Use of consomic rats for genomic insights into ventilator-associated lung injury

Nonas, Stephanie; Vinasco, Liliana Moreno; Fan, Shwu; Jacobson, Jeffrey R.; Desai, Ankit A.; Dudek, Steven M.; Flores, Carlos; Hassoun, Paul M.; Sam, Lee; Ye, Shui Q.; Moitra, Jaideep; Barnard, Joe; Grigoryev, Dmitry N.; Lussier, Yves A.; Garcia, Joe G.N.

doi:10.1152/ajplung.00481.2006

Cited by 41 publications

(41 citation statements)

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“…Evan's blue dye (EBD) deposition and BAL protein in lung tissue were used as markers of vascular permeability, as previously described (5,25). The tissue deposition of EBD was measured and normalized to serum EBD for each animal.…”

Section: Histology and Immunohistochemical Stainingmentioning

confidence: 99%

“…We have identified cyclooxygenase-2 (COX-2) as an important candidate gene in ventilator-induced lung injury (5,6). In contrast to COX-1, which is constitutively expressed and involved in housekeeping functions, COX-2 is an inducible enzyme that catalyzes the conversion of arachidonic acid to downstream prostanoids involved in inflammation and vascular homeostasis.…”

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confidence: 99%

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The Role of Cyclooxygenase-2 in Mechanical Ventilation–Induced Lung Injury

Robertson

Sauer

Gold

et al. 2012

Am J Respir Cell Mol Biol

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Mechanical ventilation is necessary for patients with acute respiratory failure, but can cause or propagate lung injury. We previously identified cyclooxygenase-2 as a candidate gene in mechanical ventilationinduced lung injury. Our objective was to determine the role of cyclooxygenase-2 in mechanical ventilation-induced lung injury and the effects of cyclooxygenase-2 inhibition on lung inflammation and barrier disruption. Mice were mechanically ventilated at low and high tidal volumes, in the presence or absence of pharmacologic cyclooxygenase-2-specific inhibition with 3-(4-methylsulphonylphenyl)-4-phenyl-5-trifluoromethylisoxazole (CAY10404). Lung injury was assessed using markers of alveolar-capillary leakage and lung inflammation. Cyclooxygenase-2 expression and activity were measured by Western blotting, real-time PCR, and lung/plasma prostanoid analysis, and tissue sections were analyzed for cyclooxygenase-2 staining by immunohistochemistry. High tidal volume ventilation induced lung injury, significantly increasing both lung leakage and lung inflammation relative to control and low tidal volume ventilation. High tidal volume mechanical ventilation significantly induced cyclooxygenase-2 expression and activity, both in the lungs and systemically, compared with control mice and low tidal volume mice. The immunohistochemical analysis of lung sections localized cyclooxygenase-2 expression to monocytes and macrophages in the alveoli. The pharmacologic inhibition of cyclooxygenase-2 with CAY10404 significantly decreased cyclooxygenase activity and attenuated lung injury in mice ventilated at high tidal volume, attenuating barrier disruption, tissue inflammation, and inflammatory cell signaling. 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. Keywords: cyclooxygenase-2; mechanical ventilation; lung injuryMechanical ventilation is a life-saving therapy for patients with acute respiratory failure. However, it can cause or worsen lung injury, particularly at larger tidal volumes (1, 2). Positive-pressure mechanical ventilation may expose the lungs, and particularly the alveoli, to overdistention, resulting in volutrauma with the subsequent release of inflammatory and vasoactive cytokines and prostanoids that propagate lung injury (1, 3). Therapeutic trials aimed at decreasing lung injury have focused on minimizing the damage from mechanical ventilation with the use of "protective" low tidal volume ventilator strategies. However, because of the heterogeneity of lung injury, even at lower tidal volumes, different regions of the lung may be subjected to higher stretch (4). Although using lower tidal volumes decreases markers of injury and inflammation and significantly improves survival in patients with acute lung injury, mortality remains high (1). A better understanding of the mechanisms by which mechanical ventilation injures the lungs will be key in identifying ...

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Section: Histology and Immunohistochemical Stainingmentioning

confidence: 99%

mentioning

confidence: 99%

The Role of Cyclooxygenase-2 in Mechanical Ventilation–Induced Lung Injury

Robertson

Sauer

Gold

et al. 2012

Am J Respir Cell Mol Biol

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“…Ventilated mice were monitored for blood pressure and arterial blood gas to ensure adequate perfusion. Bronchoalveolar lavage (BAL) fluid was collected and indices of lung vascular leak were assessed as previously described (14). All animal experiments were approved by the Animal Care and Use Committees of the University of Illinois at Chicago, Chicago, IL.…”

Section: Preclinical Model Of Vilimentioning

confidence: 99%

“…Expression profiling was performed using Affymetrix Mouse 430 2.0 arrays and protocols (Affymetrix, Santa Clara, CA) as described previously (14). Chips were scanned using a GeneChip Scanner 3000 (Affymetrix).…”

Section: Treatment Of Gadd45amentioning

confidence: 99%

Role of Growth Arrest and DNA Damage–inducible α in Akt Phosphorylation and Ubiquitination after Mechanical Stress-induced Vascular Injury

Mitra

Sammani

Wang

et al. 2011

Am J Respir Crit Care Med

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Rationale: The stress-induced growth arrest and DNA damageinducible a (GADD45a) gene is up-regulated by mechanical stress with GADD45a knockout (GADD45a 2/2 ) mice demonstrating both increased susceptibility to ventilator-induced lung injury (VILI) and reduced levels of the cell survival and vascular permeability signaling effector (Akt). However, the functional role of GADD45a in the pathogenesis of VILI is unknown. Objectives: We sought to define the role of GADD45a in the regulation of Akt activation induced by mechanical stress. Methods: VILI-challenged GADD45a 2/2 mice were administered a constitutively active Akt1 vector and injury was assessed by bronchoalveolar lavage cell counts and protein levels. Human pulmonary artery endothelial cells (EC) were exposed to 18% cyclic stretch (CS) under conditions of GADD45a silencing and used for immunoprecipitation, Western blotting or immunofluoresence. EC were also transfected with mutant ubiquitin vectors to characterize site-specific Akt ubiquitination. DNA methylation was measured using methylspecific polymerase chain reaction assay. Measurements and Main Results: Studies exploring the linkage of GADD45a with mechanical stress and Akt regulation revealed VILIchallenged GADD45a 2/2 mice to have significantly reduced lung injury on overexpression of Akt1 transgene. Increased mechanical stress with 18% CS in EC induced Akt phosphorylation via E3 ligase tumor necrosis factor receptor-associated factor 6 (TRAF6)-mediated Akt K63 ubiquitination resulting in Akt trafficking and activation at the membrane. GADD45a is essential to this process because GADD45a-silenced endothelial cells and GADD45a 2/2 mice exhibited increased Akt K48 ubiquitination leading to proteasomal degradation. These events involve loss of ubiquitin carboxyl terminal hydrolase 1 (UCHL1), a deubiquitinating enzyme that normally removes K48 polyubiquitin chains bound to Akt thus promoting Akt K63 ubiquitination. Loss of GADD45a significantly reduces UCHL1 expression via UCHL1 promoter methylation resulting in increased Akt K48 ubiquitination and reduced Akt levels. Conclusions: These studies highlight a novel role for GADD45a in the regulation of site-specific Akt ubiquitination and activation and implicate a significant functional role for GADD45a in the clinical predisposition to VILI.Keywords: GADD45a; AKT; UCHL1; ubiquitin; mechanical stress Acute lung injury (ALI) is a devastating disorder commonly encountered in the intensive care unit, with approximately 75,000 deaths annually in the United States (1). Although insults, such as infection and trauma, often precipitate in ALI, ALI morbidity and mortality are heavily influenced by excessive mechanical stress produced by mechanical ventilation. Mechanical ventilator support is required to provide adequate gas exchange but potentially generates excessive mechanical stress, a condition known as ventilator-induced lung injury (VILI) (2). Multiple lines of evidence, including marked ethnic and racial disparities in ALI mortality, support the contribu...

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“…84 For example, introgressions of VALI-sensitive BN chromosomes 13 and 16 into the VALIresistant SS resulted in significantly increased inflammation (compared with parental SS strain), which suggests that genes residing on BN chromosomes 13 and 16 confer increased sensitivity to high tidal volume ventilation. Interestingly, previous animal studies have identified several VALI/ALI candidate genes (IL-6, PAI1, CCL2, COX2) that map to these chromosomes, which increases their potential role in the VALI phenotype.…”

Section: Novel Animal Models: Consomic and Congenic Rodentsmentioning

confidence: 99%

Integrating genomic and clinical medicine: Searching for susceptibility genes in complex lung diseases

Desai

Hysi

Garcia

2008

Translational Research

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The integration of molecular, genomic, and clinical medicine in the post-genome era provides the promise of novel information on genetic variation and pathophysiologic cascades. The current challenge is to translate these discoveries rapidly into viable biomarkers that identify susceptible populations and into the development of precisely targeted therapies. In this article, we describe the application of comparative genomics, microarray platforms, genetic epidemiology, statistical genetics, and bioinformatic approaches within examples of complex pulmonary pathobiology. Our search for candidate genes, which are gene variations that drive susceptibility to and severity of enigmatic acute and chronic lung disorders, provides a logical framework to understand better the evolution of genomic medicine. The dissection of the genetic basis of complex diseases and the development of highly individualized therapies remain lofty but achievable goals.Increased morbidity and mortality from acute and chronic pulmonary disorders represent sources of enormous health-care expenditures 1 -6 and mandate better understanding of lung pathobiology. The unraveling of the genetic basis of complex pulmonary diseases such as asthma, emphysema, acute lung inury (ALI), and pulmonary hypertension (PH) provides an opportunity to improve the delivery of targeted therapies that reduce the suffering of patients with these disorders. The challenge, however, historically has been daunting as traditional methods of genetic research, with limited technologies, could only consider the study of individual genes. The complexity of genomic structure and function, disease heterogeneity, the influence of the environment on disease development and progression, and epigenetic mechanisms also contribute to the challenge of mastering the genetic underpinnings of complex lung diseases. Fortunately, in the era after the completion of the Human Genome Project, the availability of multiple high-throughput genomic and genetic technologies now allows elucidation of complex pathophysiology cascades produced by the carefully orchestrated spatial and temporal regulation of tens to hundreds of genes and proteins. In this article, we provide examples of the application of these emerging genomic tools as we integrate genomic knowledge with clinical medicine. We discuss the use of several novel and potentially useful approaches: whole genome linkage analysis scans, conventional candidate gene and single nucleotide polymorphism (SNP)-based approaches, and preclinical animal models of human disease. Ultimately, the promise of the post-genome era is that the increased application of genomic technologies and innovative bioinformatics will translate clinical-based discovery into the personalized medicine experience with the development and identification of novel biomarkers, diagnostic strategies, prognostic indicators, and targets for therapeutic intervention.

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Use of consomic rats for genomic insights into ventilator-associated lung injury

Cited by 41 publications

References 53 publications

The Role of Cyclooxygenase-2 in Mechanical Ventilation–Induced Lung Injury

The Role of Cyclooxygenase-2 in Mechanical Ventilation–Induced Lung Injury

Role of Growth Arrest and DNA Damage–inducible α in Akt Phosphorylation and Ubiquitination after Mechanical Stress-induced Vascular Injury

Integrating genomic and clinical medicine: Searching for susceptibility genes in complex lung diseases

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