The Role of Cyclooxygenase 2 in Mechanical Stress-Induced Lung Injury
Principal Investigator: Stephanie A Nonas
Abstract: The goal of this KOS application is provide the essential skills and experience that will allow the Principal Investigator to become a successful, independent physician-scientist. This proposal seeks to define a role for cyclooxygenase 2 (C0X2) in the pathophysiology and treatment of acute lung injury (ALI). ALI is a devastating clinical syndrome that affects more than 200,000 patients per year, with a mortality of 30-50%. Although a mainstay of therapy for ALI, mechanical ventilation, especially with high tidal volumes, can worsen existing injury or even cause de novo lung injury, a phenomenon referred to as ventilator induced lung inury (VILI). C0X2 is an inducible enzyme known to be involved in acute inflammation and increased vascular permeability. However, little is known about the expression of C0X2 in response to mechanical stress and its involvement in mechanical stress-induced lung injury. Preliminary data generated by the Principal Investigator have identified C0X2 as a candidate gene in VILI, demonstrating increased expression of C0X2 associated with increased lung inflammation and vascular barrier disruption in response to high tidal volume mechanical ventilation. Additionally, pharmacologic inhibition of C0X2 is protective, decreasing acute inflammation and enhanced permeability. We hypothesize that C0X2 expression is induced in response to high tidal volume mechanical ventilation and plays an important role in the acute inflammation and endothelial barrier disruption that accompanies VILI. We additionally hypothesize that the administration of selective C0X2 inhibitors may attenuate or prevent VILI. The Principal Investigator proposes to explore the precise mechanisms of action of C0X2 in mechanical stress-induced lung injury, using both in vivo and in vitro models. In SA #1, we will characterize the role of C0X2 in a well established, murine model of VILI correlating C0X2 expression and prostanoid production with biochemical and histologic indices of injury and exploring the regulation of 00X2 in response to mechanical stress. SA #2 will focus on cyclic stretch, a unique in vitro model of mechanical stress-induced lung injury. Using measures of endothelial resistance, immunohistochemistry, protein biochemistry, sIRNA, real time/RT-POR, and Western blotting, we will define the role of 00X2 in cyclic stress-induced cytoskeletal reorganization. In SA #3, define the efficacy of local and systemic 00X2 inhibition in VILI, using pharmacologic inhibition and gene silencing techniques. RELEVANCE (See instructions); Acute lung injury (ALI) is a devastating syndrome that kills more than 74,000 patients each year in the US and has very few therapeutic options. Mechanical ventilation is required for patients with ALI, however can itself cause or worsen lung injury. Research into the effect of mechanical stress on lung from ventilation are necessary to better understand this syndrome and to develop new treatments.
Funding Period: 2009-07-15 - 2014-06-30
more information: NIH RePORT
- The role of cyclooxygenase-2 in mechanical ventilation-induced lung injuryJoshua A Robertson
Division of Pulmonary and Critical Care, Oregon Health and Science University, Portland, OR 97239, USA
Am J Respir Cell Mol Biol 47:387-94. 2012..This study demonstrates the induction of cyclooxygenase-2 by mechanical ventilation, and suggests that the therapeutic inhibition of cyclooxygenase-2 may attenuate ventilator-induced acute lung injury...
- MAP Kinase Signaling in Apoptosis-Induced Ventilator-Associated Lung InjuryMahendra Damarla; Fiscal Year: 2013..We have identified a pathway and a potential mechanism that is relevant in mediating injury due to mechanical ventilation. We hope that further insight will help identify novel therapeutic targets...
- Cell Adhesion Mechanisms in Vascular Disease &ThrombosisMARK HOWARD GINSBERG; Fiscal Year: 2013..abstract_text> ..
- Vascular Subphenotypes of Lung DiseaseMark T Gladwin; Fiscal Year: 2013..vascular disease Project 3: Pulmonary vascular-targeted NO therapeutic strategies Core A: Administrative core Core B: Pre-Clinical Models of PAH Core C: Translational Vascular Phenomics, Genomics and Epidemiology Core ..
- Hypoxia Inducible Factor in Acute Lung InjuryHolger K Eltzschig; Fiscal Year: 2013..PHS 398/2590 (Rev. 09/04, Reissued 4/2006) Page Continuation Format Page ..
- Role of cGMP in Ventilator-Induced Lung Endothelial Barrier DysfunctionDavid B Pearse; Fiscal Year: 2013..The cells lining the blood vessels of the lung respond to mechanical distension in complex ways that could be modified by medications if the cellular effects are unraveled. ..
- Targeting Membrane Repair in Deformation-Induced Lung InjuryXiaoli Zhao; Fiscal Year: 2013..In addition, our results will push the efforts for advancing a safe and potent therapy for VALI that involves in large-scale production of a protein naturally exists in the human body. ..
- Extracellular Adenosine During Ventilator Induced Lung InjuryHolger K Eltzschig; Fiscal Year: 2013..PUBLIC HEALTH RELEVANCE: These studies will lay the groundwork for novel and specific therapeutic approaches in the treatment of acute lung injury. ..
- The Role of Xanthine Oxidoreductase in Ventilator-Associated Lung InjuryPaul M Hassoun; Fiscal Year: 2013....
- Immune-Based Interventions Against Infectious DiseasesAlan L Rothman; Fiscal Year: 2013..3. Recruit promising junior investigators and provide mentoring by established NIH-funded researchers. 4. Support a multidisciplinary research program led by junior investigators in translational infectious diseases immunology. ..
- Endothelial Injury and Repair: CardioPulmonary Vascular Biology COBRESHARON IRENE SMITH ROUNDS; Fiscal Year: 2013..abstract_text> ..
- Improved ventilation of the edematous lungCarrie E Perlman; Fiscal Year: 2013..Using these methods, we will assess the ability of surface tension manipulations and custom-designed ventilation waveforms to protect the edematous lung from VILI. ..
- Pathophysiology of Alveolar Epithelial Lung InjuryJacob I Sznajder; Fiscal Year: 2013..The insights gained from the data generated from these studies will provide novel molecular targets for the development of new therapeutic strategies to treat patients with lung injury. ..
- Digitalis-Induced Signaling by Cardiac Na+/K+-ATPaseAmir Askari; Fiscal Year: 2013..abstract_text> ..
- Improving Cardiac Function After Myocardial InfarctionSteven R Houser; Fiscal Year: 2013..A gene vector core will generate AAV6 vectors with novel therapeutics for testing in the pig Ml model. An administrative core will ensure data sharing and effective use of all resources. ..
- INTEGRATED MECHANISMS OF CARDIAC MALADAPTATIONR John Solaro; Fiscal Year: 2013..Studies proposed here offer the potential for novel diagnostic procedures early in the progression of the disorders, and targets for novel therapies. (End of Abstract) ..
- Acute Renal Failure Mediated Lung InjurySarah Faubel; Fiscal Year: 2013..The experiments in this grant will provide useful leads into the development of interventions to affect the systemic consequences of AKI and improve the mortality of patients with AKI. ..
- RAGE and Mechanisms of Vascular DysfunctionShi Fang Yan; Fiscal Year: 2013..Using novel and state-of-the-art techniques, floxed mice and molecular approaches to gene regulation, we are well-positioned to lead the study of RAGE in the next cycle of this Program. ..