Peroxisome Proliferator‐Activated Receptor‐g Agonist Treatment Increases Septation and Angiogenesis and Decreases Airway Hyperresponsiveness in a Model of Experimental Neonatal Chronic Lung Disease

Chronic lung disease (CLD) affects premature newborns requiring supplemental oxygen and results in impaired lung development and subsequent airway hyperreactivity. We hypothesized that the maintenance of peroxisome proliferator‐activated receptor gamma (PPARγ) signaling is important for normal lung...

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Published in:	Anatomical record (Hoboken, N.J. : 2007) Vol. 292; no. 7; pp. 1045 - 1061
Main Authors:	Takeda, K., Okamoto, M., de Langhe, S., Dill, E., Armstrong, M., Reisdorf, N., Irwin, D., Koster, M., Wilder, J., Stenmark, K.R., West, J., Klemm, D., Gelfand, E.W., Nozik‐Grayck, E., Majka, S.M.
Format:	Journal Article
Language:	English
Published:	Hoboken Wiley Subscription Services, Inc., A Wiley Company 01-07-2009
Subjects:	airway hyperresonsiveness (AHR) Animals Animals, Newborn Bronchoconstriction - drug effects Bronchoconstriction - physiology Cell Differentiation - drug effects Cell Differentiation - physiology chronic lung disease (CLD) Disease Models, Animal Fibroblasts - drug effects Fibroblasts - metabolism Humans Hyperoxia - physiopathology Infant, Newborn Infant, Newborn, Diseases - drug therapy Infant, Newborn, Diseases - metabolism Infant, Newborn, Diseases - physiopathology Lung - drug effects Lung - growth & development Lung - physiopathology Lung Diseases - drug therapy Lung Diseases - physiopathology lung simplification Mice Mice, Inbred C57BL Muscle, Smooth - drug effects Muscle, Smooth - growth & development Muscle, Smooth - metabolism Neovascularization, Physiologic - drug effects Neovascularization, Physiologic - physiology PPAR gamma PPAR gamma - agonists PPAR gamma - metabolism Respiratory System - drug effects Respiratory System - growth & development Respiratory System - physiopathology rosiglitazone Thiazolidinediones - pharmacology Thiazolidinediones - therapeutic use Treatment Outcome Vasodilator Agents - pharmacology Vasodilator Agents - therapeutic use
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Summary:	Chronic lung disease (CLD) affects premature newborns requiring supplemental oxygen and results in impaired lung development and subsequent airway hyperreactivity. We hypothesized that the maintenance of peroxisome proliferator‐activated receptor gamma (PPARγ) signaling is important for normal lung morphogenesis and treatment with PPARγ agonists could protect against CLD and airway hyperreactivity (AHR) following chronic hyperoxic exposure. This was tested in an established hyperoxic murine model of experimental CLD. Newborn mice and mothers were exposed to room air (RA) or moderate hyperoxia (70% oxygen) for 10 days and fed a standard diet or chow impregnated with the PPARγ agonist rosiglitazone (ROSI) for the duration of study. Following hyperoxic exposure (HE) animals were returned to RA until postnatal day (P) 13 or P41. The accumulation of ROSI in neonatal and adult tissue was confirmed by mass spectrometry. Analyses of body weight and lung histology were performed on P13 and P41 to localize and quantitate PPARγ expression, determine alveolar and microvessel density, proliferation and alpha‐smooth muscle actin (α‐SMA) levels as a measure of myofibroblast differentiation. Microarray analyses were conducted on P13 to examine transcriptional changes in whole lung. Pulmonary function and airway responsiveness were analyzed at P55. ROSI treatment during HE preserved septation and vascular density. Key array results revealed ontogeny groups differentially affected by hyperoxia including cell cycle, angiogenesis, matrix, and muscle differentiation/contraction. These results were further confirmed by histological evaluation of myofibroblast and collagen accumulation. Late AHR to methacholine was present in mice following HE and attenuated with ROSI treatment. These findings suggest that rosiglitazone maintains downstream PPARγ effects and may be beneficial in the prevention of severe CLD with AHR. Anat Rec, 2009. © 2009 Wiley‐Liss, Inc.
Bibliography:	Fax: (303) 724 3051 ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1932-8486 1932-8494
DOI:	10.1002/ar.20921