Cigarette smoke-induced kinin B1 receptor promotes NADPH oxidase activity in cultured human alveolar epithelial cells

Peptides. 2011 Jul;32(7):1447-56. doi: 10.1016/j.peptides.2011.05.005. Epub 2011 May 11.

Abstract

Pulmonary inflammation is an important pathological feature of tobacco smoke-related lung diseases. Kinin B1 receptor (B1R) is up-regulated in the rat trachea chronically exposed to cigarette-smoke. This study aimed at determining (1) whether exposure to total particulate matter of the cigarette smoke (TPM) can induce B1R in human alveolar epithelial A549 cells, (2) the mechanism of B1R induction, (3) the functionality of de novo synthesized B1R, and (4) the role of B1R in TPM-induced increase of superoxide anion (O₂(●⁻)) level. Results show that A549 cells exposed to 10 μg/ml TPM increased O₂(●⁻) level along with B1R (protein and mRNA) and IL-1β mRNA. In contrast, B2R and TNF-α mRNA were not affected by TPM. The increasing effect of TPM on O₂(●⁻) level was not significantly affected by the B1R antagonist SSR240612. TPM-increased B1R mRNA was prevented by co-treatments with N-acetyl-l-cysteine (potent antioxidant), diphenyleneiodonium (NADPH oxidase inhibitor), IL-1Ra (interleukin-1R antagonist) and SN-50 (specific inhibitor of NF-kB activation) but not by pentoxifylline (TNF-α release inhibitor), indomethacin and niflumic acid (COX-1 and -2 inhibitors). Stimulation of B1R with a selective agonist (des-Arg⁹-BK, 10 μM; 30 min) increased O₂(●⁻)production which was prevented by apocynin and diphenyleneiodonium (NADPH oxidase inhibitors). Data suggest that the increased expression of B1R by TPM in A549 cells is mediated by oxidative stress, IL-1β and NF-kB but not by cyclooxygenases or TNF-α. The amplification of O₂(●⁻) levels via the activation of B1R-NADPH oxidase may exacerbate pulmonary inflammation and contribute to the chronicity of tobacco smoke-related lung diseases.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Bradykinin B1 Receptor Antagonists
  • Bradykinin B2 Receptor Antagonists
  • Cells, Cultured
  • Cyclooxygenase 1 / genetics
  • Cyclooxygenase 1 / metabolism
  • Cyclooxygenase 2 / genetics
  • Cyclooxygenase 2 / metabolism
  • Enzyme Activation / drug effects*
  • Enzyme Inhibitors / pharmacology
  • Epithelial Cells / drug effects
  • Epithelial Cells / immunology
  • Epithelial Cells / metabolism*
  • Epithelial Cells / pathology
  • Gene Expression / drug effects
  • Humans
  • Inflammation / immunology
  • Inflammation / metabolism*
  • Inflammation / pathology
  • Interleukin-1beta / antagonists & inhibitors
  • Interleukin-1beta / genetics
  • Interleukin-1beta / metabolism
  • NADPH Oxidases / antagonists & inhibitors
  • NADPH Oxidases / genetics
  • NADPH Oxidases / metabolism*
  • NF-kappa B / antagonists & inhibitors
  • NF-kappa B / genetics
  • NF-kappa B / metabolism
  • Oxidative Stress / drug effects
  • Particulate Matter / adverse effects
  • Particulate Matter / pharmacology*
  • Pulmonary Alveoli / drug effects
  • Pulmonary Alveoli / immunology
  • Pulmonary Alveoli / metabolism*
  • Pulmonary Alveoli / pathology
  • Receptor, Bradykinin B1 / genetics
  • Receptor, Bradykinin B1 / metabolism*
  • Receptor, Bradykinin B2 / genetics
  • Receptor, Bradykinin B2 / metabolism
  • Signal Transduction / drug effects
  • Smoke / adverse effects
  • Smoking / adverse effects*
  • Superoxides / analysis
  • Superoxides / metabolism
  • Tumor Necrosis Factor-alpha / antagonists & inhibitors
  • Tumor Necrosis Factor-alpha / genetics
  • Tumor Necrosis Factor-alpha / metabolism

Substances

  • Bradykinin B1 Receptor Antagonists
  • Bradykinin B2 Receptor Antagonists
  • Enzyme Inhibitors
  • Interleukin-1beta
  • NF-kappa B
  • Particulate Matter
  • Receptor, Bradykinin B1
  • Receptor, Bradykinin B2
  • Smoke
  • Tumor Necrosis Factor-alpha
  • Superoxides
  • Cyclooxygenase 1
  • Cyclooxygenase 2
  • PTGS1 protein, human
  • PTGS2 protein, human
  • NADPH Oxidases