Adrenomedullin Inhibits the Secretion of Cytokine-Induced Neutrophil Chemoattractant, a Member of the Interleukin-8 Family, from Rat Alveolar Macrophages

doi:10.1006/bbrc.1995.1914

Biochemical and Biophysical Research Communications

Volume 211, Issue 3, 26 June 1995, Pages 1031-1035

https://doi.org/10.1006/bbrc.1995.1914 Get rights and content

Abstract

This study was undertaken to determine the effects of adrenomedullin (AM) on the secretion of cytokine-induced neutrophil chemoattractant (CINC), a member of the interleukin-8 family, from lipopolysaccharide-stimulated rat alveolar macrophages in vitro. AM significantly increased cAMP levels in alveolar macrophages in a dose-dependent fashion. On the other hand, AM significantly inhibited CINC secretion from alveolar macrophages in a dose-dependent fashion, and 8-bromo-cyclic adenosine monophosphate (8-Br-cAMP) also significantly inhibited CINC secretion. These findings suggest that AM may play important roles in the regulation of airway inflammation via a cAMP-dependent mechanism.

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Similarly, according to a report by Isumi et al. (1999), AM suppressed interleukin-1β-induced tumor necrosis factor-α production in the Swiss T3T fibroblast cell line. These effects were reportedly mimicked by 8-bromo-cAMP or attenuated by H-89, a protein kinase A inhibitor, suggesting a cAMP-dependent intracellular mechanism of action (Isumi et al., 1999; Kamoi et al., 1995). On the basis of these findings from patients or immune cells, a number of experimental therapeutic studies were carried out with various animal models of systematic inflammatory response syndrome or sepsis (Ertmer et al., 2007; Hyvelin et al., 2002; Müller-Redetzky et al., 2014; Yang et al., 2002).
The bioactive peptide adrenomedullin (AM) exerts pleiotropic actions in various organs and tissues. In the heart, AM has an inhibitory effect on ventricular remodeling, suppressing cardiomyocyte hypertrophy and the proliferation of cardiac fibroblasts. This pharmacological property was shown not only in rat models of acute myocardial infarction, but also clinically in patients with this cardiac disease. An originally characterized feature of AM was a potent vasodilatory effect, but this peptide was found to be important for vascular integrity and angiogenesis. AM-induced angiogenesis is involved in tumor growth, while AM inhibits apoptosis of some types of tumor cell. A unique pharmacological property is anti-inflammatory activity, which has been characterized in sepsis and inflammatory bowel diseases; thus, there is an ongoing clinical trial to test the efficacy of AM for patients with intractable ulcerative colitis. These activities are assumed to be mediated via the specific receptor formed by calcitonin receptor-like receptor and receptor activity-modifying protein 2 or 3, while some questions remain to be answered about the molecular mechanisms of this signal transduction system. Taking these findings together, AM is a bioactive peptide with pleiotropic effects, with potential as a therapeutic tool for a wide range of human diseases from myocardial infarction to malignant tumors or inflammatory bowel diseases.
Stable-state midrange-proadrenomedullin level is a strong predictor of mortality in patients with COPD
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The higher mortality rate in patients with higher serum MR-proADM levels may reflect an increased severity of inflammatory lung disease, which is not directly reflected by the ADO score or BODE index. A variety of cells may augment ADM secretion in response to various cytokines.38,39 The increased MR-proADM may also reflect the more systemic effects of COPD, including COPD-induced cardiopulmonary stress or cardiovascular comorbidity.
Midrange-proadrenomedullin (MR-proADM) has been shown to be elevated in patients hospitalized for an acute exacerbation of COPD (AECOPD) and in patients with community-acquired pneumonia. When measured during AECOPDs, MR-proADM has also been shown to be a predictor of mortality. We hypothesized that MR-proADM levels measured in a stable state could also predict mortality.
We included 181 patients in whom we had paired plasma samples for MR-proADM determinations during a stable state and at hospitalization for an AECOPD when they also produced sputum. Time to death or censoring was compared between patients with MR-proADM above or below the median of 0.71 nmol/L. The predictive value of MR-proADM for survival was determined by calculating the C statistic.
Patients with COPD and MR-proADM levels > 0.71 nmol/L in the stable state had a threefold-higher risk of dying than did patients with MR-proADM levels < 0.71 nmol/L (hazard ratio, 2.98 [95% CI, 1.51-5.90]; C statistic, 0.76). The corrected OR for 1-year mortality was 8.90 (95% CI, 1.94-44.6) in patients with high MR-proADM levels measured in the stable state, compared with patients with low levels measured in the stable state.
MR-proADM measured in the stable state appeared to be a strong predictor of mortality in patients with COPD. MR-proADM is far easier to measure than other predictors of mortality in COPD, such as BMI, airflow obstruction, dyspnea, and exercise capacity score.
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Alveolar macrophages are likely the main source of increased AM expression in the lungs, as their expression of AM mRNA is substantially elevated in rats and humans with severe heart failure [98]. The elevated AM levels may limit pulmonary infiltration of neutrophils because AM inhibits the cytokine-induced secretion of neutrophil chemoattractant from rat alveolar macrophages in vitro [62]. Hemodynamic stress and angiotensin II are both key mediators of cardiac hypertrophy induced by pressure overload (POL; by aortic banding) or volume overload (VOL; by aortocaval shunt).
Adrenomedullin (AM) is a novel hypotensive peptide that exerts a variety of strongly protective effects against multiorgan damage. AM-specific receptors were first identified as heterodimers composed of calcitonin-receptor-like receptor (CLR), a G protein coupled receptor, and one of two receptor activity-modifying proteins (RAMP2 or RAMP3), which are accessory proteins containing a single transmembrane domain. RAMPs are required for the surface delivery of CLR and the determination of its phenotype. CLR/RAMP2 (AM₁ receptor) is more highly AM-specific than CLR/RAMP3 (AM₂ receptor). Although there have been no reports showing differences in intracellular signaling via the two AM receptors, in vitro studies have shed light on their distinct trafficking and functionality. In addition, the tissue distributions of RAMP2 and RAMP3 differ, and their gene expression is differentially altered under pathophysiological conditions, which is suggestive of the separate roles played byAM₁ and AM₂ receptors in vivo. Both AM and the AM₁ receptor, but not the AM₂ receptor, are crucial for the development of the fetal cardiovascular system and are able to effectively protect against various vascular diseases. However, AM₂ receptors reportedly play an important role in maintaining a normal body weight in old age and may be involved in immune function. In this review article, we focus on the shared and separate functions of the AM receptor subtypes and also discuss the potential for related drug discovery. In addition, we mention their possible function as receptors for AM2 (or intermedin), an AM-related peptide whose biological functions are similar to those of AM.
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Citation Excerpt :
Therefore, decrease of AM release also contributes to attenuation of the prolonged inflammatory cycle in allergic inflammation through regulating histamine release and CC-chemokine production. In a study of pulmonary inflammation, it was shown that AM may play a role in the inhibitory regulation of inflammatory processes by several pathways, such as inhibition of binding of neutrophils to vascular endothelial cells and subsequent neutrophil emigration [17,38] and inhibition of cytokine secretion from macrophages, such as TNF-α, IL-6 and cytokine-induced neutrophil chemoattractant [17,23]. Although we have no direct evidence, the immunostaining pattern observed in the present study suggests that mast cells may compensate for the decreased content of AM.
Adrenomedullin (AM) is a potent hypotensive and vasodilatory peptide. AM may exert protective actions against the development of many diseases by modulating the blood circulation and body fluid balance. In addition to these functions, it has recently been reported to play important roles in the development of allergy and infections. The purpose of the present study was to demonstrate the existence of AM in the human nasal mucosa and to discuss whether AM might contribute to the pathogenesis of nasal congestion. We measured the total AM concentrations in the nasal discharge. The total AM concentration in the nasal discharge was significantly higher in the non-allergy group (72.1 ± 55.5 fmol/ml) than in the allergy group (37.1 ± 44.2 fmol/ml). By immunohistochemical examination, we identified AM-containing cells in the nasal mucosa from both subjects with and without nasal allergy, and also in nasal polyps. Moreover, those cells were positive for anti-tryptase antibody which recognizes mast cells. In nasal allergy, vasodilatation and increase in vascular permeability are characteristic features of the immediate phase response. Reduced AM levels in the nasal discharge may be associated with attenuation of both of these factors. On the other hand, immunohistochemical analysis demonstrated AM-immunoreactive cells in the chronic phase of rhinosinusitis. In the late and inflammatory phase, mast cells produce AM, which possibly acts as an inhibitor of inflammatory cell migration. In conclusion, AM may be actively secreted into the nasal discharge. AM in the nasal discharge may have protective and anti-inflammatory effects in the nasal mucosa.

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Regular ArticleAdrenomedullin Inhibits the Secretion of Cytokine-Induced Neutrophil Chemoattractant, a Member of the Interleukin-8 Family, from Rat Alveolar Macrophages

Abstract

Regular Article
Adrenomedullin Inhibits the Secretion of Cytokine-Induced Neutrophil Chemoattractant, a Member of the Interleukin-8 Family, from Rat Alveolar Macrophages