Acute lung injury, such as that seen with adult and pediatric respiratory distress syndromes, is characterized by endothelial injury, and pulmonary edema. High concentrations of oxygen (hyperoxia; 100% O2) are commonly administered to patients in these clinical scenarios. Although such concentrations of O2 are considered therapeutic since they increase alveolar and arterial oxygen tension and augment tissue O2 delivery, they also contribute to the generation of acute lung injury and the perpetuation and/or worsening of respiratory distress syndromes. Surprisingly, little is known about the mechanisms by which hyperoxia injures blood vessels and induces pulmonary edema. We undertook studies designed to determine if VEGF, Angiopoietin 1 or Angiopoietin 2 are regulated by hyperoxia-induced acute lung injury. Our studies demonstrated a marked induction of Angiopoietin 2, a modest induction of VEGF, and a marked decrease in Angiopoietin 1 during the course of this insult. These changes were reversed when the mice were allowed to recover from hyperoxia-induced acute lung injury. We also demonstrated that transgenic VEGF induces pulmonary edema when overexpressed in a lung-specific fashion and that hyperoxiainduced acute lung injury is ameliorated in Angiopoietin 2 null mutant animals. As a result of these findings, we have generated the following hypotheses: 1. Endothelial injury and permeability changes in the setting of hyperoxia-induced acute lung injury are mediated via alterations in VEGF, Angiopoietin 1, and Angiopoietin 2. 2. The permeability alterations seen in respiratory distress syndromes are mediated, in part, by the increase in VEGF, increase in Angiopoietin 2, and decrease in Angiopoietin 1 that is seen in this setting.
Specific Aims : Characterize the alterations in VEGF, Angiopoietin 1 and Angiopoiefin 2 in a model of hyperoxia-induced acute lung injury in adult mice. Define the contributions that VEGF, Angiopoietin 1, and Angiopoiefin 2 make to the pathogenesis ofhyperoxiainduced acute lung injury in adult mice. Determine the differences and the degree to which the response to hyperoxia-induced acute lung injury differs in adult, newborn and fetal mice with regard to VEGF, Angiopoietin 1 and Angiopoietin 2.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08HL074195-05
Application #
7248679
Study Section
Special Emphasis Panel (ZHL1-CSR-M (M1))
Program Officer
Colombini-Hatch, Sandra
Project Start
2003-07-24
Project End
2008-12-30
Budget Start
2007-07-01
Budget End
2008-12-30
Support Year
5
Fiscal Year
2007
Total Cost
$133,285
Indirect Cost
Name
Yale University
Department
Pediatrics
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
Choo-Wing, Rayman; Syed, Mansoor A; Harijith, Anantha et al. (2013) Hyperoxia and interferon-?-induced injury in developing lungs occur via cyclooxygenase-2 and the endoplasmic reticulum stress-dependent pathway. Am J Respir Cell Mol Biol 48:749-57
Sun, Huanxing; Choo-Wing, Rayman; Fan, Juan et al. (2013) Small molecular modulation of macrophage migration inhibitory factor in the hyperoxia-induced mouse model of bronchopulmonary dysplasia. Respir Res 14:27
Sun, Huanxing; Choo-Wing, Rayman; Sureshbabu, Angara et al. (2013) A critical regulatory role for macrophage migration inhibitory factor in hyperoxia-induced injury in the developing murine lung. PLoS One 8:e60560
Bhandari, Vineet; Choo-Wing, Rayman; Harijith, Anantha et al. (2012) Increased hyperoxia-induced lung injury in nitric oxide synthase 2 null mice is mediated via angiopoietin 2. Am J Respir Cell Mol Biol 46:668-76
Li, Zhang; Choo-Wing, Rayman; Sun, Huanxing et al. (2011) A potential role of the JNK pathway in hyperoxia-induced cell death, myofibroblast transdifferentiation and TGF-?1-mediated injury in the developing murine lung. BMC Cell Biol 12:54
Meller, Stephanie; Bhandari, Vineet (2011) VEGF levels in humans and animal models with RDS and BPD: temporal relationships. Exp Lung Res 38:192-203
Harijith, Anantha; Choo-Wing, Rayman; Cataltepe, Sule et al. (2011) A role for matrix metalloproteinase 9 in IFNýý-mediated injury in developing lungs: relevance to bronchopulmonary dysplasia. Am J Respir Cell Mol Biol 44:621-30
Bizzarro, Matthew J; Jiang, Yuan; Hussain, Naveed et al. (2011) The impact of environmental and genetic factors on neonatal late-onset sepsis. J Pediatr 158:234-8.e1
Aghai, Z H; Saslow, J G; Meniru, C et al. (2010) High-mobility group box-1 protein in tracheal aspirates from premature infants: relationship with bronchopulmonary dysplasia and steroid therapy. J Perinatol 30:610-5
Bhandari, Vineet (2010) Hyperoxia-derived lung damage in preterm infants. Semin Fetal Neonatal Med 15:223-9

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