Relationship between gene expression and lung function in Idiopathic Interstitial Pneumonias

Abstract

BackgroundIdiopathic 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.ResultsUsing 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-1α, 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.ConclusionsWe 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s12864-015-2102-3) contains supplementary material, which is available to authorized users.

Transcriptional regulatory model of fibrosis progression in the human lung

“…The first was that we assessed whether findings of our model were consistent with what was previously known. This was done at the level of the genes and showed our results were highly consistent with previous transcriptomic analyses of IPF lungs (22,49,50), including a recent paper that applied gene expression module networks to identify coexpression pathways in IPF (23). A second layer of validation was whether our model would identify pathways and regulators consistent with what is known in the literature -2 examples are the WNT pathway and the presence of mitochondrial dysfunction.…”

Localized hypoxia links ER stress to lung fibrosis through induction of C/EBP homologous protein

“…Although the molecular mechanisms underlying CHOP-induced apoptosis may be context dependent, our studies showed that CHOP upregulates expression of numerous apoptosis-related genes in AECs following exposure to hypoxia, including GADD45A, ATF5, and BNIP3L, which we verified in lungs of CHOP -/mice after recurrent bleomycin injury. GADD45A can regulate cell cycle checkpoints, apoptosis, and DNA repair by contributing to activation of p53 (29), a protein that is upregulated in AECs in IPF (30). ATF5 has been identified as a direct downstream target of CHOP in mouse embryonic fibroblasts and has been reported to cooperate with CHOP for full induction of a specific subset of downstream genes (31).…”

Long-Term Culture of Distal Airway Epithelial Cells Allows Differentiation Towards Alveolar Epithelial Cells Suited for Influenza Virus Studies

“…By contrast, we found many genes upregulated during default differentiation that have been associated with idiopathic pulmonary fibrosis, e.g. CCL2 [ 40 ], CCL3 [ 41 ], SERPINE2 [ 42 ], [ 43 ] and MMP7 [ 44 , 45 ]. Current tools to support research in this field include animal models, cell lines such as the AEII cell line A549, non-epithelial models, as well as primary human bronchial epithelial, airway and alveolar epithelial cells [ [46] , [47] , [48] , [49] , [50] ].…”