness. The non-atopic variant of asthma that appears later in life has no allergic background and is more severe and resistant to standard treatment. Hapten-induced asthma models can be utilized to investigate mechanisms behind the development of non-atopic and occupational asthma, in which non-allergic processes seems to play significant role. The development of adequate animal models of non-allergic asthma is a necessary prerequisite both for understanding the pathophysiology of non-allergic asthma and for the possibility of testing new therapies. Still, there is no ideal model that represents all the hallmarks of this complex disease. In this review, we examine the most popular hapten-induced murine models of occupational and non-atopic asthma. For this reason, we describe the most popular sensitizing haptens, sensitization and challenge protocols, symptoms produced by asthma, and advantages and disadvantages of the models.