adrenomedullin and Asthma

Adrenomedullin (AM) is a pluripotent peptide hormone with contradictory effects in human health and disease. In chronic inflammatory lung diseases, such as asthma and COPD, AM has been shown to inhibit inflammation and cell proliferation. In the present study, we aimed to investigate the effect of AM on pro-angiogenic and pro-inflammatory cytokines in asthma and COPD.. Serum levels of pro-AM were measured in patients with asthma, COPD and matched controls. The effect of AM on intracellular signaling proteins and cytokine secretion was assessed in primary cultures of epithelial cells (EC) and airway smooth muscle cells (ASMC) established from endo-bronchial biopsies of patients with asthma, COPD and controls.. Serum pro-AM was higher in patients with asthma and COPD, compared to controls. AM stimulated cAMP in ASMC but not in EC. In EC, AM decreased Erk1/2 MAPK expression and activation but in ASMC, AM activated Erk1/2. This effect was similar in asthma, COPD and controls. AM stimulated the secretion of pro-angiogenic CXCL1 by EC of controls and CXCL5 by EC of asthma patients. AM did not affect the secretion of IL-6 or IL-8 by EC but stimulated the secretion of IL-6 by ASMC. In EC, AM inhibited the stimulatory effect of TGF-β and IL-4 on the secretion of IL-6 and IL-8 but had an additive stimulatory effect with TGF-β in ASMC.. These data suggest that AM mediates the secretion of pro-angiogenic and pro-inflammatory cytokines in a cell-type and/or a disease-specific way, explaining its association with clinical outcomes in COPD.

Topics: Adrenomedullin; Aged; Asthma; Cells, Cultured; Cytokines; Epithelial Cells; Female; Humans; Inflammation; Male; Middle Aged; Myocytes, Smooth Muscle; Neovascularization, Physiologic; Pulmonary Disease, Chronic Obstructive

The anti-inflammatory peptide, adrenomedullin (AM), and its cognate receptor are expressed in lung tissue, but its pathophysiological significance in airway inflammation is unknown.. This study investigated whether allergen-induced airway inflammation involves an impaired local AM response.. Airway AM expression was measured in acute and chronically sensitized mice following allergen inhalation and in airway epithelial cells of asthmatic and nonasthmatic patients. The effects of AM on experimental allergen-induced airway inflammation and of AM on lung epithelial repair in vitro were investigated.. Adrenomedullin mRNA levels were significantly (P < 0.05) reduced in acute ovalbumin (OVA)-sensitized mice after OVA challenge, by over 60% at 24 h and for up to 6 days. Similarly, reduced AM expression was observed in two models of chronic allergen-induced inflammation, OVA- and house dust mite-sensitized mice. The reduced AM expression was restricted to airway epithelial and endothelial cells, while AM expression in alveolar macrophages was unaltered. Intranasal AM completely attenuated the OVA-induced airway hyperresponsiveness and mucosal plasma leakage but had no effect on inflammatory cells or cytokines. The effects of inhaled AM were reversed by pre-inhalation of the putative AM receptor antagonist, AM ((22-52)) . AM mRNA levels were significantly (P < 0.05) lower in human asthmatic airway epithelial samples than in nonasthmatic controls. In vitro, AM dose-dependently (10(-11) -10(-7) M) accelerated experimental wound healing in human and mouse lung epithelial cell monolayers and stimulated epithelial cell migration.. Adrenomedullin suppression in T(H) 2-related inflammation is of pathophysiological significance and represents loss of a factor that maintains tissue integrity during inflammation.

Topics: Administration, Intranasal; Adrenomedullin; Allergens; Animals; Asthma; Capillary Permeability; Cytokines; Disease Models, Animal; Endothelial Cells; Epithelial Cells; Gene Expression Regulation; Humans; Inflammation; Macrophages, Alveolar; Mice; Mice, Inbred BALB C

Adrenomedullin (ADM), a newly identified vasodilating peptide, is reported to be expressed in lungs and have a bronchodilating effect. We hypothesized whether ADM could be involved in the pathogenesis of bronchial asthma. We examined the role of ADM in airway responsiveness using heterozygous ADM-deficient mice (AM+/-) and their littermate control (AM+/+). Here, we show that airway responsiveness is enhanced in ADM mutant mice after sensitization and challenge with ovalbumin (OVA). The immunoreactive ADM level in the lung tissue after methacholine challenge was significantly greater in the wild-type mice than that in the mutant. However, the impairment of ADM gene function did not affect immunoglobulins (OVA-specific IgE and IgG1), T helper 1 and 2 cytokines, and leukotrenes. Thus the conventional mechanism of allergen-induced airway responsiveness is not relevant to this model. Furthermore, morphometric analysis revealed that eosinophilia and airway hypersecretion were similarly found in both the OVA-treated ADM mutant mice and the OVA-treated wild-type mice. On the other hand, the area of the airway smooth muscle layer of the OVA-treated mutant mice was significantly greater than that of the OVA-treated wild-type mice. These results suggest that ADM gene disruption may be associated with airway smooth muscle hyperplasia as well as enhanced airway hyperresponsiveness. ADM mutant mice might provide novel insights to study the pathophysiological role of ADM in vivo.

Topics: Adrenomedullin; Allergens; Animals; Asthma; Bronchial Provocation Tests; Hypersensitivity; Mice; Mice, Knockout; Ovalbumin

To study the formation and localization of ADM mRNA in lung tissues and investigate the effects of ADM on isolated tracheal strip contraction induced by histamine in asthmatic guinea pig.. The guinea pigs (n = 22) were randomly divided into two groups of 11 each: asthmatic group and control group. The formation and localization of ADM mRMA were observed by in site hybridization. The effect of exogenous ADM on contractions of isolated tracheal strip of the asthmatic guinea pigs to histamine was examined.. There were strong positive expression for ADM mRNA in airway epithelial cells (AEC), smooth muscle cells (ASMC) in asthmatic group. The control group showed significantly decreased number of ADM mRNA positive cells in lung tissues. From 10(-11) mol/L to 10(-7) mol/L, ADM may cause concentration depend pentiation of the isolated tracheal strip contraction induced by histamine of asthmatic group which was higher significantly compared the control group (P < 0.05). 10(-8) mol/L ADM reached the maximal relaxation, with the increasing of ADM, neither asthmatic nor control group can increase the relaxation.. There is ADM mRNA overproduction in AEC and ASMC and exogenous ADM may inhibit isolated tracheal strip contraction induced by histamine of asthmatic guinea pig, which may contribute to airway inflammation and hyperresponsiveness in asthma.

Topics: Adrenomedullin; Airway Resistance; Animals; Asthma; Guinea Pigs; In Vitro Techniques; Lung; Male; Trachea

Adrenomedullin (ADM) is a newly discovered endogenous vasorelaxing peptide isolated from pheochromocytoma. Some experimental studies suggest that ADM plays a role in asthma. The purposes of the present study were to assess the plasma ADM levels in adults with mild to severe asthma and controls and to correlate those with the findings on lung function test results and other clinical indices. We recruited 16 mild, 10 moderate, and 11 severely asthmatic patients and 12 healthy controls. We measured the plasma concentrations of ADM in patients with asthma and in healthy subjects using RIA. We assessed FEV1, FEV1 predicted %, FEV1/FVC, symptom score, IgE, ECP, and morning and evening peak expiratory flow measurements. There was no significant difference between the asthmatic and the control group ADM levels, which were 26.3 +/- 24.2 pg/mL and 22.9 +/- 17.6 pg/mL, respectively. Furthermore, plasma ADM levels increased as the severity of the disease increased in asthmatic patients (20.7 +/- 14.4 pg/mL in mild, 25.2 +/- 24.3 pg/mL in moderate, and 35.5 +/- 33.6 pg/mL in severe asthmatics), although they did not result in any statistical significance. However, the plasma ADM levels correlated negatively with the FEV1 levels in the asthmatic group (p < 0.02, r = -0.37). Peripheral blood eosinophilia, IgE, and ECP levels did not correlate with plasma ADM levels. These results suggest that the measurement of ADM concentration in plasma will not be of diagnostic use in asthma, but may be a reflection of the severity of asthma.

Topics: Adrenomedullin; Adult; Asthma; Calcitonin Gene-Related Peptide; Case-Control Studies; Eosinophilia; Female; Humans; Immunoglobulin E; Male; Middle Aged; Peptides; Respiratory Function Tests; Skin Tests; Vasodilator Agents

A novel vasorelaxant peptide, adrenomedullin (AM), has been isolated from the acid extract of human pheochromocytoma. We have recently shown that AM inhibits histamine- and acetylcholine-induced bronchoconstriction in anesthetized guinea pigs in vivo, and this bronchodilatory effect is long-lasting. Here, we measured plasma AM concentrations in nine patients with an acute attack of bronchial asthma. The results were compared with values in 30 age-matched normal control subjects and seven age-matched stable asthmatic patients. The mean AM concentrations of patients with an acute asthma attack (98 +/- 22 pg/mL) were clearly higher than those of normal control subjects (18 +/- 2 pg/mL) and stable asthmatic patients (21 +/- 3 pg/mL). Reverse-phase high-performance liquid chromatography (HPLC) showed that the major component of plasma immunoreactive AM in patients with an asthma attack and in normal subjects equally corresponded to authentic human AM(1-52). Our results suggest that plasma AM is markedly increased in many of the patients during an acute attack of bronchial asthma, but it is not observed in stable asthmatic patients. Although this report is preliminary, the observed increase of circulating AM during an acute asthma attack may represent a compensatory mechanism against the bronchoconstriction, probably through its bronchodilatory action.

Topics: Acute Disease; Adrenomedullin; Adult; Aged; Asthma; Humans; Middle Aged; Peptides; Vasodilator Agents