Oxidants and signaling by mitogen-activated protein kinases in lung epithelium

Our plain-English summary of Oxidants and signaling by mitogen-activated protein kinases in lung epithelium, by B.T. Mossman, K.M. Lounsbury, S.P. Reddy (American Journal of Respiratory Cell and Molecular Biology, 2006).

The study

• Authors: B.T. Mossman, K.M. Lounsbury, S.P. Reddy
• Journal: American Journal of Respiratory Cell and Molecular Biology
• Published: 2006;34(6):666-9
• Type of article: Review
• Cited by: 132 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Oxidants in cigarette smoke and generated from asbestos fibers activate mitogen-activated protein kinase (MAPK) signaling cascades in lung epithelial cells in vitro and in vivo. These signaling pathways lead to the enhanced ability of Jun and Fos family members (i.e., components of the activator protein [AP]-1 transcription factor) to activate transcription of a number of AP-1-dependent target genes involved in cell proliferation or death, differentiation, and inflammation. Research by the Basbaum laboratory has been critical in showing that mucin transcription in response to cigarette smoke and gram-positive bacteria is mediated through activation of the epidermal growth factor receptor and MAPK cascades. Work from our laboratories supports the concept that MAPK signaling and AP-1 transactivation by cigarette smoke and asbestos may synergize in lung epithelial cell injury, compensatory proliferation of lung epithelial cells, and carcinogenesis, supporting a mechanistic framework for the striking increases in lung cancer incidence in asbestos workers who smoke. Targeting of MAPKs and inter-related signaling cascades may be critical to the prevention of lung cancers and control of mucin overproduction in a number of lung diseases including asthma, cystic fibrosis, chronic bronchitis, and chronic obstructive pulmonary disease.

In plain English

This article was a short review, written as a tribute to Carol Basbaum. It summarized laboratory research, mostly from the authors' own laboratories and the Basbaum laboratory, on how oxidants from cigarette smoke and asbestos fibers switch on signaling pathways (MAPK cascades) and the AP-1 transcription factor in lung cells. It reported no new data of its own. The earlier work it described included these findings. In rodent pleural mesothelial cells, asbestos activated the ERK1/2 pathway, while other nonpathogenic particles and synthetic fibers did not. Blocking ERK1 or Fra-1 reversed asbestos-transformed rodent mesothelioma cells toward normal mesothelial cells. In mice, inhaled chrysotile asbestos changed the expression of more than 38 signaling and oxidative-stress genes over a 40-day period. In a mouse lung epithelial cell line, lower asbestos concentrations led cells toward dividing and higher concentrations preceded cell death. The authors concluded that this work supported a mechanistic framework for the striking increases in lung cancer in asbestos workers who smoke. They noted that their model rested on studies testing each agent separately, and that studies of combined exposure in mice were still under way.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: short review (tribute article) summarizing earlier laboratory studies, mainly from the authors' and the Basbaum laboratories; no new data
• Who was studied: no study population of its own; the reviewed studies used cultured cells (rodent pleural mesothelial cells, human mesothelial cells, human airway cell lines H441 and 1HAEo, the murine alveolar type II epithelial cell line C10) and mouse lungs
• Exposure: oxidants from cigarette smoke and from asbestos fibers; the reviewed studies included chrysotile inhalation in mice and crocidolite applied to human mesothelial cells in vitro
• Main results:
  • Earlier work reviewed: in rodent pleural mesothelial cells, asbestos activated ERK1/2, whereas other nonpathogenic particles and synthetic fibers did not
  • Earlier work reviewed: in asbestos-transformed rodent mesothelial cells, dominant negative ERK1 or Fra-1 constructs reversed the mesothelioma cell phenotype to that of normal mesothelial cells
  • Earlier work reviewed: Fra-1 expression is increased in human mesotheliomas and other tumor types
  • Earlier work reviewed: in mouse lungs, time-dependent expression of more than 38 signal transduction and oxidative-stress genes was found after chrysotile inhalation over a 40-day period
  • Earlier work reviewed: after inhalation, activated ERKs appeared preferentially in distal bronchiolar and alveolar duct epithelium, the sites where asbestos fibers lodge
  • Earlier work reviewed: in C10 cells, low, proliferative asbestos concentrations produced a nuclear accumulation of phosphorylated ERK1/2 that diminished over time and led to cells entering S phase
  • Earlier work reviewed: at higher asbestos concentrations in C10 cells, phosphorylated ERK1/2 accumulated in the nucleus before cell death (apoptosis)
• The authors' conclusion: The authors concluded that their laboratories' work on MAPK signaling and AP-1 by cigarette smoke and asbestos supports a mechanistic framework for the striking increases in lung cancer incidence in asbestos workers who smoke
• Limitations the authors state:
  • The proposed model is based on studies that tested cigarette smoke and asbestos separately, not together
  • Interplay between MAPK activation and other signaling pathways makes these events difficult to separate

Topics

Medical terms in this study, explained in our Lexicon: Epithelium, Inflammation, Carcinogenesis, Lung Cancer, Fibrosis.

Related studies

• Fibroblast growth factor-10 prevents asbestos-induced alveolar epithelial cell apoptosis by a mitogen-activated protein kinase-dependent mechanism — D. Upadhyay, V. Panduri, et al. (2005)
• Retinoid signaling and activator protein-1 expression in ferrets given beta-carotene supplements and exposed to tobacco smoke — X.D. Wang, C. Liu, et al. (1999)
• Role of Mitogen-Activated Protein Kinases, Early Response Protooncogenes, and Activator Protein-1 in Cell Signaling by Asbestos — B. Mossman, A. Hubbard, et al. (2000)
• Role of extracellular signal-regulated protein kinases in apoptosis by asbestos and H2O2 — L.A. Jiménez, C. Zanella, et al. (1997)
• Regulation of antioxidant enzymes in lung after oxidant injury — T. Quinlan, S. Spivack, et al. (1994)
• Mitogen-activated protein kinase expression and activation does not differentiate benign from malignant mesothelial cells — L. Vintman, S. Nielsen, et al. (2005)

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