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Abnormal Vascular Phenotypes in Patients With Idiopathic Pulmonary Fibrosis and Secondary Pulmonary Hypertension* FREE TO VIEW

James Gagermeier, MD; James Dauber, MD, FCCP; Samuel Yousem, MD; Kevin Gibson, MD; Naftali Kaminski, MD
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*From the Simmons Center for Interstitial Lung Disease, University of Pittsburgh Medical Center, Pittsburgh, PA.

Correspondence to: James P. Gagermeier, MD, University of Pittsburgh, Department of PUD AI CCM, NW 628 Montefiore Hospital, Pittsburgh, PA 15213; e-mail: gagermeierjp@upmc.edu

Chest. 2005;128(6_suppl):601S. doi:10.1378/chest.128.6_suppl.601S
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Secondary pulmonary hypertension (PH), frequently seen in patients with idiopathic pulmonary fibrosis (IPF), is associated with increased morbidity and mortality. The nature of the changes in vascular phenotypes that occur in IPF is still under debate. We intend to identify the transcription networks that underlie the abnormal vascular phenotype in IPF patients with secondary PH.

The database of the Simmons Center for Interstitial Lung Disease was queried to evaluate for the presence of PH by echocardiography or right-heart catheterization in IPF patients. Microarray analysis was performed on 13 of these IPF samples. Briefly, total RNA was extracted from surgical remnants of video-assisted thoracoscopic lung biopsy specimens and from lung explants from patients with IPF undergoing lung transplantation. Labeled complementary RNA was hybridized to oligonucleotide microarrays. Data analysis was performed using Scoregene and GeneExpress analysis packages.

One hundred fifty-five patients with IPF were identified in the database. A substantial percentage of these patients (47 of 117 patients, 40.1%) had PH based on echocardiography (estimated right ventricular systolic pressure > 30 mm Hg). Interestingly, 20 of 117 patients (17.1%) had moderate-to-severe PH (estimated right ventricular systolic pressure > 45 mm Hg). We identified 88 probes on the Uniset arrays that represent 86 unique genes known to be associated with vascular endothelium. The majority (69.8%) of these genes were unchanged in IPF. Surprisingly, underexpressed genes (19.8%) included angiogenic factors such as vascular endothelial growth factor and platelet endothelial cell adhesion molecule, as well as factors affecting vessel tone such as angiotensin-converting enzyme and endothelin-1 (p value < 0.05). Overexpressed genes included phospholipase A2 (10.4%) and other factors that mediate remodeling.

We identified secondary PH in a significant percentage of our IPF patient population, including moderate and severe PH, previously believed to be unassociated with IPF. Gene expression patterns suggest an abnormal vascular phenotype in these IPF patients. Although the majority of endothelial-related genes are unchanged, we identified a subset of differentially expressed genes that reached statistical significance. The decrease in angiogenic factors as well as the increase in inflammatory and remodeling genes may reflect a fundamental alteration in the vascular cell phenotype in IPF that may contribute to the development of PH. We are currently verifying the spatial and temporal nature of these changes by obtaining gene expression profiles on laser microdissected specimens and through the use of immunohistochemical analysis.

Abbreviations: IPF = idiopathic pulmonary fibrosis; PH = pulmonary hypertension




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