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Relationship between gene expression and lung function in Idiopathic Interstitial Pneumonias.

ABSTRACT: BACKGROUND:Idiopathic interstitial pneumonias (IIPs) are a group of heterogeneous, somewhat unpredictable diseases characterized by progressive scarring of the interstitium. Since lung function is a key determinant of survival, we reasoned that the transcriptional profile in IIP lung tissue would be associated with measures of lung function, and could enhance prognostic approaches to IIPs. RESULTS:Using gene expression profiling of 167 lung tissue specimens with IIP diagnosis and 50 control lungs, we identified genes whose expression is associated with changes in lung function (% predicted FVC and % predicted DLCO) modeled as categorical (severe vs mild disease) or continuous variables while adjusting for smoking status and IIP subtype; false discovery rate (FDR) approach was used to correct for multiple comparisons. This analysis identified 58 transcripts that are associated with mild vs severe disease (categorical analysis), including those with established role in fibrosis (ADAMTS4, ADAMTS9, AGER, HIF-1?, SERPINA3, SERPINE2, and SELE) as well as novel IIP candidate genes such as rhotekin 2 (RTKN2) and peptidase inhibitor 15 (PI15). Protein-protein interactome analysis of 553 genes whose expression is significantly associated with lung function when modeled as continuous variables demonstrates that more severe presentation of IIPs is characterized by an increase in cell cycle progression and apoptosis, increased hypoxia, and dampened innate immune response. Our findings were validated in an independent cohort of 131 IIPs and 40 controls at the mRNA level and for one gene (RTKN2) at the protein level by immunohistochemistry in a subset of samples. CONCLUSIONS:We identified commonalities and differences in gene expression among different subtypes of IIPs. Disease progression, as characterized by lower measures of FVC and DLCO, results in marked changes in expression of novel and established genes and pathways involved in IIPs. These genes and pathways represent strong candidates for biomarker studies and potential therapeutic targets for IIP severity.

SUBMITTER: Steele MP

PROVIDER: S-EPMC4621862 | biostudies-literature | 2015 Oct

REPOSITORIES: biostudies-literature

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Relationship between gene expression and lung function in Idiopathic Interstitial Pneumonias.

Steele Mark P MP Luna Leah G LG Coldren Christopher D CD Murphy Elissa E Hennessy Corinne E CE Heinz David D Evans Christopher M CM Groshong Steve S Cool Carlyne C Cosgrove Gregory P GP Brown Kevin K KK Fingerlin Tasha E TE Schwarz Marvin I MI Schwartz David A DA Yang Ivana V IV

BMC genomics 20151026

<h4>Background</h4>Idiopathic interstitial pneumonias (IIPs) are a group of heterogeneous, somewhat unpredictable diseases characterized by progressive scarring of the interstitium. Since lung function is a key determinant of survival, we reasoned that the transcriptional profile in IIP lung tissue would be associated with measures of lung function, and could enhance prognostic approaches to IIPs.<h4>Results</h4>Using gene expression profiling of 167 lung tissue specimens with IIP diagnosis and ...[more]

PMID: 26503507

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Project description:Chronic fibrosing idiopathic interstitial pneumonia (IIP) is characterized by alveolar epithelial damage, activation of fibroblast proliferation, and loss of normal pulmonary architecture and function. This study aims to investigate the genetic backgrounds of IIP through gene expression profiling and pathway analysis, and to identify potential biomarkers that can aid in diagnosis and serve as novel therapeutic targets.RNA extracted from lung specimens of 12 patients with chronic fibrosing IIP was profiled using Illumina Human WG-6 v3 BeadChips, and Ingenuity Pathway Analysis was performed to identify altered functional and canonical signaling pathways. For validating the results from gene expression analysis, immunohistochemical staining of 10 patients with chronic fibrosing IIP was performed.Ninety-eight genes were upregulated in IIP patients relative to control subjects. Some of the upregulated genes, namely desmoglein 3 (DSG3), protocadherin gamma-A9 (PCDHGA9) and discoidin domain-containing receptor 1 (DDR1) are implicated in cell-cell interaction and/or adhesion; some, namely collagen type VII, alpha 1 (COL7A1), contactin-associated protein-like 3B (CNTNAP3B) and mucin-1 (MUC1) are encoding the extracellular matrix molecule or the molecules involved in cell-matrix interactions; and the others, namely CDC25C and growth factor independent protein 1B (GFI1B) are known to affect cell proliferation by affecting the progression of cell cycle or regulating transcription. According to pathway analysis, alternated pathways in IIP were related to cell death and survival and cellular growth and proliferation, which are more similar to cancer than to inflammatory response and immunological diseases. Using immunohistochemistry, we further validate that DSG3, the most highly upregulated gene, shows higher expression in chronic fibrosing IIP lung as compared to control lung.We identified several genes upregulated in chronic fibrosing IIP patients as compared to control, and found genes and pathways implicated in cancer, rather than in inflammatory or immunological disease to play important roles in the pathogenesis of IIPs. Moreover, DSG3 is a novel potential biomarker for chronic fibrosing IIP with its significantly high expression in IIP lung.

Project description:BACKGROUND AND OBJECTIVE:The idiopathic interstitial pneumonias (IIPs) are diffuse parenchymal lung disorders that are associated with substantial morbidity and mortality. Early diagnosis and disease stratification of IIP patients are important because these are related with the treatment and prognosis. Idiopathic pulmonary fibrosis (IPF) and nonspecific interstitial pneumonia (NSIP) are two major distinctive pathologic patterns of pulmonary fibrosis. We researched the application of the fluid-structure interaction (FSI) to the respiratory system and compared the pulmonary acinus mechanics and functions in healthy and IIP models. METHODS:The human pulmonary alveolus is idealized by a three-dimensional honeycomb-like geometry, and a fluid-structure interaction analysis is performed to study the normal and diseased breathing mechanics. The computational domain consists of two generations of alveolar ducts within the pulmonary acinus, with alveolar geometries approximated as closely packed 14-sided polygons. FINDINGS:In a normal breathing cycle, the flow rate of the healthy model is significantly larger than that of the NSIP and IPF models. Similar trends are observed for the volume change and the maximum pressure drop. The flow rate and the volume change of the NSIP are almost the same as those of IPF. The maximum pressure drop of NSIP is 5.5% larger than that of IPF. There is a 47% decrease in the pulmonary acinus compliance for the NSIP and IPF compared with that of the healthy model. The acinus resistances of NSIP and IPF are higher than those of the healthy lung by 6.4~11.2%. In particular, the pulmonary acinus resistance of the NSIP lung is higher than that of the IPF lung by 4.5%. CONCLUSIONS:Our study demonstrates the differences of air flow and lung function in the pulmonary acinus between the healthy and the IIP models. These changes in the lung are important considerations for early diagnosis and disease stratification in patients. Patient-based geometry can to be included in the computational models in future studies.

Project description:BackgroundPleuroparenchymal fibroelastosis (PPFE) is characterised by predominant upper lobe pleural and subpleural lung parenchymal fibrosis. Radiological PPFE-like lesion has been associated with various types of interstitial lung diseases. However, the prevalence and clinical significance of radiological PPFE-like lesion in patients with idiopathic interstitial pneumonias (IIPs) are not fully understood. We aimed to determine the prevalence and clinical impact on survival of radiological PPFE-like lesion in patients with IIPs.MethodsA post-hoc analysis was conducted using data from the Japanese nationwide cloud-based database of patients with IIPs. All the patients in the database were diagnosed as having IIPs by multidisciplinary discussion. Patients diagnosed with idiopathic PPFE were excluded. Clinical data and chest computed tomography (CT) image of 419 patients with IIPs were analysed. The presence of radiological PPFE-like lesion was independently evaluated by two chest radiologists blind to the clinical data.ResultsOf the 419 patients with IIPs, radiological PPFE-like lesions were detected in 101 (24.1%) patients, mainly in idiopathic pulmonary fibrosis (IPF) and unclassifiable IIPs, but less in idiopathic nonspecific interstitial pneumonia. Prognostic analyses revealed that radiological PPFE-like lesion was significantly associated with poor outcome in patients with IIPs, which was independent of age, IPF diagnosis and %FVC. In survival analyses, the patients with radiological PPFE-like lesions had poor survival compared with those without (log-rank, p < 0.0001). Subgroup analyses demonstrated that radiological PPFE-like lesion was significantly associated with poor survival both in patients with IPF and those with unclassifiable IIPs.ConclusionRadiological PPFE-like lesion is a condition that could exist in IIPs, mainly in IPF and unclassifiable IIPs. Importantly, the radiological PPFE-like lesion is a non-invasive marker to predict poor outcome in patients with IIPs, which should be carefully considered in clinical practice.

Dataset Information

Relationship between gene expression and lung function in Idiopathic Interstitial Pneumonias.

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Relationship between gene expression and lung function in Idiopathic Interstitial Pneumonias.

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