We want to know how alveolar epithelial Type II cells respond to elevated oxygen (hyperoxia) typically used to treat patients suffering from respiratory distress. Type II cells produce pulmonary surfactant lipids and proteins that maintain alveolar homeostasis and immunity against respiratory pathogens. They are also transient amplifying progenitors for Type I cells that exchange oxidant gases between the lung and blood.

Since Type II cells are more resistant to hyperoxia than Type I cells, they presumably express pro-survival genes that enable them to act as precursor cells during alveolar repair. By understanding how Type II cells respond to hyperoxia, we hope to develop new therapies to mitigate oxygen-induced lung injury, as well as general insight into how cells respond to chronic oxidative stress and damage typically caused by the aging process, inflammation, and environmental pollutants.

Project 1. Developmental origins of oxidative lung disease.

Children who are exposed to elevated oxygen at birth are more likely to have viral infections, asthma, increased sensitivity to second hand cigarette smoke, and more out-of-school sick days than children who were not exposed to oxygen. Consistent with these epidemiologic findings, we found that adult mice exposed to hyperoxia as newborns have fewer Type II cells and exhibit increased susceptibility to influenza A virus infection. While investigating how hyperoxia disrupts alveolar epithelial development, we identified a novel subpopulation of alveolar Type II cells that selectively expresses genes that destroy RNA viruses and bacteria, and control asymmetric cell division of stem/progenitor cells. Our laboratory is testing the hypothesis that hyperoxia permanently disrupts alveolar lung development by stimulating the differentiation of alveolar epithelial Type II into Type I cells and this is associated with enhanced susceptibility to influenza virus due to loss of a virus-resistant subpopulation of Type II cells.

Project 2. Activation of pro-survival pathways during oxidant lung injury.

Reactive oxygen species (ROS) that are formed during aerobic respiration oxidize DNA, RNA, and proteins. Such damage can occur when lungs are exposed to elevated oxygen (hyperoxia) or by the chronic exposure to oxygen over a lifetime. In order to prevent abnormal lung development or remodeling, it is essential that oxidative damage be recognized and repaired or terminally injured cells be efficiently removed and replaced. Our studies have shown that hyperoxia sequentially activates hSMG-1, a phosphatidylinositol 3-kinase-like kinase involved in nonsense mediated mRNA decay, and the related kinase ATM, which recognizes DNA strand breaks. These kinases phosphorylate the tumor suppressor p53, an essential regulator of the cyclin-dependent kinase inhibitor p21. P21 in turn inhibits cell proliferation and protects against hyperoxia by maintaining expression of the anti-apoptotic proteins Bcl-XL and Mcl-1 that block Bax/Bak-dependent cell death. Our laboratory is studying how hSMG-1 and ATM activate the p53/p21 pathway and how p21 selectively maintains expression of Bcl-XL and Mcl-1.

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Recent publications

Lew BJ, Collins LL, O’Reilly MA, Lawrence BP. Activation of the aryl hydrocarbon receptor (AhR) during different critical windows in pregnancy alters mammary epithelial cell proliferation and differentiation. Toxicol Sci. 2009 Jun 5. [Epub ahead of print.]

Vitiello PF, Wu YC, Staversky RJ, O’Reilly MA. p21(Cip1) protects against oxidative stress by suppressing ER-dependent activation of mitochondrial death pathways. Free Radic Biol Med. 2009 Jan 1;46(1):33-41. [Epub 2008 Oct 7.]

Pryhuber GS, Huyck HL, Bhagwat S, O’Reilly MA, Finkelstein JN, Gigliotti F, Wright TW. Parenchymal Cell TNF Receptors Contribute to Inflammatory Cell Recruitment and Respiratory Failure in Pneumocystis carinii-Induced Pneumonia. J Immunol. 2008 Jul 15;181(2):1409-1419.

Gehen SC, Staversky RJ, Bambara RA, Keng PC, O’ Reilly MA. hSMG-1 and ATM sequentially and independently regulate the G(1) checkpoint during oxidative stress. Oncogene. 2008 Mar 10; [Epub ahead of print]

O’Reilly MA, Marr SH, Yee M, McGrath-Morrow SA, Lawrence BP. Neonatal Hyperoxia Enhances the Inflammatory Response in Adult Mice Infected With Influenza A Virus. Am J Respir Crit Care Med. 2008 Feb 21; [Epub ahead of print]

Yao H, Yang SR, Edirisinghe I, Rajendrasozhan S, Caito S, Adenuga D, O’Reilly MA, Rahman I. Disruption of p21 Attenuates Lung Inflammation Induced by Cigarette Smoke, LPS and fMLP in Mice. Am J Respir Cell Mol Biol. 2008 Jan 31; [Epub ahead of print]

Vitiello PF, Staversky RJ, Keng PC, O’Reilly MA. PUMA inactivation protects against oxidative stress through p21/Bcl-XL inhibition of bax death. Free Radic Biol Med. 2008 Feb 1;44(3):367-374. Epub 2007 Oct 10.

Gehen SC, Vitiello PF, Bambara RA, Keng PC, O’Reilly MA. 2007. Downregulation of PCNA potentiates p21-mediated growth inhibition in response to hyperoxia. Am J Physiol Lung Cell Mol Physiol. Mar;292(3):L716-724

Bijli KM, Minhajuddin M, Fazal F, O’Reilly MA, Platanias LC, Rahman A. 2007. c-Src interacts with and phosphorylates RelA/p65 to promote thrombin-induced ICAM-1 expression in endothelial cells. Am J Physiol Lung Cell Mol Physiol. Feb;292(2):L396-404

Staversky RJ, Vitiello PF, Gehen SC, Helt CE, Rahman A, Keng PC, O’Reilly MA. 2006 . p21(Cip1/Waf1/Sdi1) protects against hyperoxia by maintaining expression of Bcl-X(L). Free Radic Biol Med. Aug 15;41(4):601-609.

Yee M, Vitiello PF, Roper JM, Staversky RJ, Wright TW, McGrath-Morrow SA, Maniscalco WM, Finkelstein JN, O’Reilly MA. 2006. Type II epithelial cells are critical target for hyperoxia-mediated impairment of postnatal lung development. Am J Physiol Lung Cell Mol Physiol. Nov;291(5):L1101-1111

Vitiello PF, Staversky RJ, Gehen SC, Johnston CJ, Finkelstein JN, Wright TW, O’Reilly MA. 2006. p21Cip1 protection against hyperoxia requires Bcl-XL and is uncoupled from its ability to suppress growth. Am J Pathol. Jun;168(6):1838-1847.

Maniscalco WM, Watkins RH, Roper JM, Staversky R, O’Reilly MA. 2005. Hyperoxic Ventilated Premature Baboons Have Increased p53, Oxidant DNA Damage and Decreased VEGF Expression. Pediatr Res. Sep;58(3):549-556.

Pryhuber GS, Huyck HL, Roper JM, Cornejo J, O’Reilly MA, Pierce RH, Tsitsikov EN. 2005. Acute tumor necrosis factor-alpha-induced liver injury in the absence of tumor necrosis factor receptor-associated factor 1 gene expression. Am J Pathol. Jun;166(6):1637-1645.

Chess PR, O’Reilly MA, Sachs F, Finkelstein JN. 2005. Reactive oxidant and p42/44 MAP kinase signaling is necessary for mechanical strain-induced proliferation in pulmonary epithelial cells. J Appl Physiol. Sep;99(3):1226-

O’Reilly MA, Vitiello PF, Gehen SC, Staversky RJ. 2005. p21(Cip1/WAF1/Sdi1) does not affect expression of base excision DNA repair enzymes during chronic oxidative stress. Antioxid Redox Signal. May-Jun;7(5-6):719-725.

Roper JM, Gehen SC, Staversky RJ, Hollander MC, Fornace Jr AJ, and O’Reilly MA. 2005. Loss of Gadd45a does not modify the pulmonary response to oxidative stress. Am J Physiol Lung Cell Mol Physiol. Apr;288(4):L663-671.

O’Reilly MA. 2005. Redox Activation of p21(Cip1/WAF1/Sdi1): A Multifunctional Regulator of Cell Survival and Death. Antioxid Redox Signal. Jan-Feb;7(1-2):108-118.

Helt CE, Cliby WA, Keng PC, Bambara RA, and O’Reilly MA. 2005. Ataxia Telangiectasia Mutated (ATM) and ATM and Rad3-related Protein Exhibit Selective Target Specificities in Response to Different Forms of DNA Damage. J Biol Chem. Jan 14;280(2):1186-1192.

Mazzatti DJ, Lee YJ, Helt CE, O’Reilly MA, Keng PC. 2005. p53 modulates radiation sensitivity independent of p21 transcriptional activation. Am J Clin Oncol. Feb;28(1):43-50.