vasoactive-intestinal-peptide and Bronchial-Hyperreactivity

Topics: Administration, Inhalation; Asthma; Bronchial Hyperreactivity; Calcitonin Gene-Related Peptide; Endothelins; Humans; Neuropeptides; Substance P; Vasoactive Intestinal Peptide

Bronchomotor tone is regulated by contraction and relaxation of airway smooth muscle (ASM). A weakened ASM relaxation might be a cause of airway hyperresponsiveness (AHR), a characteristic feature of bronchial asthma. Pituitary adenylyl cyclase-activating polypeptide (PACAP) is known as a mediator that causes ASM relaxation. To date, whether or not the PACAP responsiveness is changed in asthmatic ASM is unknown. The current study examined the hypothesis that relaxation induced by PACAP is reduced in bronchial smooth muscle (BSM) of allergic asthma. The ovalbumin (OA)-sensitized mice were repeatedly challenged with aerosolized OA to induce asthmatic reaction. Twenty-four hours after the last antigen challenge, the main bronchial smooth muscle (BSM) tissues were isolated. Tension study showed a BSM hyperresponsiveness to acetylcholine in the OA-challenged mice. Both quantitative RT-PCR and immunoblot analyses revealed a significant decrease in PAC

Topics: Animals; Asthma; Bronchi; Bronchial Hyperreactivity; Mice; Muscle Relaxation; Muscle, Smooth; Pituitary Adenylate Cyclase-Activating Polypeptide; Respiratory Hypersensitivity; Surface-Active Agents; Vasoactive Intestinal Peptide

Hyperoxia exposure leads to the development of lung injury and bronchial hyperreactivity (BHR) via involvement of nitric oxide (NO) pathway. We aimed at characterizing whether the stimulation of the NO pathway by sildenafil or vasoactive intestinal peptide (VIP) is able to prevent the hyperoxia-induced development of BHR. The respective roles of the preserved lung volume and alveolar architecture, the anti-inflammatory and anti-apoptotic potentials of these treatments in the diminished lung responsiveness were also characterized.. Immature (28-day-old) rats were exposed for 72 hours to room air (Group C), hyperoxia (>95%, Group HC), or hyperoxia with the concomitant administration of vasoactive intestinal peptide (VIP, Group HV) or sildenafil (Group HS). Following exposure, the end-expiratory lung volume (EELV) was assessed plethysmographically. Airway and respiratory tissue mechanics were measured under baseline conditions and following incremental doses of methacholine to assess BHR. Inflammation was assessed by analyzing the bronchoalveolar lavage fluid (BALF), while biochemical and histological analyses were used to characterize the apoptotic and structural changes in the lungs.. The BHR, the increased EELV, the aberrant alveolarization, and the infiltration of inflammatory cells into the BALF that developed in Group HC were all suppressed significantly by VIP or sildenafil treatment. The number of apoptotic cells increased significantly in Group HC, with no evidence of statistically significant effects on this adverse change in Groups HS and HV.. These findings suggest that stimulating the NO pathway by sildenafil and VIP exert their beneficial effect against hyperoxia-induced BHR via preserving normal EELV, inhibiting airway inflammation and preserving the physiological lung structure, whereas the antiapoptotic potential of these treatments were not apparent in this process.

Topics: Animals; Bronchial Hyperreactivity; Hyperoxia; Lung; Male; Piperazines; Purines; Rats; Rats, Sprague-Dawley; Sildenafil Citrate; Sulfonamides; Vasoactive Intestinal Peptide

The development of bronchial hyperreactivity (BHR) subsequent to precapillary pulmonary hypertension (PHT) was prevented by acting on the major signalling pathways (endothelin, nitric oxide, vasoactive intestine peptide (VIP) and prostacyclin) involved in the control of the pulmonary vascular and bronchial tones.. Five groups of rats underwent surgery to prepare an aorta-caval shunt (ACS) to induce sustained precapillary PHT for 4 weeks. During this period, no treatment was applied in one group (ACS controls), while the other groups were pretreated with VIP, iloprost, tezosentan via an intraperitoneally implemented osmotic pump, or by orally administered sildenafil. An additional group underwent sham surgery. Four weeks later, the lung responsiveness to increasing doses of an intravenous infusion of methacholine (2, 4, 8 12 and 24 μg/kg/min) was determined by using the forced oscillation technique to assess the airway resistance (Raw).. BHR developed in the untreated rats, as reflected by a significant decrease in ED50, the equivalent dose of methacholine required to cause a 50% increase in Raw. All drugs tested prevented the development of BHR, iloprost being the most effective in reducing both the systolic pulmonary arterial pressure (Ppa; 28%, p = 0.035) and BHR (ED50 = 9.9 ± 1.7 vs. 43 ± 11 μg/kg in ACS control and iloprost-treated rats, respectively, p = 0.008). Significant correlations were found between the levels of Ppa and ED50 (R = -0.59, p = 0.016), indicating that mechanical interdependence is primarily responsible for the development of BHR.. The efficiency of such treatment demonstrates that re-establishment of the balance of constrictor/dilator mediators via various signalling pathways involved in PHT is of potential benefit for the avoidance of the development of BHR.

Topics: Administration, Oral; Airway Resistance; Analysis of Variance; Animals; Antihypertensive Agents; Blood Pressure; Bronchial Hyperreactivity; Bronchial Provocation Tests; Bronchoconstriction; Disease Models, Animal; Endothelin Receptor Antagonists; Endothelins; Hypertension, Pulmonary; Iloprost; Infusion Pumps, Implantable; Infusions, Parenteral; Lung; Lung Volume Measurements; Male; Nitric Oxide; Phosphodiesterase 5 Inhibitors; Piperazines; Prostaglandins I; Purines; Pyridines; Rats; Rats, Sprague-Dawley; Receptors, Endothelin; Signal Transduction; Sildenafil Citrate; Sulfones; Tetrazoles; Time Factors; Vasoactive Intestinal Peptide; Vasodilator Agents

Vasoactive intestinal peptide (VIP) is a neuropeptide with cytokine properties that is abundant in the lung. VIP null mice exhibit spontaneous airway inflammation and hyperresponsiveness emphasizing VIP's "anti-asthma" potential. Although VIP's impending protective role in the lung has been demonstrated, its localization in the naïve and allergic murine lungs has not. To this aim, we analyzed the availability of VIP and its protease, neutral peptidase (NEP), in naïve and Aspergillus-sensitized and challenged murine lungs after 3, 7, and 14days. Both VIP and NEP were predominantly localized to the columnar epithelia of the airways in naïve lungs. A marked decrease in VIP occurred in these cells 3days after allergen challenge. NEP localization in the columnar epithelia decreased after allergen challenge. At day 14, VIP localization in the columnar epithelia and arteriolar smooth muscle increased while NEP localization at these sites remained low. This study provides new insights into the local regulation of VIP in the columnar epithelia of the allergic lung. Its altered availability in the context of allergy provides fresh evidence for the modulation of pulmonary inflammation by VIP.

Topics: Allergens; Animals; Aspergillus fumigatus; Bronchial Hyperreactivity; Hypersensitivity; Immunohistochemistry; Lung; Mice; Mice, Inbred C57BL; Neprilysin; Vasoactive Intestinal Peptide

The mechanisms leading to asthma, and those guarding against it, are yet to be fully defined. The neuropeptide VIP is a cotransmitter, together with nitric oxide (NO), of airway relaxation, and a modulator of immune and inflammatory responses. NO-storing molecules in the lung were recently shown to modulate airway reactivity and were proposed to have a protective role against the disease. We report here that mice with targeted deletion of the VIP gene spontaneously exhibit airway hyperresponsiveness to the cholinergic agonist methacholine as well as peribronchiolar and perivascular cellular infiltrates and increased levels of inflammatory cytokines in bronchoalveolar lavage fluid. Immunologic sensitization and challenge with ovalbumin generally enhanced the airway hyperresponsiveness and airway inflammation in all mice. Intraperitoneal administration of VIP over a 2-wk period in knockout mice virtually eliminated the airway hyperresponsiveness and reduced the airway inflammation in previously sensitized and challenged mice. The findings suggest that 1) VIP may be an important component of endogenous anti-asthma mechanisms, 2) deficiency of the VIP gene may predispose to asthma pathogenesis, and 3) treatment with VIP or a suitable agonist may offer potentially effective replacement therapy for this disease.

Topics: Animals; Asthma; Bronchial Hyperreactivity; Bronchoalveolar Lavage Fluid; Chemokines; Cytokines; Female; Lung; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Peptide Hydrolases; Pneumonia; Severity of Illness Index; Vasoactive Intestinal Peptide

To explore the role of intrapulmonary neuropeptides in the development of airway hyperresponsiveness, we established an animal model of airway hyperresponsiveness (AHR) in rabbits by using ozone exposure. With the model, after test of the mechanics of respiration and bronchoalveolar lavage assay, the levels of vasoactive intestinal peptide (VIP) and calcitonin gene-related peptide (CGRP) in the lungs were determined by radioimmunoassay, and the expression of mRNA coding receptors of these two neuropeptides was evaluated by reverse transcriptional-polymerase chain reaction (RT-PCR). At the same time, the distribution of VIP receptor-1 (VIPR1) and CGRP receptor-1 (CGRPR1) in lung tissues and its time-course were examined by in situ hybridization. The results showed: (1) in ozone-stressing groups, airway resistance increased significantly and typical inflammatory pathological changes were observed in pulmonary tissue slides, including neutrophil and eosinophil infiltration, mucus exudation and bronchial epithelial cells (BECs) shedding; (2) with elongation of ozone exposure, the levels of VIP and CGRP in the lungs increased at first, reaching a peak on d 2 to 4, then decreased slowly, and CGRP peaked somewhat earlier than VIP; (3) mRNA expression of the two neuropeptide receptors in the lungs changed in a similar manner like VIP and CGRP, but the high level of mRNA expression of VIPR1 lasted longer than that of CGRPR1; and (4) in situ hybridization for neuropeptide receptors demonstrated that, in unstressed control, VIPR1 and CGRPR1 positive cells appeared in the airway epithelium, pulmonary interstitial and focal areas of airway and vascular smooth muscles. With the elongation of ozone exposure, hybridization stained deeper and the majority of positive cells were located around the vessels and bronchus except a few in the alveoli. At 8 d, only a small number of positive cells were seen in the lungs. From the results, it is concluded that ozone-stressing can induce the development of AHR, in which VIP and CGRP may play important roles. That implies, through binding to CGRPR1, CGRP stimulates an early inflammation response which contributes in cleaning up of irritants, while VIP exerts a later dampening of pulmonary inflammation response. These two neuropeptides may play sequential and complementary roles in the development of AHR.

Topics: Animals; Bronchi; Bronchial Hyperreactivity; Bronchoalveolar Lavage Fluid; Calcitonin Gene-Related Peptide; Epithelium; Lung; Ozone; Rabbits; Receptors, Calcitonin Gene-Related Peptide; Receptors, Vasoactive Intestinal Peptide; Vasoactive Intestinal Peptide

To determine the possible involvement of vasoactive intestinal peptide (VIP) in the development of airway hyper responsiveness (AHR).. Twenty-five rabbits were randomly divided into five groups (5 animals each). Four groups were exposed to 2.0 ppm ozone 1 h/day for 1 (group B(0)), 2 (group B(1)), 4 (group B(2)), and 8 (group B(3)) days, respectively. The control group (group A) breathed only filtered room air. The changes of the VIP level and the mRNA expression of VIP receptor 1 (VIPR1) in the lung were detected at various ozone-stressing time points. In situ hybridization was performed to examine the distribution of VIPR1 in the lung.. (1) The concentration of VIP in the lung increased slowly and were maximal at day 4, then returned to the normal level. (2) The changing pattern of the VIPR1 mRNA in the lung was similar to those observed for VIP. Increases in VIPR1 mRNA were detectable by 1 day and maximal by 2 - 4 days, and then decreased slowly. (3) In group A, VIPR1 was expressed on airway epithelium, in pulmonary interstitial and focal areas of airways and vascular smooth muscles. By days 2 to 4, hybridization staining increased and the majority of VIPR1-positive cells was located in the perivascular and peribronchiolar area. On day 8, very few positive cells were seen in the lung.. VIP may play an important role in the development of AHR by binding with VIPR1.

Topics: Animals; Bronchial Hyperreactivity; Lung; Male; Ozone; Rabbits; Random Allocation; Receptors, Vasoactive Intestinal Peptide; Receptors, Vasoactive Intestinal Polypeptide, Type I; RNA, Messenger; Vasoactive Intestinal Peptide

The characteristic feature of asthma is bronchial hyperresponsiveness (BHR). It is due predominately to inflammation of airways. Pathologically, there are inflammatory infiltration, epithelial sloughing and mucosal edema in the bronchi. The objective of this study is to investigate the relationship between BHR and airway inflammation.. 57 cases of asthma and 22 normal subjects were tested with bronchial reactivity examination and P-selectin, substance P (SP) and vasoactive intestinal peptide (VIP) in plasma.. It was found that the bronchial reactivity to inhaled methacholine was positive in 53 of the 57 asthmatic patients (92.98%), while the remaining four were negative (7.02%). Twenty-two normal subjects were all negative with the test of bronchial reactivity. The levels of P-selectin and SP in asthmatics with corticosteroids treatment (n = 27) were higher than those in the control group (P < 0.05), but lower than those in asthmatics treated with aminophylline and salbutamol sulfate (n = 30), (P < 0.01). The concentration of VIP in asthmatics with corticosteroids treatment was significantly higher than that of asthmatics with out corticosteroids treatment (P < 0.01) but lower than that in the control group (P < 0.01). There was positive relationship between bronchial reactivity and P-selectin (r = 0.328, P < 0.05), as well as SP (r = 0.529, P < 0.01) in asthmatics, but negative relationship between bronchial reactivity and VIP (r = -0.419, P < 0.05).. The increase of P-selectin and SP and decrease of VIP can induce BHR, corticosteroids can reduce levels of P-selectin, SP and enhance the level of VIP, therefore it can improve the reactivity of airway and relieve symptoms.

Topics: Adult; Asthma; Bronchial Hyperreactivity; Bronchial Provocation Tests; Female; Glucocorticoids; Humans; Male; Middle Aged; P-Selectin; Substance P; Tachykinins; Vasoactive Intestinal Peptide

Vasoactive intestinal peptide (VIP), which is localized in normal human lung, may play an important role in regulating bronchial tone, pulmonary blood flow and mucus secretion. The level of plasma VIP and bronchial responsiveness were studied in patients with asthma, chronic bronchitis and the healthy subjects. The results showed that the level of plasma VIP in asthmatic patients during acute attack and symptom-free period was significantly lower than that in the patients with bronchitis and the healthy subjects and it is negatively correlated with the bronchial hyperresponsiveness. It is suggested that both asthmatic attack and bronchial tone are related with the decrease of VIP.

Topics: Adult; Aged; Airway Resistance; Asthma; Bronchial Hyperreactivity; Bronchitis; Female; Humans; Male; Middle Aged; Vasoactive Intestinal Peptide