Different Types Of Interstitial Lung Diseases Research Articles

Genetic Programs Between Steroid-Sensitive and Steroid-Insensitive Interstitial Lung Disease

The effectiveness of corticosteroids (GCs) varies greatly in interstitial lung diseases (ILDs). In this study, we aimed to compare the gene expression profiles of patients with cryptogenic organizing pneumonia (COP), idiopathic pulmonary fibrosis (IPF), and non-specific interstitial pneumonia (NSIP) and identify the molecules and pathways responsible for GCs sensitivity in ILDs. Three datasets (GSE21411, GSE47460, and GSE32537) were selected. Differentially expressed genes (DEGs) among COP, IPF, NSIP, and healthy control (CTRL) groups were identified. Functional enrichment analysis and protein–protein interaction network analysis were performed to examine the potential functions of DEGs. There were 128 DEGs when COP versus CTRL, 257 DEGs when IPF versus CTRL, 205 DEGs when NSIP versus CTRL, and 270 DEGs when COP versus IPF. The DEGs in different ILDs groups were mainly enriched in the inflammatory response. Further pathway analysis showed that “interleukin (IL)-17 signaling pathway” (hsa04657) and “tumor necrosis factor (TNF) signaling pathway” were associated with different types of ILDs. A total of 10 genes associated with inflammatory response were identified as hub genes and their expression levels in the IPF group were higher than those in the COP group. Finally, we identified two GCs’ response-related differently expressed genes (FOSL1 and DDIT4). Our bioinformatics analysis demonstrated that the inflammatory response played a pathogenic role in the progression of ILDs. We also illustrated that the inflammatory reaction was more severe in the IPF group compared to the COP group and identified two GCs’ response-related differently expressed genes (FOSL1 and DDIT4) in ILDs.

Incidence and risk factors of venous thrombotic events in patients with interstitial lung disease during hospitalization

BackgroundStudies on the incidence of venous thromboembolism (VTE) events in patients with interstitial lung disease (ILD) are limited and the results are inconsistent. The aim of this research was to investigate the incidence and risk factors of VTE in ILD during hospitalization.Materials and methodsIn this retrospective, cross-sectional, observational study, a total of 5009 patients diagnosed with ILD from January 2016 to March 2022 in our hospital were retrospectively included. In ILD patients, VTE including pulmonary thromboembolism (PTE) and deep vein thrombosis (DVT) were screened from the electronic medical record system. Diagnosis of PTE and DVT were performed by CT pulmonary angiography (CTPA), CTV or ultrasound. And then the incidence and risk factors of VTE in different types of ILD were assessed.ResultsAmong 5009 patients with ILD, VTE was detected in 129 (2.6%) patients, including 15(0.3%) patients with both PTE and DVT, 34 (0.7%) patients with PTE and 80 (1.6%) patients with DVT. 85.1% of patients with APE were in the intermediate-low risk group. The incidence of VTE in Anti-Neutrophil Cytoplasmic Antibodies -associated vasculitis related ILD (ANCA-AV-ILD), hypersensitivity pneumonitis and idiopathic pulmonary fibrosis (IPF) respectively was 7.9% and 3.6% and 3.5%. In patients with connective tissue disease-associated ILD (CTD-ILD), the incidence of VTE, DVT, PTE, combined PTE and DVT respectively was 3.0%, 2.3%, 0.4% and 0.3%. Among the various risk factors, different ILD categories, age ≥ 80 years (OR 4.178, 95% CI 2.097–8.321, P < 0.001), respiratory failure (OR 2.382, 95% CI 1.533–3.702, P < 0.001) and varicose veins (OR 3.718, 95% CI 1.066–12.964, P = 0.039) were independent risk factors of VTE. The incidence of VTE in patients with ILD increased with the length of time in hospital from 2.2% (< 7 days) to 6.4% (> 21 days).ConclusionThe incidence of VTE during hospitalization in ILD patients was 2.6%, with a 1.6% incidence of DVT, higher than the 0.7% incidence of PTE. Advanced age, ILD categories, respiratory failure and varicose veins as independent risk factors for the development of VTE should be closely monitored.

Vitamin d deficiency and effect of its supplementation on interstitial lung disease (ILD): a randomized clinical trial

Background: Vitamin D is a steroid hormone that affects the immune system, lung remodeling, and bone health. Aim of the work: to assess serum vitamin D level in non-connective tissue disease-associated interstitial lung diseases (ILD), and to evaluate the impact of vitamin D supplementation. Patients and methods: One hundred and four patients with different types of ILD were randomly assigned to either; Group 1 (intervention): included 52 patients who received vitamin D for 3 months besides their standard treatment, and Group 2 (control): included 52 patients who received only the standard treatment of ILD. Follow up after 3 months. All patients were subjected to; dyspnea scoring, spirometry, six minutes walk test (6-MWT), and measurement of serum vitamin D at the time of enrollment and after 3 months for the intervention group. Results: The mean serum vitamin D level was (8.53 ± 6.29) ng/ml. After 3 months of supplementation; it significantly increased [5.7 to 18.5 (ng/ml), p &lt; 0.001], dyspnea score significantly decreased, significant increase of forced vital capacity (FVC)% and forced expiratory volume in the first second (FEV1)% (P=0.004 &amp; 0.02), with improvement of six minute walk distance (6-MWD) and oxygen saturation.

Tumor markers are associated with rapidly progressive interstitial lung disease in adult-dermatomyositis.

DM-associated rapidly progressive interstitial lung disease (DM-RP-ILD) has been the clinical conundrum. We assess the serum levels of tumor markers (TMs) in different types of ILD, and explore the diagnostic utility of TMs for DM/ADM-RP-ILD. This was a retrospective cohort study, data including clinical and laboratory records were collected from the first affiliated hospital of Zhengzhou University from December 2015, to June 2020. Tumor markers (TMs) include CEA, CA153, CA724, CA125, and CA199. Spearman analysis, ROC, and Kaplan-Meier curve were used for data analysis. Total 272 patients (149 DM and 123 ADM) were enrolled, 152 (55.88%) with ILD (116 with chronic ILD, 36 with RP-ILD) and 120 (44.12%) without ILD among them. The serum levels of CEA and ferritinwere significantly higher in patients with RP-ILD than in the other two groups. Serum CA125, CA199, and CA153 levels in patients with RP-ILD were higher than those without ILD. CEA levels were associated with the ferritin, KL-6 and anti-MDA5 levels, and CEA concentration was significantly negatively correlated with DLco (P = 0.016, R2 = - 0.281). CEA [AUC = 0.7, 95% CI = (0.594, 0.806)] and ferritin [AUC = 0.737, 95% CI = (0.614, 0.860)] had diagnosed value for patients developing RP-ILD. Patients with high serum CEA levels had higher mortality rate within the DM-ILD population. TMs and ferritin were increased in DM/ADM-RP-ILD, and serum CEA and CA153 levels can evaluate disease severity of DM. And CEA and ferritin can be used as noninvasive diagnostic biomarkers for patients with DM-RP-ILD. Key Points • Interstitial lung disease (ILD) is a serious complication of DM, and is a leading cause of mortality, especially rapidly progressive ILD. • Tumor markers as a kind of noninvasive detection can reflect the disease severity of DM, and CEA and ferritin can be used to identify patients with RP-ILD.

Prognostic impact of HNF4α expression in interstitial lung disease.

Pneumocyte injury is a crucial factor influencing the severity of interstitial lung disease (ILD). In this study, we investigated the potential of hepatocyte nuclear factor α (HNF4α) as an immunohistochemical marker to detect pneumocyte injury and as a prognostic marker. Surgical lung biopsy specimens were collected from 309 patients with different types of ILDs (61 idiopathic pulmonary fibrosis (IPF), 173 non-IPF, and 75 unclassifiable ILD). HNF4α expression were examined and the frequency of positive cells (per mm2 ) was calculated. HNF4α was strongly expressed in regenerating pneumocytes present on fibroblastic foci, Masson bodies/organizing alveoli. In the non-IPF and unclassifiable ILD groups, cases with high frequency expression showed significantly poorer outcome. Particularly, in the unclassifiable ILD group, the prognostic impact was more significant (death due to ILD, log-rank test, p < 0.0001), with a 10-year survival rate (hazard ratio 11.1, Wald test, p = 0.0003), as compared to the non-IPF group (log-rank test, p = 0.0269; hazard ratio 2.7, Wald test, p = 0.0334). Multivariable analysis focusing on the unclassifiable ILD group confirmed that the frequent HNF4α expression was an independent prognostic factor (hazard ratio 28.6; Wald test, p = 0.0033). Thus, HNF4α can be utilized as an immunohistochemical marker for pneumocyte injury and have prognostic impact particularly in unclassifiable ILD.

Interstitial lung disease revisited

Interstitial lung disease (ILD), consisting of more than 200 subtypes of diseases, is a large group of heterogeneous diseases characterized by varying degrees of alveolitis and pulmonary parenchymal fibrosis. There are many challenges in its diagnosis and treatment. In recent years, new understanding of the clinical classification, disease behavior, early diagnosis, and treatment of ILD has been obtained. The anti-fibrotic drugs have been expanded successfully from treatment of idiopathic pulmonary fibrosis (IPF) to progressive-fibrosing interstitial lung diseases (PF-ILD). A new international clinical practice guideline categorized hypersensitivity pneumonitis (HP) into two clinical phenotypes, namely nonfibrotic and fibrotic HP. The clinical classification of ILD according to disease behavior and a progressing fibrotic phenotype is of important value for the establishment of treatment strategies for patients with ILD. Interstitial pulmonary abnormalities (ILA) may represent the subclinical stages of different types of ILD, and long-term follow-up of ILA is key to improving the early diagnosis of ILD. Interstitial pneumonia with autoimmune features (IPAF) may represent an early phase or prodromal state of a connective tissue disease (CTD), and patients with IPAF need to be under longitudinal surveillance for evolution to CTD.

Can YKL-40 be used as a biomarker for interstitial lung disease?: A systematic review and meta-analysis.

Background:Interstitial lung disease (ILD) has a poor prognosis and lacks specific biomarkers for early diagnosis, assessment of disease severity, and prognosis. YKL-40 levels were found to be elevated in patients with ILD, but these results are inconsistent. Therefore, we conducted a systematic review and meta-analysis to accurately study the relation between YKL-40 and ILD.Methods:We performed a systematic literature search in many databases (PubMed, Embase, the China National Knowledge Infrastructure, and Wanfang databases) and commercial Internet search engines to identify studies involving the role of YKL-40 in patients with ILD. The weighted mean difference with its 95% confidence interval were used to investigate the effect sizes. If obvious heterogeneity was found in the meta-analysis, the level of YKL-40 was directly compared by the Mann-Whitney test.Results:Sixteen eligible articles were finally identified. The results showed that the serum YKL-40 levels of patients with idiopathic pulmonary fibrosis, connective tissue-related ILD, sarcoidosis, cryptogenic tissue pneumonia, asbestosis-ILD, and idiopathic nonspecific interstitial pneumonia were higher than those in controls, but there was no increase in patients with pulmonary alveolar proteinosis. We also found that there are certain differences in the serum YKL-40 levels in patients with different types of ILD. The results showed that the bronchoalveolar lavage fluid YKL-40 levels of patients with idiopathic pulmonary fibrosis were significantly higher than that in controls. A systematic review indicated that there were correlations between the serum YKL-40 levels and lung function in patients with different ILD. In addition, YKL-40 may be used as a valuable biomarker for survival, with risk ratios ranging from 1.006 to 10.9.Conclusions:This study suggests that YKL-40 may be a useful biomarker for the diagnosis and prognosis of ILD.

When things go wrong: exploring possible mechanisms driving the progressive fibrosis phenotype in interstitial lung diseases.

Interstitial lung diseases (ILDs) comprise a large and heterogeneous group of disorders of known and unknown aetiology characterised by diffuse damage of the lung parenchyma. In recent years it has become evident that patients with different types of ILD are at risk of developing progressive pulmonary fibrosis, known as progressive fibrosing ILD (PF-ILD). This is a phenotype that behaves similar to idiopathic pulmonary fibrosis, the archetypical example of progressive fibrosis. PF-ILD is not a distinct clinical entity but describes a group of ILDs with similar clinical behaviour. This phenotype may occur in diseases displaying distinct aetiologies and different biopathology during their initiation and development. Importantly, these entities may have the potential for improvement or stabilisation prior to entering the progressive fibrosing phase. The crucial questions are: 1) why does a subset of patients develop a progressive and irreversible fibrotic phenotype even with appropriate treatment? and 2) what are the possible pathogenic mechanisms driving progression? Here, we provide a framework highlighting putative mechanisms underlying progression, including genetic susceptibility, ageing, epigenetics, structural fibrotic distortion, aberrant composition and stiffness of the extracellular matrix, and the emergence of distinct pro-fibrotic cell subsets. Understanding the cellular and molecular mechanisms behind PF-ILD will provide the basis for identifying risk factors and appropriate therapeutic strategies.

Predictors of postoperative acute exacerbation of interstitial lung disease: a case–control study

IntroductionPatients with interstitial lung disease (ILD) are known to develop an acute exacerbation (AE) after surgery. Previous studies have evaluated the predictors of postoperative AE. However, it remains unclear whether...

EP33 Sjögren’s and lymphoproliferative disorders

Case report - IntroductionSjögren’s syndrome (SS) is a chronic autoimmune inflammatory condition characterised by lymphocytic infiltration of predominantly exocrine glands as well as other organs involving more commonly in skin, lungs, and neurological system. It is associated with increased risk of both benign and malignant lymphoproliferative disorders.Case report - Case descriptionA 29-year-old woman with 5-year history of Primary SS (ANA, Ro/La positive) was reviewed in a routine follow up. She has mild dry eyes, intermittent vasculitic rash around the ankles, occasional pleuritic chest pain but no cough or dyspnoea initially. She used artificial tears but took no regular mediations. Oxygen saturation at rest was 99% and BP 127/70. Heart sounds were normal, and chest was clear.Blood results showed alanine transaminase (ALT) had risen from 50 (normal 5-45) to 145 over 6 months. Viral screen (hepatitis, HIV, CMV, EBV) and liver ANA panel were negative. C4 was low 0.09 (n 0.15-0.55), C3 normal and DsDNA antibodies 1 (n 0-15.1). Ig G was high, fluctuating between 27 - 33 (n 7.67-15.9). ESR had been mildly elevated at 26 (n 0-19). CRP had always been within normal limits. Ultrasound abdomen showed enlarged spleen (15 cm). CT chest abdomen and pelvis showed multifocal groundless opacification affecting mid to upper zones, bilateral cyst formation, solid nodularity, and mild septal thickening with no pleural effusion. There were multiple prominent bilateral axillary and mediastinal lymph nodes measuring upto15 mm. The spleen measured 15.4 cm. Six months later, she developed mild dyspnoea on exertion. Examination revealed fine basal crackles. Oxygen saturation remained 99% at rest. TLco was mildly reduced and Kco in lower limit of normal. Echocardiogram was normal. Ultrasound guided core biopsy of axillary lymph node showed benign reactive features with follicular hyperplasia and plasmacytosis.The diagnosis of lymphocytic interstitial pneumonitis was made. She was started on a reducing dose of Prednisolone 30 mg and Mycophenolate stepwise increment to 1 gm BD. Chest pain resolved shortly after starting glucocorticoid therapy and exercise tolerance improved.Liver enzyme normalised. Case report - DiscussionThe diagnosis of lymphocytic interstitial pneumonia (LIP) in this patient was incidental from the retrospective investigation of the persistently abnormal unexplained liver function test. Splenomegaly is a recognised manifestation of active systemic SS. The main differential diagnoses are lymphoma and other types of interstitial lung diseases (ILD). Her presentation was insidious and there were no constitutional symptoms. Her ANA, Ro, La and Rheumatoid factor were strongly positive. She has hypergammaglobulinemia which is commonly associated with LIP. Histological findings were typical reactive changes with characteristic polymorphic plasmacytosis. In the absence of malignant lymphoid cells and radiological features of ground glass changes and bilateral cysts formation suggested that the most likely diagnosis was LIP secondary to primary SS.The management strategies vary for different types of ILD based on their etiological conditions. There are no specific guidelines for the treatment of LIP. For initial acute stage, glucocorticoid therapy is usually prescribed for symptomatic improvement. For later stages and cysts, immunosuppressants are used and depending on the severity, azathioprine, cyclosporin, rituximab and cyclophosphamide have been used.Median survival for LIP is 11.2 years. Increased risk of secondary infection because of immunosuppressive therapy is common and there are recommendations for atypical chest infection prophylaxis.Case report - Key learning pointsInterstitial lung disease is commonly associated with SS and predicts a higher mortality rate.Glucocorticoid is the main stay of treatment for ILD acute stage with active inflammatory changes.For refractory cases and chronic cystic stages on radiological findings, further immunosuppression therapy may be required.Standardised treatment guidelines are not available.Secondary chest infections may be seen in those with cystic disease and on immunosuppression.Close monitoring and MDT approach is required in the management of LIP.LIP may transform into lymphoma or co-present with lymphoma associated with SS.

Risk factors of interstitial lung diseases in clinically amyopathic dermatomyositis.

BackgroundClinically amyopathic dermatomyositis (CADM) is a unique sub-type of idiopathic inflammatory myopathies with a high prevalence of interstitial lung disease (ILD). Poor prognosis of the patients was strongly associated with rapid progressive ILD. The aim of this study was to identify risk factors for prediction of different types of ILD in CADM.MethodsIn this study, data of 108 inpatients with CADM were collected, including 87 with ILD. The baseline clinical data and laboratory parameters, including myositis-specific and associated antibodies and tumor-associated antigens were analyzed to identify risk factors for acute or subacute interstitial pneumonitis (A/SIP) and chronic interstitial pneumonitis (CIP).ResultsIn 87 patients with CADM-ILD, 39 (36.1%) were A/SIP, and 48 (44.4%) were CIP. There were 22 (20.4%) patients with asymptomatic ILD who were detected by routine high resolution computed tomography. Cytokeratin-19 fragment (CYFRA21-1) was significantly higher in CADM-ILD than that in CADM patients without ILD; carcinoembryonic antigen and neuron-specific enolase were significantly elevated in A/SIP than that in CIP. Patients with A/SIP had a higher positive rate of anti-melanoma differentiation-associated gene 5 (MDA5), while patients with CIP had a higher positive rate of anti PL-12 and anti-Ro-52. Logistic regression analysis indicated that elevation of CYFRA21-1 was a risk factor for ILD, higher titer of anti-MDA5 indicated increased likelihood for A/SIP, and higher titer of anti-Ro-52 was also clearly associated with CIP.ConclusionsThis study indicated that the prevalence of ILD was high in CADM. Asymptomatic ILD has been previously underestimated. Anti-MDA5 was a risk factor for the presence of A/SIP, and CYFRA21-1 was a risk factor for ILD.

Role of telomerase expression in interstitial lung diseases

BackgroundTelomeres are hexameric nucleotide sequences. The biological role of telomeres is to prevent shortening of DNA to preserve integrity of the genome. Length of telomeres is determined by age, sex, and environmental exposures. Telomeres are vulnerable to injury by oxidative stress. Telomere length is sustained by telomerase, a ribonucleoprotein telomerase reverse transcriptase (TERT). Telomerase may help cell growth and secure against cell death. ‘Telomeropathy’ is associated with genetic mutations. The most common phenotype related to telomerase mutation is pulmonary fibrosis.ObjectiveTo investigate the associations of both TERT and telomerase RNA component C with disease progression in patients with interstitial lung diseases (ILDs), which include idiopathic pulmonary fibrosis (IPF), and to compare results between patients with ILD and control.Patients and methodsA total of 46 patients with different types of ILDs were enrolled as well as 15 healthy persons as control. Whole blood sample was obtained from both patients and healthy control for detection of expression of telomerase gene by quantitative real-time PCR.ResultsThere was a significant negative correlation between telomerase reverse transcriptase (h-TERT) and partial pressure of oxygen (r=−23, P=0.03). Both h-TERT and telomerase reverse transcriptaseRNA component (h-TERC) were relatively more expressed in patients with IPF with pulmonary hypertension, whereas there was a significant elevation of h-TERT relative expression in patients with IPF with honeycombing high-resolution computed tomography pattern in comparison with those with reticulonodular pattern, with median of 0.85 versus 0.29, respectively.ConclusionHypoxia may affect DNA damage in the telomere region. Expression of telomerase may take part in pulmonary fibrosis. Exposure to hypoxia or growth factors can stimulate the expression of telomerase on cells of vascular smooth muscle.

Seasonal variation of serum KL-6 concentrations is greater in patients with hypersensitivity pneumonitis.

BackgroundSerum KL-6 is a useful biomarker for the diagnosis of interstitial lung diseases (ILD). However, KL-6 has not been used to discriminate different types of ILD. Serum KL-6 concentrations can vary depending on antigen exposure levels in patients with hypersensitivity pneumonitis (HP); however, seasonal changes in serum KL-6 concentrations in ILD have not been determined. We hypothesized that seasonal variation of serum KL-6 is greater in HP than for the other ILD. The aim of this study was to determine seasonal variation of serum KL-6 concentrations in various ILD.MethodsSerum KL-6 concentrations in the summer season from June 1 to September 30 and the winter season from November 1 to February 28 were retrospectively analyzed in patients with idiopathic pulmonary fibrosis (IPF, n = 16), non-specific interstitial pneumonia (NSIP, n = 16), collagen vascular disease-associated interstitial pneumonia (CVD-IP, n = 33), house-related HP (House-HP, n = 9), bird-related HP (Bird-HP, n = 9), and combined pulmonary fibrosis and emphysema (CPFE, n = 13).ResultsBird-HP and House-HP showed greater seasonal serum KL-6 variation than the other ILD. Serum KL-6 concentrations in Bird-HP were significantly increased in the winter and KL-6 concentrations in House-HP were significantly increased in the summer. Serum KL-6 variation was significantly greater in acute HP than chronic HP. Receiver operating characteristic curve analysis revealed that greater seasonal variation in serum KL-6 concentrations is diagnostic for Bird-HP.ConclusionHP should be considered in ILD with greater seasonal changes in serum KL-6 concentrations.

Systematic review: the relationship between interstitial lung diseases and gastro‐oesophageal reflux disease

BACKGROUND A potential relationship has been suggested between gastro-oesophageal reflux disease (GERD) and interstitial lung diseases (ILDs). AIM To evaluate whether there is a causal relationship between GERD and different ILDs. METHODS We conducted a systematic search of literature published between 1980 and 2010. After a review by two independent authors, each study was assigned an evidence-based rating according to a standard scoring system. RESULTS We identified 319 publications and 22 of them met the entry criteria. Of those, the relationship between GERD and idiopathic pulmonary fibrosis (IPF) was investigated in 14 articles, pulmonary involvement in systemic sclerosis (SSc) in six articles and pulmonary involvement in mixed connective tissue disease (MCTD) in two articles. We found the prevalence of GERD and/or oesophageal dysmotility to be higher in patients with different types of ILD as compared with those without ILD [Evidence B]. Among patients with IPF, 67-76% demonstrated abnormal oesophageal acid exposure off PPI treatment. No relationship was demonstrated between severity of GERD and severity of IPF [Evidence B]. Data are scant on outcomes of antireflux treatment in patients with IPF. There is a correlation between the severity of ILD and the degree of oesophageal motor impairment in patients with SSc and MCTD [Evidence B]. CONCLUSIONS Based on the currently available data, a causal relationship between GERD and idiopathic pulmonary fibrosis cannot be established. There is scant evidence about antireflux therapy in idiopathic pulmonary fibrosis patients. There may be an association between lung and oesophageal involvement in systemic sclerosis and mixed connective tissue disease, but a causal relationship cannot be established.

Systems biology of interstitial lung diseases: integration of mRNA and microRNA expression changes

BackgroundThe molecular pathways involved in the interstitial lung diseases (ILDs) are poorly understood. Systems biology approaches, with global expression data sets, were used to identify perturbed gene networks, to gain some understanding of the underlying mechanisms, and to develop specific hypotheses relevant to these chronic lung diseases.MethodsLung tissue samples from patients with different types of ILD were obtained from the Lung Tissue Research Consortium and total cell RNA was isolated. Global mRNA and microRNA were profiled by hybridization and amplification-based methods. Differentially expressed genes were compiled and used to identify critical signaling pathways and potential biomarkers. Modules of genes were identified that formed a regulatory network, and studies were performed on cultured cells in vitro for comparison with the in vivo results.ResultsBy profiling mRNA and microRNA (miRNA) expression levels, we found subsets of differentially expressed genes that distinguished patients with ILDs from controls and that correlated with different disease stages and subtypes of ILDs. Network analysis, based on pathway databases, revealed several disease-associated gene modules, involving genes from the TGF-β, Wnt, focal adhesion, and smooth muscle actin pathways that are implicated in advancing fibrosis, a critical pathological process in ILDs. A more comprehensive approach was also adapted to construct a putative global gene regulatory network based on the perturbation of key regulatory elements, transcription factors and microRNAs. Our data underscores the importance of TGF-β signaling and the persistence of smooth muscle actin-containing fibroblasts in these diseases. We present evidence that, downstream of TGF-β signaling, microRNAs of the miR-23a cluster and the transcription factor Zeb1 could have roles in mediating an epithelial to mesenchymal transition (EMT) and the resultant persistence of mesenchymal cells in these diseases.ConclusionsWe present a comprehensive overview of the molecular networks perturbed in ILDs, discuss several potential key molecular regulatory circuits, and identify microRNA species that may play central roles in facilitating the progression of ILDs. These findings advance our understanding of these diseases at the molecular level, provide new molecular signatures in defining the specific characteristics of the diseases, suggest new hypotheses, and reveal new potential targets for therapeutic intervention.