Asbestos activates mitogen-activated protein kinase (MAPK) cascades in alveolar type II epithelial (C10) cells in vitro and in vivo. In C10 cells, these signaling events precede early increases in mRNA levels of fos/jun family members and more protracted increases in mRNA levels of fra-1 and Fra-1/Jun (AP-1) complexes. We hypothesize that activation of ERK and JNK pathways by asbestos leads to changes in expression of AP-1 family members and subunit composition that then govern cell cycle changes, injury and subsequent proliferation of pulmonary epithelial cells.
In Specific Aim #1, we will determine in C10 alveolar type II epithelial cells using transfection techniques whether activation of ERK and JNK cascades by asbestos are linked causally to increased expression of the fos/jun members, c-fos, c-jun and fra-1, composition of AP-1 complexes, transactivation of AP-1 dependent gene expression, and subsequent outcomes (cell cycle alterations, injury and compensatory proliferation).
In Specific Aim #2, we will assess using transgenic mice over-expressing dominant negative (dn)MEK1 or dnJNK1 with lung epithelial cell promoters (CC10 and SPC), whether ERK and JNK pathways are causally related to proliferation of distal bronchiolar and alveolar type II epithelial cells and the development of fibrosis in a murine model of asbestosis.
In Specific Aim #3, we will determine using laser capture microdissection and real time PCR (TaqMan) whether c-fos, c-jun and fra-1 expression is increased in distal bronchiolar and alveolar type II epithelial cells of mice exposed to asbestos, and whether patterns are modified in transgenic mice expressing epithelial cell-specific dnMEK1, dnJNK1 or backcrosses of these mice to block both pathways. The goals of this Project are related to the theme of the Program Project, the role of MAPK cascades in epithelial cell injury and proliferation, and will ascertain whether modification of these cell signaling events modifies these outcomes in vitro and in an inhalation model of asbestosis. Our hypothesis are novel in that they will provide a mechanistic framework for MAPK pathways and AP-1 subunit composition in the causation of epithelial cell injury and compensatory hyperplasia.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL067004-05
Application #
7056714
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Project Start
Project End
Budget Start
2005-05-01
Budget End
2006-04-30
Support Year
5
Fiscal Year
2005
Total Cost
$248,128
Indirect Cost
Name
University of Vermont & St Agric College
Department
Type
DUNS #
066811191
City
Burlington
State
VT
Country
United States
Zip Code
05405
Sayan, Mutlay; Mossman, Brooke T (2016) The NLRP3 inflammasome in pathogenic particle and fibre-associated lung inflammation and diseases. Part Fibre Toxicol 13:51
Sabo-Attwood, Tara; Ramos-Nino, Maria E; Eugenia-Ariza, Maria et al. (2011) Osteopontin modulates inflammation, mucin production, and gene expression signatures after inhalation of asbestos in a murine model of fibrosis. Am J Pathol 178:1975-85
Buder-Hoffmann, Sylke A; Shukla, Arti; Barrett, Trisha F et al. (2009) A protein kinase Cdelta-dependent protein kinase D pathway modulates ERK1/2 and JNK1/2 phosphorylation and Bim-associated apoptosis by asbestos. Am J Pathol 174:449-59
Janssen-Heininger, Yvonne M W; Mossman, Brooke T; Heintz, Nicholas H et al. (2008) Redox-based regulation of signal transduction: principles, pitfalls, and promises. Free Radic Biol Med 45:1-17
Manning, Christopher B; Sabo-Attwood, Tara; Robledo, Raymond F et al. (2008) Targeting the MEK1 cascade in lung epithelium inhibits proliferation and fibrogenesis by asbestos. Am J Respir Cell Mol Biol 38:618-26
Barlow, Christy A; Kitiphongspattana, Kajorn; Siddiqui, Nazli et al. (2008) Protein kinase A-mediated CREB phosphorylation is an oxidant-induced survival pathway in alveolar type II cells. Apoptosis 13:681-92
Fukagawa, Naomi K; Li, Muyao; Sabo-Attwood, Tara et al. (2008) Inhaled asbestos exacerbates atherosclerosis in apolipoprotein E-deficient mice via CD4+ T cells. Environ Health Perspect 116:1218-25
Mossman, Brooke T (2008) Assessment of the pathogenic potential of asbestiform vs. nonasbestiform particulates (cleavage fragments) in in vitro (cell or organ culture) models and bioassays. Regul Toxicol Pharmacol 52:S200-3
Levis, Jamie; Loi, Roberto; Butnor, Kelly J et al. (2008) Decreased asbestos-induced lung inflammation and fibrosis after radiation and bone marrow transplant. Am J Respir Cell Mol Biol 38:16-25
Dostert, Catherine; Petrilli, Virginie; Van Bruggen, Robin et al. (2008) Innate immune activation through Nalp3 inflammasome sensing of asbestos and silica. Science 320:674-7

Showing the most recent 10 out of 58 publications