Gene Expression Profiles Distinguish Idiopathic Pulmonary Fibrosis from Hypersensitivity Pneumonitis

Selman, Moisés; Pardo, Annie; Barrera, Lourdes; Estrada, Andrea; Watson, Susan R.; Wilson, Keith E.; Aziz, Natasha; Kaminski, Naftali; Zlotnik, Albert

doi:10.1164/rccm.200504-644oc

Cited by 415 publications

(335 citation statements)

References 58 publications

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“…Although more research is needed, multiple lines of evidence suggest that UIP and NSIP do not always represent distinct forms of IIP. However, different subtypes of NSIP were identified on the basis of gene expression profiles (similar to IPF, similar to HP, or not similar to either) (29). Our study identified only a few differences between transcription profiles of whole lungs despite differences in cell types (i.e., the presence of lymphocytes in NSIP) and biological processes (formation of fibroblastic foci, and aberrant epithelial and vascular remodeling in UIP) present in the two disease subtypes.…”

Section: Discussionmentioning

confidence: 57%

“…These findings support the hypothesis that pulmonary fibrosis is a disease of constant matrix deposition and removal that is associated with modest chronic inflammation. In another study, the IPF gene expression signature was defined by the expression of tissue-remodeling, epithelial, and myofibroblast genes when compared with hypersensitivity pneumonitis (HP), in which genes associated with inflammation, T-cell activation, and immune responses predominated (29). On the basis of these signatures, the authors classified some NSIPs as more IPF-like and some as more HP-like but also identified a subset of NSIP cases that were not similar in expression to either HP or IPF.…”

Section: What This Study Adds To the Fieldmentioning

confidence: 99%

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Gene Expression Profiling of Familial and Sporadic Interstitial Pneumonia

Yang

Burch

Steele

et al. 2007

Am J Respir Crit Care Med

156

125

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Rationale: Idiopathic interstitial pneumonia (IIP) and its familial variants are progressive and largely untreatable disorders with poorly understood molecular mechanisms. Both the genetics and the histologic type of IIP play a role in the etiology and pathogenesis of interstitial lung disease, but transcriptional signatures of these subtypes are unknown. Objectives: To evaluate gene expression in the lung tissue of patients with usual interstitial pneumonia or nonspecific interstitial pneumonia that was either familial or nonfamilial in origin, and to compare it with gene expression in normal lung parenchyma. Methods: We profiled RNA from the lungs of 16 patients with sporadic IIP, 10 with familial IIP, and 9 normal control subjects on a whole human genome oligonucleotide microarray. Results: Significant transcriptional differences exist in familial and sporadic IIPs. The genes distinguishing the genetic subtypes belong to the same functional categories as transcripts that distinguish IIP from normal samples. Relevant categories include chemokines and growth factors and their receptors, complement components, genes associated with cell proliferation and death, and genes in the Wnt pathway. The role of the chemokine CXCL12 in disease pathogenesis was confirmed in the murine bleomycin model of lung injury, with C57BL/6 CXCR4؉/؊ mice demonstrating significantly less collagen deposition than C57BL/6 CXCR4؉/؉ mice. Whereas substantial differences exist between familial and sporadic IIPs, we identified only minor gene expression changes between usual interstitial pneumonia and nonspecific interstitial pneumonia. Conclusions: Taken together, our findings indicate that differences in gene expression profiles between familial and sporadic IIPs may provide clues to the etiology and pathogenesis of IIP.

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Section: Discussionmentioning

confidence: 57%

Section: What This Study Adds To the Fieldmentioning

confidence: 99%

Gene Expression Profiling of Familial and Sporadic Interstitial Pneumonia

Yang

Burch

Steele

et al. 2007

Am J Respir Crit Care Med

156

125

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“…In this regard, increased expression of two TCF/β-catenin-regulated genes (i.e., cyclin D1 and MMP-7) was observed in the airways of IPF patients (15,16). Lungs of IPF patients demonstrate increased expression of several Wnt family members (e.g., Wnt1-inducible signal pathway protein and secreted frizzled related protein 1), although accumulation of nuclear β-catenin, a hallmark of activated Wnt signaling, has been observed in both epithelial (AT2) and mesenchymal (myofibroblasts) cells in lungs of IPF patients (15,38,39). A dichotomous role of Wnt signaling in stem cells, organ development, maintenance, and repair is a commonly observed phenomenon (40), with Wnt signaling playing roles in the seemingly opposing processes of cell proliferation and differentiation.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Wnt/β-catenin/CREB binding protein (CBP) signaling reverses pulmonary fibrosis

Henderson

Emil

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

422

328

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Idiopathic pulmonary fibrosis (IPF)/usual interstitial pneumonia is a ravaging condition of progressive lung scarring and destruction. Anti-inflammatory therapies including corticosteroids have limited efficacy in this ultimately fatal disorder. An important unmet need is to identify new agents that interact with key molecular pathways involved in the pathogenesis of pulmonary fibrosis to prevent progression or reverse fibrosis in these patients. Because aberrant activation of the Wnt/β-catenin signaling cascade occurs in lungs of patients with IPF, we have targeted this pathway for intervention in pulmonary fibrosis using ICG-001, a small molecule that specifically inhibits T-cell factor/β-catenin transcription in a cyclic AMP response-element binding protein binding protein (CBP)-dependent fashion. ICG-001 selectively blocks the β-catenin/CBP interaction without interfering with the β-catenin/p300 interaction. We report here that ICG-001 (5 mg/kg per day) significantly inhibits β-catenin signaling and attenuates bleomycin-induced lung fibrosis in mice, while concurrently preserving the epithelium. Administration of ICG-001 concurrent with bleomycin prevents fibrosis, and late administration is able to reverse established fibrosis and significantly improve survival. Because no effective treatment for IPF exists, selective inhibition of Wnt/β-catenin-dependent transcription suggests a potential unique therapeutic approach for pulmonary fibrosis.

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“…(88) In other cases, NSIP can exhibit a gene profile indistinguishable from that of HP. (89) In NSIP, ground-glass opacity is common and, when accompanied by traction bronchiectasis or irregular reticulation, reflects the fibrotic form of disease (cellular NSIP is quite rare). At this juncture, given the inherent diversity of conditions known to produce the NSIP pattern on HRCT scans and histopathologically, a degree of caution is advisable when attempting to predict prognosis for a given patient.…”

Section: Acute Interstitial Pneumoniamentioning

confidence: 99%

Padrões tomográficos das doenças intersticiais pulmonares difusas com correlação clínica e patológica

et al. 2008

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High-resolution computed tomography (HRCT) is the radiological imaging technique best suited to revealing changes in lung structure. Various HRCT findings, taken together, can represent typical patterns. These patterns, in conjunction with the anatomical distribution of findings and with clinical data, can narrow the differential diagnosis of diffuse interstitial lung disease and, in many cases, indicate the correct diagnosis with a high degree of accuracy. The most common HRCT patterns seen in cases of diffuse interstitial lung diseases are the nodular pattern, linear/reticular opacities, cystic lesions, ground-glass opacities and consolidations. This article reviews the correlations between HRCT patterns and pathologic findings, summarizing the most common causes, as well as detailing the methods of investigation employed in order to diagnose the most common types of chronic diffuse lung disease.Keywords: Lung diseases, interstitial/pathology; Tomography, X-Ray computed; Diagnostic techniques, respiratory system. ResumoA tomografia de alta resolução (TCAR) é a técnica de imagem radiológica que reflete mais de perto as alterações da estrutura pulmonar. Os vários achados tomográficos podem ser combinados para formar padrões típicos. Estes, conjuntamente com a distribuição anatômica dos achados, e com os dados clínicos, podem estreitar o diagnóstico das doenças intersticiais pulmonares difusas, e em vários casos sugerir o diagnóstico correto com alto grau de acurácia. Os padrões mais comuns das doenças intersticiais pulmonares difusas na TCAR são o nodular, linear e reticular, lesões císticas, opacidades em vidro fosco e consolidações. Este artigo revisa as correlações entre os padrões tomográficos na TCAR e os achados patológicos e resume as causas mais comuns e os métodos de investigação para se atingir um diagnóstico nas doenças pulmonares crônicas difusas mais comuns.Descritores: Doenças pulmonares intersticiais/patologia; Tomografia computadorizada por raios X; Técnicas de diagnóstico do sistema respiratório.* Study carried out in the

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Gene Expression Profiles Distinguish Idiopathic Pulmonary Fibrosis from Hypersensitivity Pneumonitis

Abstract: Our results underscore the value of gene expression signatures to classify the interstitial lung diseases and to understand pathogenic mechanisms, and suggest new ways to improve the diagnosis and treatment of patients with these diseases.

Cited by 415 publications

References 58 publications

Gene Expression Profiling of Familial and Sporadic Interstitial Pneumonia

Gene Expression Profiling of Familial and Sporadic Interstitial Pneumonia

Inhibition of Wnt/β-catenin/CREB binding protein (CBP) signaling reverses pulmonary fibrosis

Padrões tomográficos das doenças intersticiais pulmonares difusas com correlação clínica e patológica

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