Cigarette smoke particle-phase extract induces HO-1 expression in human tracheal smooth muscle cells: Role of the c-Src/NADPH oxidase/MAPK/Nrf2 signaling pathway

Shin Ei Cheng, I-Ta Lee, Chih Chung Lin, Yu Ru Kou, Chuen Mao Yang

Research output: Contribution to journalArticlepeer-review

72 Citations (Scopus)

Abstract

Heme oxygenase-1 (HO-1) is known as an oxidative stress protein that is up-regulated by various stimuli. HO-1 has been shown to protect cells against oxidative damage. Cigarette smoke is a potential inflammatory mediator that causes chronic obstructive pulmonary disease and asthma. In this study, we report that cigarette smoke particle-phase extract (CSPE) is an inducer of HO-1 expression mediated through various signaling pathways in human tracheal smooth muscle cells (HTSMCs). CSPE-induced HO-1 protein, mRNA expression, and promoter activity were attenuated by pretreatment with a ROS scavenger (N-acetyl-l-cysteine) and inhibitors of c-Src (PP1), NADPH oxidase [diphenylene iodonium chloride (DPI) and apocynin (APO)], MEK1/2 (U0126), p38 MAPK (SB202190), and JNK1/2 (SP600125) or transfection with siRNAs for Src, p47phox, NOX2, p42, p38, JNK2, or NF-E2-related factor 2 (Nrf2). CSPE-stimulated translocation of p47phox and Nrf2, ROS production, and NADPH oxidase activity was attenuated by transfection with siRNAs for Src, p47phox, and NOX2 or pretreatment with PP1, DPI, or APO. Furthermore, CSPE-induced NOX2, c-Src, and p47phox complex formation was revealed by immunoprecipitation using an anti-NOX2, anti-p47phox, or anti-c-Src Ab followed by Western blot against anti-NOX2, anti-p47phox, or anti-c-Src Abs. These results demonstrate that CSPE-induced ROS generation is mediated through a c-Src/NADPH oxidase/MAPK pathway and in turn initiates the activation of Nrf2 and ultimately induces HO-1 expression in HTSMCs.

Original languageEnglish
Pages (from-to)1410-1422
Number of pages13
JournalFree Radical Biology and Medicine
Volume48
Issue number10
DOIs
Publication statusPublished - May 1 2010
Externally publishedYes

Keywords

  • Cigarette smoke extract
  • Free radicals
  • Heme oxygenase-1
  • Reactive oxygen species
  • Signaling transduction
  • Tracheal smooth muscle cells

ASJC Scopus subject areas

  • Biochemistry
  • Physiology (medical)

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