Key points are not available for this paper at this time.
We have previously reported that airborne particulate matter air pollution (PM) activates the intrinsic apoptotic pathway in alveolar epithelial cells through a pathway that requires the mitochondrial generation of reactive oxygen species (ROS) and the activation of p53. We sought to examine the source of mitochondrial oxidant production and the molecular links between ROS generation and the activation of p53 in response to PM exposure. Using a mitochondrially targeted ratiometric sensor (Ro-GFP) in cells lacking mitochondrial DNA (ρ0 cells) and cells stably expressing a small hairpin RNA directed against the Rieske iron-sulfur protein, we show that site III of the mitochondrial electron transport chain is primarily responsible for fine PM (PM2.5)-induced oxidant production. In alveolar epithelial cells, the overexpression of SOD1 prevented the PM2.5-induced ROS generation from the mitochondria and prevented cell death. Infection of mice with an adenovirus encoding SOD1 prevented the PM2.5-induced death of alveolar epithelial cells and the associated increase in alveolar-capillary permeability. Treatment with PM2.5 resulted in the ROS-mediated activation of the oxidant-sensitive kinase ASK1 and its downstream kinase JNK. Murine embryonic fibroblasts from ASK1 knock-out mice, alveolar epithelial cells transfected with dominant negative constructs against ASK1, and pharmacologic inhibition of JNK with SP600125 (25 μm) prevented the PM2.5-induced phosphorylation of p53 and cell death. We conclude that particulate matter air pollution induces the generation of ROS primarily from site III of the mitochondrial electron transport chain and that these ROS activate the intrinsic apoptotic pathway through ASK1, JNK, and p53. We have previously reported that airborne particulate matter air pollution (PM) activates the intrinsic apoptotic pathway in alveolar epithelial cells through a pathway that requires the mitochondrial generation of reactive oxygen species (ROS) and the activation of p53. We sought to examine the source of mitochondrial oxidant production and the molecular links between ROS generation and the activation of p53 in response to PM exposure. Using a mitochondrially targeted ratiometric sensor (Ro-GFP) in cells lacking mitochondrial DNA (ρ0 cells) and cells stably expressing a small hairpin RNA directed against the Rieske iron-sulfur protein, we show that site III of the mitochondrial electron transport chain is primarily responsible for fine PM (PM2.5)-induced oxidant production. In alveolar epithelial cells, the overexpression of SOD1 prevented the PM2.5-induced ROS generation from the mitochondria and prevented cell death. Infection of mice with an adenovirus encoding SOD1 prevented the PM2.5-induced death of alveolar epithelial cells and the associated increase in alveolar-capillary permeability. Treatment with PM2.5 resulted in the ROS-mediated activation of the oxidant-sensitive kinase ASK1 and its downstream kinase JNK. Murine embryonic fibroblasts from ASK1 knock-out mice, alveolar epithelial cells transfected with dominant negative constructs against ASK1, and pharmacologic inhibition of JNK with SP600125 (25 μm) prevented the PM2.5-induced phosphorylation of p53 and cell death. We conclude that particulate matter air pollution induces the generation of ROS primarily from site III of the mitochondrial electron transport chain and that these ROS activate the intrinsic apoptotic pathway through ASK1, JNK, and p53. Epidemiologic studies have consistently demonstrated a strong link between the daily levels of particulate matter air pollution <2.5 μm in diameter (PM2.5) 3The abbreviations used are: PM, particulate matter air pollution; ROS, reactive oxygen species; JNK, c-Jun N-terminal kinase; ASK, apoptosis signaling kinase; shRNA, small hairpin RNA; MAPKKK, mitogen-activated signaling kinase kinase kinase; GFP, green fluorescent protein; PBS, phosphate-buffered saline; pfu, plaque forming unit(s); TUNEL, deoxynucleotidyltransferase-mediated dUTP nick end labeling; MEF, murine embryonic fibroblast. and PM <10 μmin diameter (PM10) and cardiopulmonary morbidity and mortality (1Dominici F. McDermott A. Zeger S.L. Samet J.M. Environ. Health Perspect.. 2003; 111: 39-44Google Scholar, 2Katsouyanni K. Touloumi G. Samoli E. Gryparis A. Le Tertre A. Monopolis Y. Rossi G. Zmirou D. Ballester F. Boumghar A. Anderson H.R. Wojtyniak B. Paldy A. Braunstein R. Pekkanen J. Schindler C. Schwartz J. Epidemiology.. 2001; 12: 521-531Google Scholar, 3Samet J.M. Dominici F. Curriero F.C. Coursac I. Zeger S.L. N. Engl. J. Med.. 2000; 343: 1742-1749Google Scholar). In humans, exposure to PM10 has been associated with an increase in mortality from ischemic cardiovascular events including stroke and myocardial infarction, an acceleration in the age-related decline in lung function in normal adults, impairment in normal lung development in children, exacerbations of asthma in children and adults, accelerated atherosclerosis in women, increased rates of lung cancer, and the development of myocardial ischemia in men with stable coronary artery disease (4Dockery D.W. Pope III, C.A. Xu X. Spengler J.D. Ware J.H. Fay M.E. Ferris Jr., B.G. Speizer F.E. N. Engl. J. Med.. 1993; 329: 1753-1759Google Scholar, 5Pope III, C.A. Burnett R.T. Thurston G.D. Thun M.J. Calle E.E. Krewski D. Godleski J.J. Circulation.. 2004; 109: 71-77Google Scholar, 6Abbey D.E. Mills P.K. Petersen F.F. Beeson W.L. Environ. Health Perspect.. 1991; 94: 43-50Google Scholar, 7Miller K.A. Siscovick D.S. Sheppard L. Shepherd K. Sullivan J.H. Anderson G.L. Kaufman J.D. N. Engl. J. Med.. 2007; 356 (8): 447-458Google Scholar, 8McCreanor J. Cullinan P. Nieuwenhuijsen M.J. Stewart-Evans J. Malliarou E. Jarup L. Harrington R. Svartengren M. Han I.K. Ohman-Strickland P. Chung K.F. Zhang J. N. Engl. J. Med.. 2007; 357: 2348-2358Google Scholar, 9Downs S.H. Schindler C. Liu L.J. Keidel D. Bayer-Oglesby L. Brutsche M.H. Gerbase M.W. Keller R. Kunzli N. Leuenberger P. Probst-Hensch N.M. Tschopp J.M. Zellweger J.P. Rochat T. Schwartz J. Ackermann-Liebrich U. N. Engl. J. Med.. 2007; 357: 2338-2347Google Scholar, 10Mills N.L. Tornqvist H. Gonzalez M.C. Vink E. Robinson S.D. Soderberg S. Boon N.A. Donaldson K. Sandstrom T. Blomberg A. Newby D.E. N. Engl. J. Med.. 2007; 357: 1075-1082Google Scholar). The intracellular generation of reactive oxygen species (ROS) has emerged as a common mechanism by which particulates might initiate signaling pathways that end in these diverse pathologic conditions (11Nel A. Science.. 2005; 308: 804-806Google Scholar). We have reported that the PM-induced generation of ROS requires a functional electron transport chain, suggesting that PM might induce the inadvertent transfer of electrons from one or more sites in the electron transport chain to molecular oxygen (12Soberanes S. Panduri V. Mutlu G.M. Ghio A. Budinger G.R. Kamp D.W. Am. J. Respir. Crit. Care Med.. 2006; 174: 1229-1238Google Scholar). One of the mechanisms by which exposure to PM can contribute to alveolar epithelial dysfunction, lung injury and inflammation, and lung cancer is by activating the intrinsic apoptotic pathway to induce cell death (11Nel A. Science.. 2005; 308: 804-806Google Scholar, 12Soberanes S. Panduri V. Mutlu G.M. Ghio A. Budinger G.R. Kamp D.W. Am. J. Respir. Crit. Care Med.. 2006; 174: 1229-1238Google Scholar). We have reported that this process requires the activation of p53; however, the molecular events linking the generation of ROS by the mitochondrial electron transport chain with the activation of p53 are not known (12Soberanes S. Panduri V. Mutlu G.M. Ghio A. Budinger G.R. Kamp D.W. Am. J. Respir. Crit. Care Med.. 2006; 174: 1229-1238Google Scholar). In this paper, we show that exposure of alveolar epithelial cells to PM2.5 induces the generation of ROS from site III of the mitochondrial electron transport chain. These mitochondrially derived oxidants activate the mitogen-activated signaling kinase kinase kinase (MAPKKK) apoptosis signaling kinase 1 (ASK1), which activates the c-Jun N-terminal kinase (JNK) signaling pathway. The activation of JNK is required for the phosphorylation of p53 and the subsequent cell death. Inhibition of mitochondrial oxidant production in mouse lungs prevents PM2.5-induced cell death and the associated PM2.5-induced increase in the permeability of the alveolar-capillary barrier. Particulate Matter (PM2.5)—The Washington, D. C. ambient PM2.5 was obtained from the National Institutes of Standards and Technology (SRM 1649a) (13Wise S.A. Watters Jr., R.L. Certificate of Analysis Standard Reference Material 1649a Urban Dust. National Institute of Standards and Technology, Gaithersburg, Maryland2007Google Scholar). The characteristics of the PM2.5 have been described previously (14Huggins F.E. Huffman G.P. Robertson J.D. J. Hazardous Mater.. 2000; 74: 1-23Google Scholar). Antibodies and Reagents—The following antibodies were purchased from Cell Signaling (Boston, MA); the catalog numbers are in parenthesis: and and and and JNK. was purchased from SOD1 was purchased from and was purchased from The against the Rieske iron-sulfur and of the cell were obtained from was purchased from SP600125 was purchased from and of cells were from as described previously G.M. C. A. H. K. S. Ghio Kamp D.W. Budinger G.R. Am. J. Respir. Cell and used cells were obtained from of the cells were in with and The cells were by cells in and for The of DNA encoding was by the described previously G.R. M. D.S. J. Scholar). and encoding with a mitochondrial was as described previously and B. E. Cell Scholar). encoding SOD1 and were of and were purchased from the of L. M.W. Scholar, Zhang Y. L. J. L. Med.. Scholar). The encoding a for the Rieske iron-sulfur was as described previously J. Budinger J. Cell 2007; and in The cells and the cells with the Rieske iron-sulfur were in encoding the with a mitochondrial was the to the The from the was the following and the was the and transfected cells, and the was used to The cells were by to in of cells was by to the of an oxidant-sensitive ratiometric (Ro-GFP) that was described by and J. 2004; Scholar, R. D. M. J. 2004; its to a of intracellular oxidants and in The for the with a mitochondrial was a and was in The was used to cells, and stably expressing were by to in The was an as described of the was by the cells of the to the mitochondria was by with the mitochondrial in the of the was the cells were from the and of the were to or 1 or 1 the of of of and was in a cell The of the cells was as the the by the in the with and B. E. Cell Scholar). and of Particulate for the of mice was by the Care and mice were with and with a to a that the the G.M. V. J. L. A. N. G. K. S. S. P. 2004; 94: Scholar, G.M. D. A. N. N. Kamp D.W. Ghio Budinger J. 2007; Scholar). We PM2.5 in of or of in Particulate matter was to the mice were in the and the for Infection in were the lungs of mice as described previously G.M. Y. M. L. V. J. C. R. G. P. 2005; Scholar). the mice were with or and with a was used to 1 of in and through the The was in which the were and to from with the of oxygen as required to was the the lungs and were and the lungs were to of with The and lungs were in and were with G.M. C. A. H. K. S. Ghio Kamp D.W. Budinger G.R. Am. J. Respir. Cell Scholar). of permeability was a of a described previously G.R. Mutlu G.M. J. M. K. U. S. 2006; Scholar). The mice were with and of was the a The mice were for which a was the for the of following the of was from the a of lung permeability was from the in the of the and the by a of Cell death was a that DNA an that in cell and a that was as described previously G.R. Mutlu G.M. J. M. K. U. S. 2006; Scholar). The cell were with the was a and to a the was with to The were with in for and with the The was with and for 1 with The was with and by was the of the of the of to the as G.R. M. D.S. J. Scholar). to the of to the of c-Jun were a to the catalog the with was to 1 were a of a described previously I. A. J. E. J. Scholar). cell were obtained exposure to and c-Jun was by of with of c-Jun The were with of and in The were with of protein, of μm for in 1 and The were by and the The were by and c-Jun was by of of of DNA in was the in cell death to of were and the and were an G.R. Mutlu G.M. J. M. K. U. S. 2006; Scholar). between were of the of a were with a for against of the were for The of ROS for PM2.5-induced Cell in previously reported that exposure of alveolar epithelial cells to PM10 from the generation of ROS G.M. C. A. H. K. S. Ghio Kamp D.W. Budinger G.R. Am. J. Respir. Cell Scholar). PM2.5-induced cell death is we alveolar cells and cells with an encoding exposure to PM2.5 from Washington, D. C. we the of the in cells that been with or with the and μm) for and the PM2.5 exposure L.J. M. Budinger G.R. J. 2004; Scholar). Treatment with prevented the PM2.5-induced of the in cells and alveolar Treatment with was used as a Cell death was in cells PM2.5 exposure. Treatment with prevented cell death in response to PM2.5 in and alveolar epithelial cells PM-induced Cell the of ROS by the in an oxidant-sensitive fluorescent we previously reported that the of PM10 to alveolar epithelial cells resulted in the generation of ROS from the PM2.5-induced mitochondrial oxidant we cells lacking mitochondrial DNA (ρ0 and cells were with an adenovirus encoding the and the of the was with PM2.5 or Treatment with PM2.5 resulted in of the in however, of the was in cells from site III of the mitochondrial electron transport chain can the mitochondrial is by or can the is by SOD1 Budinger G.R. Med.. 2007; Scholar). The is by or by of which are in in the mitochondria Budinger G.R. Med.. 2007; Scholar). The cells were with the of the and of a SOD1 or the cells were with PM2.5 and the of the was for with cells, the cells with the of the with PM2.5 with SOD1 increased of SOD1 in cell and of the in response to The cells with increased of in cell and an PM2.5-induced of the and were obtained cells were to PM2.5 and of the was the inhibition of oxidant generation by SOD1 or cell cells were with a or exposure to PM2.5 or PBS, and DNA was with cells with the was a increase in DNA in cells the adenovirus with increase in DNA was in cells with SOD1 with these cells with the or not the SOD1 a increase in and of with III of the for PM2.5-induced ROS of mitochondrial oxidant production in site or III of the mitochondrial electron transport chain Budinger G.R. Med.. 2007; Scholar). site III, the inadvertent transfer of a electron to molecular oxygen the or can a oxidant generation site of the mitochondrial electron transport chain was required for PM2.5-induced ROS we used a to a stable cell expressing cell was with a expressing a against the Rieske iron-sulfur or with a The Rieske iron-sulfur is required for the generation of the from the of this the transfer of electrons through the Budinger G.R. Med.. 2007; Scholar). The cells were by in and The cells of the Rieske iron-sulfur and required for as by These cells were with PM2.5 and the of the was with cells, the cells with a of the Rieske iron-sulfur of the in response to PM2.5 with these cell death was not from in cells lacking the Rieske iron-sulfur with PM2.5 The of SOD1 in the PM2.5-induced Cell and in ROS generation was required for PM2.5-induced cell death in we mice with a adenovirus or an adenovirus encoding the mice were with of or PM2.5 in the of with mice with the the levels of SOD1 were in lung obtained from mice with the SOD1 adenovirus The of in lung obtained with PM2.5 was in mice with a adenovirus in mice with SOD1 the increase in alveolar-capillary permeability in the with PM2.5 was not in mice with the SOD1 adenovirus of the lungs of and with PM2.5 a response that was not in mice with PM2.5-induced Cell the of ASK1 and sought to examine the molecular link between mitochondrial oxidant production and alveolar epithelial cell death. The has been to in response to oxidant and to activate cell death primarily through its to activate the JNK pathway. We cells with PM2.5 in the or of μm) or and cell an against Treatment with PM2.5 resulted in activation of ASK1 that was by with lacking mitochondrial DNA (ρ0 cells) to ASK1 in response to PM2.5 of cells with a dominant negative ASK1 the exposure prevented PM2.5-induced cell death the of ASK1 in PM2.5-induced cell we murine embryonic fibroblasts from and knock-out mice to PM2.5 and cell death not a increase in cell death in response to PM2.5 In of oxidant the activation of ASK1 has been to its by activating the JNK pathway. ASK1 was required for PM2.5-induced JNK we the phosphorylation of c-Jun by of or and a JNK kinase of JNK was in not exposure to PM2.5 examine the of JNK in PM2.5-induced cell we JNK phosphorylation in alveolar cells with with cells, JNK phosphorylation was increased as as with PM2.5 and was The phosphorylation of JNK in cells with PM2.5 was prevented by of the cells with μm) for and a exposure to PM2.5-induced activation of the JNK pathway was in cells a kinase that the phosphorylation of c-Jun by cell in the or of the JNK SP600125 (25 μm) cells with the or were with PM2.5 and the cell were for the activation of JNK a kinase with the cells, the cells with SOD1 activation of in response to cells with an response oxidant generation site III of the mitochondrial electron transport chain is required for the PM2.5-induced activation of JNK, we PM2.5-induced JNK activation in cells stably transfected with a encoding or a encoding an to the Rieske iron-sulfur with activation of JNK was in transfected not Rieske iron-sulfur transfected cells activation of JNK was required for PM2.5-induced cell we alveolar cells with the JNK SP600125 (25 μm) and with and cell death was The cells with SP600125 were against PM2.5-induced cell death was in cells not We have previously reported that exposure to PM the and of p53 and that the of p53 is required for apoptosis in and in In of oxidant phosphorylation of has been associated with the and of p53. We alveolar cells with SP600125 as described and the phosphorylation of p53 Treatment with SP600125 prevented the PM2.5-induced phosphorylation of p53 to airborne particulate matter air pollution is associated with in cardiopulmonary morbidity and mortality (1Dominici F. McDermott A. Zeger S.L. Samet J.M. Environ. Health Perspect.. 2003; 111: 39-44Google Scholar, 2Katsouyanni K. Touloumi G. Samoli E. Gryparis A. Le Tertre A. Monopolis Y. Rossi G. Zmirou D. Ballester F. Boumghar A. Anderson H.R. Wojtyniak B. Paldy A. Braunstein R. Pekkanen J. Schindler C. Schwartz J. Epidemiology.. 2001; 12: 521-531Google Scholar, 3Samet J.M. Dominici F. Curriero F.C. Coursac I. Zeger S.L. N. Engl. J. Med.. 2000; 343: 1742-1749Google Scholar, D.W. Pope III, C.A. Xu X. Spengler J.D. Ware J.H. Fay M.E. Ferris Jr., B.G. Speizer F.E. N. Engl. J. Med.. 1993; 329: 1753-1759Google Scholar, 5Pope III, C.A. Burnett R.T. Thurston G.D. Thun M.J. Calle E.E. Krewski D. Godleski J.J. Circulation.. 2004; 109: 71-77Google Scholar, 6Abbey D.E. Mills P.K. Petersen F.F. Beeson W.L. Environ. Health Perspect.. 1991; 94: 43-50Google Scholar, 7Miller K.A. Siscovick D.S. Sheppard L. Shepherd K. Sullivan J.H. Anderson G.L. Kaufman J.D. N. Engl. J. Med.. 2007; 356 (8): 447-458Google Scholar, 8McCreanor J. Cullinan P. Nieuwenhuijsen M.J. Stewart-Evans J. Malliarou E. Jarup L. Harrington R. Svartengren M. Han I.K. Ohman-Strickland P. Chung K.F. Zhang J. N. Engl. J. Med.. 2007; 357: 2348-2358Google Scholar, 9Downs S.H. Schindler C. Liu L.J. Keidel D. Bayer-Oglesby L. Brutsche M.H. Gerbase M.W. Keller R. Kunzli N. Leuenberger P. Probst-Hensch N.M. Tschopp J.M. Zellweger J.P. Rochat T. Schwartz J. Ackermann-Liebrich U. N. Engl. J. Med.. 2007; 357: 2338-2347Google Scholar, 10Mills N.L. Tornqvist H. Gonzalez M.C. Vink E. Robinson S.D. Soderberg S. Boon N.A. Donaldson K. Sandstrom T. Blomberg A. Newby D.E. N. Engl. J. Med.. 2007; 357: 1075-1082Google Scholar). an of has the production of ROS in response to the with is known the molecular mechanisms by which the oxidants and the link between these oxidants and intracellular signaling that of the Rieske iron-sulfur in lung epithelial cells prevents PM2.5-induced mitochondrial oxidant production that site III of the mitochondrial electron transport chain is a to PM2.5-induced oxidant production. that the site III is the mitochondrial and from to the to induce the activation of the oxidant-sensitive kinase The activation of ASK1 is required for the PM2.5-induced activation of JNK, which p53 to induce cell death. The of apoptosis in the injury by PM2.5 is by that overexpression of SOD1 in the lung PM2.5-induced apoptosis and prevents the PM2.5-induced increase in the permeability of the alveolar-capillary barrier. The mitochondrial electron transport chain is a in the mitochondrial that electrons and the through to molecular The in these is used to the required for the of The electron transport chain is sites or of which of sites of the electron transport chain as as of the are in the by the mitochondrial and transfer electrons from or to site III, which the of electrons from to molecular oxygen is by the The transfer of electrons to the requires the transfer of electrons from the Rieske iron-sulfur to the or a is the and is to transfer an electron to molecular oxygen a of ROS by the is in cells in which is or with We that cells lacking mitochondrial DNA (ρ0 cells) to ROS in response to suggesting that a functional electron transport chain was required for We a stable of the Rieske iron-sulfur to the of electrons the that these cells to ROS in response to PM2.5 that the is responsible for the of PM2.5-induced oxidant The is a of the the of the and to the of the the site is the the site is the mitochondrial between the can in the generation of and is by the The in the mitochondrial is SOD1 is primarily in the mitochondrial and the We that overexpression of not prevented the PM2.5-induced generation of These with we obtained cells and cells with a stable of the Rieske iron-sulfur protein, that PM2.5-induced mitochondrial oxidant production from the These of against the generation of of from or of the electron transport chain in response to in cells with a stable of the Rieske iron-sulfur protein, the electron site the ROS production. the these are primarily in the mitochondrial these sites to by Budinger G.R. Med.. 2007; Scholar). and N. M. 2003; 109: have the of PM2.5 obtained in and in The of a of or that is the of this and and in the are the N. A. R. C. J. A. J. 2000; Scholar, T. P. N. C. A. Environ. Health Perspect.. 2004; the of the and demonstrated that the in was to increase oxidant generation in an mitochondria In cells, N. C. A. D. C. J. M. T. J. Health Perspect.. 2003; 111: the of electron 1 these by the site of oxidant generation to site III of the mitochondrial electron transport chain in the The that we a of the mitochondrially following the of PM2.5 that the of the and to the mitochondria are responsible for oxidant We used an oxidant-sensitive to the generation of reactive oxygen species in response to R. D. M. J. 2004; reported that these to the generation of and with in the from and that the of the to directed to the or the is ratiometric and of the associated with oxidant-sensitive including and J. J. B. Scholar, Scholar). We that PM2.5 exposure is associated with an increase in the of this mitochondrially the ROS and the subsequent cell death was prevented by a the overexpression of and a of the Rieske iron-sulfur These that mitochondrial oxidant generation is required for PM2.5-induced cell death. not the that PM2.5 induces oxidant generation the the or in the studies or to required to these The of the apoptotic pathway in the development of cardiopulmonary morbidity to PM2.5 exposure is by that the overexpression of SOD1 prevented the development of apoptosis in the lung as and prevented the increase in the permeability of the alveolar-capillary the of PM2.5 primarily the of the and the K. K. M. J. L. M. A. J. Scholar). cells the lung are to and the is from the is to conclude that the we resulted from the overexpression of SOD1 in the alveolar In of oxidant the ASK1 has been to as a linking intracellular oxidant generation with the apoptotic pathway H. H. H. J.M. Cell 2000; Scholar). In the ASK1 is in the to M. H. M. K. K. Y. M. K. H. Scholar). can in its from of ASK1 through and or K. M. H. J. Cell Scholar). ASK1 primarily through and to activate JNK or through and to activate of these by ASK1 is and is responsible for apoptosis K. A. T. H. K. K. K. T. H. 2001; Scholar, T. A. S. Y. T. K. K. S. H. K. J. 2000; Scholar, H. E. K. P. M. T. M. K. K. Y. Science.. Scholar). We that exposure to PM2.5 the activation of ASK1 and that the inhibition of mitochondrial oxidant generation with or by the generation of cells prevented the activation of inhibition of ASK1 prevented PM2.5-induced cell its in the pathway. The JNK pathway is by a of including oxidant DNA and H. Scholar, J.M. J. 2001; Scholar, J. Cell Scholar, 2000; Scholar). One of the mechanisms by which JNK has been to induce apoptosis is through activation of the p53 by phosphorylation X. Scholar). We have previously reported that PM2.5-induced apoptosis in the alveolar requires activation of p53 and is associated with its we the of JNK in the PM2.5-induced of We that PM2.5 resulted in the activation of JNK and that inhibition of the JNK pathway prevented the phosphorylation of p53 and the subsequent cell death. of p53 as in the has been to the activation of p53 in of oxidant X. C.A. 2003; Scholar, J.D. Y. K. E. Scholar). In we that mitochondrial oxidant production is required for PM2.5-induced apoptosis in alveolar epithelial The of the ROS generation from the in the electron transport chain, from the oxidants are required for the PM2.5-induced activation of ASK1 and cell death. The activation of ASK1 induces apoptosis by activating the JNK which activate the intrinsic apoptotic pathway by p53. The of oxidant production in the in response to PM2.5 is by the that overexpression of SOD1 in the alveolar the PM2.5-induced impairment in the function of the alveolar-capillary barrier. The dominant negative ASK1 was a of of encoding SOD1 and were of of
Soberanes et al. (Wed,) studied this question.