Muscarinic receptors, leukotriene B4 production and neutrophilic inflammation in COPD patients

• Published in: Allergy (Copenhagen) Vol. 60; no. 11; pp. 1361 - 1369
• Main Authors: Profita, M., Giorgi, R. Di, Sala, A., Bonanno, A., Riccobono, L., Mirabella, F., Gjomarkaj, M., Bonsignore, G., Bousquet, J., Vignola, A. M.
• Format: Journal Article
• Language: English
• Published: Oxford, UK Munksgaard International Publishers 01.11.2005; Blackwell
• Subjects: Acetylcholine - pharmacology; Aged; Allergic diseases; Biological and medical sciences; Calcium-Binding Proteins - antagonists & inhibitors; Calcium-Binding Proteins - pharmacology; Cells, Cultured; Chemotaxis, Leukocyte; chronic obstructive pulmonary disease; ERK1/2; Female; Flavonoids - pharmacology; Fundamental and applied biological sciences. Psychology; Fundamental immunology; Humans; Immunohistochemistry; Immunopathology; induced sputum; Leukocytes, Mononuclear - drug effects; Leukocytes, Mononuclear - metabolism; leukotriene B4; Leukotriene B4 - analysis; Leukotriene B4 - metabolism; Male; Medical sciences; Middle Aged; Mitogen-Activated Protein Kinase 3 - drug effects; Mitogen-Activated Protein Kinase 3 - metabolism; muscarinic receptors; Neutrophils - metabolism; Protozoan Proteins - antagonists & inhibitors; Protozoan Proteins - pharmacology; Pulmonary Disease, Chronic Obstructive - immunology; Pulmonary Disease, Chronic Obstructive - metabolism; Receptors, Muscarinic - metabolism; Sputum - cytology; Sputum - metabolism; Human; Immunopathology; Lung disease; Allergy; Respiratory disease; Enzyme; Chronic disease; Arachidonic acid derivatives; Mitogen-activated protein kinase; Inflammation; muscarinic receptors; Cholinergic receptor; ERK1/2; Immunology; Leukotriene B4; Extracellular signal-regulated protein kinase 1; Eicosanoid; Bronchus disease; Muscarinic receptor; Obstructive pulmonary disease; Induced sputum; chronic obstructive pulmonary disease
• ISSN: 0105-4538; 1398-9995
• DOI: 10.1111/j.1398-9995.2005.00892.x

Background:  Acetylcholine (ACh) plays an important role in smooth muscle contraction and in the development of airway narrowing; preliminary evidences led us to hypothesize that ACh might also play a role in the development of airways inflammation in chronic obstructive pulmonary disease (COPD). Methods:  We evaluated the concentrations of leukotriene B4 (LTB4) in induced sputum, and the expression of Ach M1, M2, and M3 receptors in sputum cells (SC) obtained from 16 patients with COPD, 11 smokers, and 14 control subjects. The SC were also treated with ACh and the production of LTB4 assessed in the presence or absence of a muscarinic antagonist (oxitropium). In blood monocytes, we evaluated LTB4 release and activation of the extracellular signal‐regulated kinases (ERK) pathway after treatment with Ach. Results:  The LTB4 concentrations were higher in COPD than in controls (P < 0.01) and correlated with the number of neutrophil (P < 0.01). The M3 receptors expression was increased in COPD subjects when compared to smokers and control (P < 0.05 and 0.0001, respectively), while M2 expression resulted decreased (P < 0.05 and 0.01). The ACh‐induced LTB4 production was observed in peripheral blood monocytes, and was sensitive to ERK inhibition. Similarly, ACh significantly increased neutrophil chemotactic activity and LTB4 released from SC of COPD patients only, and these effects were blocked by pretreatment with the inhibitor of ERK pathway PD98059. Conclusions:  The results obtained show that muscarinic receptors may be involved in airway inflammation in COPD subjects through ACh‐induced, ERK1/2‐dependent LTB4 release. Muscarinic antagonism may contribute to reduce neutrophil infiltration and activation in COPD.