A Placebo-Controlled Randomized Trial of Warfarin in Idiopathic Pulmonary Fibrosis

Idiopathic pulmonary fibrosis (IPF) is a fatal progressive interstitial pneumonia. The innate immune system provides a crucial function in the recognition of tissue injury and infection. Toll-like receptor 3 (TLR3) is an innate immune system receptor. We investigated the role of a functional TLR3 single-nucleotide polymorphism in IPF. To characterize the effects of the TLR3 Leu412Phe polymorphism in primary pulmonary fibroblasts from patients with IPF and disease progression in two independent IPF patient cohorts. To investigate the role of TLR3 in a murine model of pulmonary fibrosis. TLR3-mediated cytokine, type 1 IFN, and fibroproliferative responses were examined in TLR3 wild-type (Leu/Leu), heterozygote (Leu/Phe), and homozygote (Phe/Phe) primary IPF pulmonary fibroblasts by ELISA, real-time polymerase chain reaction, and proliferation assays. A murine model of bleomycin-induced pulmonary fibrosis was used in TLR3 wild-type (tlr3(+/+)) and TLR3 knockout mice (tlr3(-/-)). A genotyping approach was used to investigate the role of the TLR3 L412F polymorphism in disease progression in IPF using survival analysis and longitudinal decline in FVC. Activation of TLR3 in primary lung fibroblasts from TLR3 L412F-variant patients with IPF resulted in defective cytokine, type I IFN, and fibroproliferative responses. We demonstrate increased collagen and profibrotic cytokines in TLR3 knockout mice (tlr3(-/-)) compared with wild-type mice (tlr3(+/+)). TLR3 L412F was also associated with a significantly greater risk of mortality and an accelerated decline in FVC in patients with IPF. This study reveals the crucial role of defective TLR3 function in promoting progressive IPF.

Cigarette smoking may impact the progression of idiopathic pulmonary fibrosis (IPF), and the intensity of smoking presents a dose-response association with IPF. We retrospectively analyzed IPF patients diagnosed in our hospital from 2014 to 2018 and performed follow-up to confirm survival status and duration, and determine the effect of smoking on the prognosis of IPF. We retrieved information on IPF from a bioinformatics database to identify the differential expression of lncRNAs and proteins in smokers. Therefore, we explored and verified the mechanism by which cigarette smoke exposure (CSE) regulates LINC00665/XBP-1 involvement in pulmonary fibrosis through cell experiments. We clarified the mechanism between LINC00665 and XBP-1 through cellular and molecular experiments, and verified the inhibitory effect of silencing LINC00665 on pulmonary fibrosis by using a bleomycin (BLM)-induced pulmonary fibrosis model. We found that smokers with IPF had a poor prognosis compared with non-smokers. Both the expression of LINC00665 and XBP-1 in IPF lung tissue and smoker lung tissue were significantly upregulated, moreover, LINC00665 was higher in smoker IPF lung tissue than in smoker healthy people. Exposure to CSE could upregulate LINC00665/XBP-1 in lung fibroblast-to-myofibroblast transition. Cellular and molecular experiments showed that LINC00665 regulates the expression of XBP-1 by targeting miR-214-3p. LINC00665 expression, was significantly upregulated in BLM-induced mouse lung fibrosis tissues, and LINC00665 knockdown inhibited fibrogenesis in BLM-induced lung fibrosis. Our study found that the high expression of LINC00665 is involved in the pathogenesis of smoker IPF and that CSE may positively regulate LINC00665/XBP-1 to participate in lung fibroblast-to-myofibroblast transition. These findings help elucidate the pathogenesis of smoker IPF and may contribute to the development of new targeted drugs for IPF therapy.

Rationale: Changes in peripheral blood cell populations have been observed, but not detailed, at single-cell resolution in idiopathic pulmonary fibrosis (IPF). Objectives: We sought to provide an atlas of the changes in the peripheral immune system in stable and progressive IPF. Methods: Peripheral blood mononuclear cells (PBMCs) from patients with IPF and control subjects were profiled using 10× chromium 5' single-cell RNA sequencing. Flow cytometry was used for validation. Protein concentrations of regulatory T cells (Tregs) and monocyte chemoattractants were measured in plasma and lung homogenates from patients with IPF and control subjects. Measurements and Main Results: Thirty-eight PBMC samples from 25 patients with IPF and 13 matched control subjects yielded 149,564 cells that segregated into 23 subpopulations. Classical monocytes were increased in patients with progressive and stable IPF compared with control subjects (32.1%, 25.2%, and 17.9%, respectively; P < 0.05). Total lymphocytes were decreased in patients with IPF versus control subjects and in progressive versus stable IPF (52.6% vs. 62.6%, P = 0.035). Tregs were increased in progressive versus stable IPF (1.8% vs. 1.1% of all PBMCs, P = 0.007), although not different than controls, and may be associated with decreased survival (P = 0.009 in Kaplan-Meier analysis; and P = 0.069 after adjusting for age, sex, and baseline FVC). Flow cytometry analysis confirmed this finding in an independent cohort of patients with IPF. The fraction of Tregs out of all T cells was also increased in two cohorts of lung single-cell RNA sequencing. CCL22 and CCL18, ligands for CCR4 and CCR8 Treg chemotaxis receptors, were increased in IPF. Conclusions: The single-cell atlas of the peripheral immune system in IPF reveals an outcome-predictive increase in classical monocytes and Tregs, as well as evidence for a lung-blood immune recruitment axis involving CCL7 (for classical monocytes) and CCL18/CCL22 (for Tregs).

Idiopathic pulmonary fibrosis (IPF) is a chronic interstitial lung disease with a high mortality rate and unclarified aetiology. Immune response is elaborately regulated during the progression of IPF, but immune cells subsets are complicated which has not been detailed described during IPF progression. Therefore, in the current study, we sought to investigate the role of immune regulation by elaborately characterize the heterogeneous of immune cells during the progression of IPF. To this end, we performed single-cell profiling of lung immune cells isolated from four stages of bleomycin-induced pulmonary fibrosis-a classical mouse model that mimics human IPF. The results revealed distinct components of immune cells in different phases of pulmonary fibrosis and close communication between macrophages and other immune cells along with pulmonary fibrosis progression. Enriched signals of SPP1, CCL5 and CXCL2 were found between macrophages and other immune cells. The more detailed definition of the subpopulations of macrophages defined alveolar macrophages (AMs) and monocyte-derived macrophages (mo-Macs)-the two major types of primary lung macrophages-exhibited the highest heterogeneity and dynamic changes in expression of profibrotic genes during disease progression. Our analysis suggested that Gpnmb and Trem2 were both upregulated in macrophages and may play important roles in pulmonary fibrosis progression. Additionally, the metabolic status of AMs and mo-Macs varied with disease progression. In line with the published data on human IPF, macrophages in the mouse model shared some features regarding gene expression and metabolic status with that of macrophages in IPF patients. Our study provides new insights into the pathological features of profibrotic macrophages in the lung that will facilitate the identification of new targets for disease intervention and treatment of IPF.

Recent clinical trial successes have created an urgent need for earlier and more sensitive endpoints of disease progression in idiopathic pulmonary fibrosis (IPF). Domiciliary spirometry permits more frequent measurement of FVC than does hospital-based assessment, which therefore affords the opportunity for a more granular insight into changes in IPF progression. To determine the feasibility and reliability of measuring daily FVC in individuals with IPF. Subjects with IPF were given handheld spirometers and instruction on how to self-administer spirometry. Subjects recorded daily FEV1 and FVC for up to 490 days. Clinical assessment and hospital-based spirometry was undertaken at 6 and 12 months, and outcome data were collected for 3 years. Daily spirometry was recorded by 50 subjects for a median period of 279 days (range, 13-490 d). There were 18 deaths during the active study period. Home spirometry showed excellent correlation with hospital-obtained readings. The rate of decline in FVC was highly predictive of outcome and subsequent mortality when measured at 3 months (hazard ratio [HR], 1.040; 95% confidence interval [CI], 1.021-1.062; P ≤ 0.001), 6 months (HR, 1.024; 95% CI, 1.014-1.033; P < 0.001), and 12 months (HR, 1.012; 95% CI, 1.007-1.016; P = 0.001). Measurement of daily home spirometry in patients with IPF is highly clinically informative and is feasible to perform for most of these patients. The relationship between mortality and rate of change of FVC at 3 months suggests that daily FVC may be of value as a primary endpoint in short proof-of-concept IPF studies.

Rationale:Changes in peripheral blood cell populations have been observed but not detailed at single-cell resolution in idiopathic pulmonary fibrosis (IPF).Objectives:To provide an atlas of the changes in the peripheral immune system in stable and progressive IPF.Methods:Peripheral blood mononuclear cells (PBMCs) from IPF patients and controls were profiled using 10x Chromium 5’ single-cell RNA sequencing (scRNA-seq). Flow cytometry was used for validation. Protein concentrations of Regulatory T-cells (Tregs) and Monocytes chemoattractants were measured in plasma and lung homogenates from patients and controls.Measurements and Main Results:Thirty-eight PBMC samples from 25 patients with IPF and 13 matched controls yielded 149,564 cells that segregated into 23 subpopulations, corresponding to all expected peripheral blood cell populations. Classical monocytes were increased in progressive and stable IPF compared to controls (32.1%, 25.2%, 17.9%, respectively, p<0.05). Total lymphocytes were decreased in IPF vs controls, and in progressive vs stable IPF (52.6% vs 62.6%, p=0.035). Tregs were increased in progressive IPF (1.8% vs 1.1%, p=0.007), and were associated with decreased survival (P=0.009 in Kaplan-Meier analysis). Flow cytometry analysis confirmed this finding in an independent cohort of IPF patients. Tregs were also increased in two cohorts of lung scRNA-seq. CCL22 and CCL18, ligands for CCR4 and CCR8 Treg chemotaxis receptors, were increased in IPF.Conclusions:The single-cell atlas of the peripheral immune system in IPF, reveals an outcome-predictive increase in classical monocytes and Tregs, as well as evidence for a lung-blood immune recruitment axis involving CCL7 (for classical monocytes) and CCL18/CCL22 (for Tregs).

Longitudinal change in collagen degradation biomarkers in idiopathic pulmonary fibrosis: an analysis from the prospective, multicentre PROFILE study

Idiopathic pulmonary fibrosis (IPF) is a debilitating, chronically progressive lung disease that leads to significant morbidity and mortality [1]. Although it is a fairly uncommon disease, its incidence has been increasing over the past decade [2]. One of the key elements contributing to the development of IPF is the inability to halt the progression of damage to lung epithelial cells. The pathogenic mechanisms involved in this process include excessive inflammation, overactivity and hyperproliferation of fibroblasts, and inadequate repair of epithelial cell injury [3]. Currently, no treatment modality has been proven to be effective in preventing or reversing the parenchymal damage occurring in IPF. However, a surge in the amount of research pursuing future therapies has occurred in recent years. A field of study that appears to be particularly promising in the development of new IPF treatments is the study of epigenetic regulatory mechanisms involved in the pathogenesis of IPF. Epigenetic factors involved in the pathogenesis of IPF, including micro RNAs (miRNAs), may be the key to the development of future treatments for this disease [4]. miRNA expression can be controlled by the very epigenetic mechanisms they themselves regulate, including DNA methylation and histone modification. Thus, the number of ways they can be utilized in the development of targeted therapies for many diseases, including IPF, seems limitless [5]. Dakhlallah et al. recently demonstrated the role of epigenetic mechanisms in IPF [3]. This researchers investigated the role of miRNA-17~92 cluster (miR-17~92) in the development of IPF, which is presumed to inhibit specific pro-fibrotic genes, including transforming growth factor-β (TGF-β), metalloproteinases, and type 1 α1 collagen (COL1A1) [3]. This cluster is also involved with lung development, as evidenced by animal studies demonstrating death by asphyxiation in mice lacking the miR-17~92 cluster [6], and high proliferation rates of undifferentiated lung epithelial cells in mice overexpressing this cluster [7]. Expression of miR-17~92 is silenced by hypomethylation via DNA (cytosine-5)-methyltransferase 1 (DNMT-1), the DNMT that is most closely involved with cellular and tissue repair. Dakhlallah et al. demonstrated that lung fibroblasts and epithelial cells from IPF patients had increased DNMT-1 expression, leading to hypermethylation of and subsequently decreased levels of miR-17~92 expression [3]. This lead to upregulation of pro-fibrotic genes, especially TGF-β, which has been shown to lead to the overproduction of miRNA-21 (miR21), an miRNA that silences inhibitors of TGF-β expression, leading to a vicious cycle of unchecked fibrosis in IPF [8]. This is further supported by the fact that decreased miR-21 expression inhibits the pro-fibrotic effects of bleomycin in the lung parenchyma of mice [8]. In the study by Dakhlallah et al., administration of the chemotherapeutic demethylating agent, 5′-aza-2′-doxyctidine, in the IPF patients lead to upregulation of miR17~92, with a subsequent decrease in DNMT-1 levels and downregulation of genes involved in fibrosis. It can be eluded from these findings that the miR-17~92 cluster is vital to lung parenchymal repair in IPF [3]. This same mechanism was also seen in mice with pulmonary fibrosis induced by bleomycin. Dakhlallah et al. then went one step further by administering 5′-aza-2′-doxyctidine to see if subsequent upregulation of miR17~92 would lead to reversal of the pulmonary fibrosis in these mice. The mice treated with 5′-aza-2′-doxyctidine did not experience significant reversal of their pulmonary fibrosis because the 5′-aza-2′-doxyctidine did not lead to breakdown of collagen already present in the lung parenchyma. However, 5′-aza-2′-doxyctidine administration did prevent further production of collagen in the mice’s lungs, and thus slowed the progression of their IPF. These results are analogous to those obtained in a study conducted by Bechtel et al. revealing that 5′-aza-2′-doxyctidine decreased DNMT-1 methylation of RASAL1, an inhibitor of Ras expression, leading to slowed progression of renal fibrosis. Interestingly, other studies have shown that RASAL1 expression is not only controlled via DNMT-1, but also through TGF-β and many miRNA’s that make up the miR17~92 cluster [9]. The study by Dakhlallah et al. presents some compelling results that support conducting further human studies examining the efficaciousness of 5′-aza-2′-doxyctidine in IPF patients [3]. A side effect of the drug that could possibly limit its effectiveness is its tendency to lead to myelosuppression with subsequent pancytopenia. It can also be concluded from this study that direct DNMT-1 inhibitors may provide an alternative IPF therapy. Animal and human studies should be conducted to investigate the effectiveness of direct DNMT-1 inhibitors in the prevention of progression and possible reversal of IPF. Human trials examining the effect of exogenous administration of miR-17~92 on the progression of IPF pathology should also be pursued. In all, epigenetic therapies represent a versatile and promising new avenue for IPF treatment. Future studies should examine these possible therapies as they provide an arsenal of new weapons to be used in the battle against IPF.

Background/Objectives: Idiopathic pulmonary fibrosis (IPF) is the most common form of pulmonary fibrosis (PF) and serves as a key reference for disease severity. Progressive pulmonary fibrosis (PPF), a distinct yet heterogeneous entity arising from various interstitial lung diseases (ILDs), shares similar pathogenetic mechanisms and clinical courses driven by self-perpetuating fibrosis. Antifibrotic therapy, notably nintedanib, can slow disease progression. However, real-world data on antifibrotic therapy’s impact on survival, especially in PPF, are limited. This study aims to compare IPF and PPF regarding phenotype, radiological patterns, comorbidities, prognostic factors, and response to nintedanib, focusing on identifying the patient subsets most likely to benefit. Outcomes assessed include safety, survival, and disease progression over one year, considering various prognostic factors. Methods: This retrospective observational study evaluated patients with fibrosing ILD, affected by either IPF or PPF, and treated with nintedanib. Data collected encompassed clinical, radiological, functional, and treatment-related information. Assessments included chest CT, pulmonary function tests, comorbidities, and survival analysis, utilizing standardized methods and statistical tools to interpret outcomes and tolerability. Results: The study population was composed of 97 patients: 64 were diagnosed with IPF and 33 with PPF. The analysis showed that in PPF patients, ongoing antifibrotic treatment resulted in higher survival (71.1 months vs. 27.4 months, p < 0.001), while no statistically significant differences were found in the IPF group (67.4 months vs. 52.5 months, p = 0.216). Nintedanib was generally well tolerated. Gastrointestinal side effects, predominantly diarrhea, were reported in 61% of patients with IPF and 50% of those with PPF. Dose reduction occurred in 43.75% of IPF patients and 36% of PPF patients, while treatment discontinuation was required in 21.87% of IPF and 21% of PPF patients. Conclusions: This study highlights that in PPF patients, antifibrotic therapy with nintedanib can improve survival. This statement underlines that the primary outcome of antifibrotic treatment should focus on improving patients’ survival.

BackgroundThe prevalence of non-small cell lung cancer (NSCLC) is notably elevated in individuals diagnosed with idiopathic pulmonary fibrosis (IPF). Secreted phosphoprotein 1 (SPP1), known for its involvement in diverse physiological processes, including oncogenesis and organ fibrosis, has an ambiguous role at the intersection of IPF and NSCLC. Our study sought to elucidate the function of SPP1 within the pathogenesis of IPF and its subsequent impact on NSCLC progression.MethodsFour GEO datasets was analyzed for common differential genes and TCGA database was used to analyze the prognosis. The immune infiltration was analyzed by TIMER database. SPP1 expression was examined in human lung tissues, the IPF fibroblasts and the BLM-induced mouse lung fibrosis model. Combined with SPP1 gene gain- and loss-of-function, qRT-PCR, Western blot, EdU and CCK-8 experiments were performed to evaluate the effects and mechanisms of SPP1 in IPF progression. Effect of SPP1 on NSCLC was detected by co-cultured IPF fibroblasts and NSCLC cells.ResultsThrough bioinformatics analysis, we observed a significant overexpression of SPP1 in both IPF and NSCLC patient datasets, correlating with enhanced immune infiltration of cancer-associated fibroblasts in NSCLC. Elevated levels of SPP1 were detected in lung tissue samples from IPF patients and bleomycin-induced mouse models, with partial colocalization observed with α-smooth muscle actin. Knockdown of SPP1 inhibits TGF-β1-induced differentiation of fibroblasts to myofibroblasts and the proliferation of IPF fibroblasts. Conversely, SPP1 overexpression promoted IPF fibroblast proliferation via PI3K/Akt/mTOR pathway. Furthermore, IPF fibroblasts promoted NSCLC cell proliferation and activated the PI3K/Akt/mTOR pathway; these effects were attenuated by SPP1 knockdown in IPF fibroblasts.ConclusionsOur findings suggest that SPP1 functions as a molecule promoting both fibrosis and tumorigenesis, positioning it as a prospective therapeutic target for managing the co-occurrence of IPF and NSCLC.

Remodeling of the interstitial matrix plays a key role in idiopathic pulmonary fibrosis (IPF). In contrast, the role of the basement membrane (BM) and its main component, type IV collagen, is less clear. The study aimed to evaluate how formation of the basement membrane is related to IPF. A total of 211 IPF patients were included from a prospective multi-center cohort of incident IPF. Type IV collagen formation was assessed in serum at baseline, 6, and 12 months using the competitive ELISA PRO-C4. Patients were divided into quartiles (Q1-Q4) based on PRO-C4 baseline levels for cross-sectional analysis. An adjusted linear regression model was used to test associations of PRO-C4 with FVC%, DLco%, and 6MWT using the PRO-C4 Q1 as reference. A linear mixed model was used to compare PRO-C4 levels longitudinally for stable or progressive patients. Disease progression was defined as &gt;5% decline in FVC and/or &gt;10% decline in DLco and/or death at 12 months. Patients in Q4 of baseline PRO-C4 had 7.5 lower DLco% [95% CI 2.2-12.7] (P=0.0057) and walked 39.1 [95% CI 0.96-77.3] meters less in 6MWT (P=0.044) compared to those in Q1. Patients with progressive IPF had higher serum levels of PRO-C4 compared to those with stable disease at 6 months (189 [95% CI 169-213] vs 159 [95% CI 143-177] ng/mL; P=0.02) and 12 months (192 [95% CI 170-216] vs 161 [95% CI 145-179] ng/mL; P=0.022). A similar trend was observed at baseline (189 [95% CI 169-211] vs 167 [95% CI 151-185] ng/mL; P=0.085). The data suggest that basement membrane formation is related to disease severity and progression and may reflect specific pathophysiologic processes in patients with IPF.

Asbestosis and idiopathic pulmonary fibrosis (IPF) share overlapping clinical and pathological features; however, differences in comorbidities and prognostic patterns between the two diseases remain poorly defined. This study aimed to compare comorbidities and prognostic factors associated with pulmonary fibrosis progression and mortality in asbestosis and IPF. This prospective cohort study included 254 patients with asbestosis and 548 patients with IPF enrolled between 2016 and 2020, with follow-up through 2022. Outcomes included progressive pulmonary fibrosis (PPF) and all-cause mortality. Multivariable Cox models were applied to identify independent risk factors associated with these outcomes. Patients with asbestosis exhibited a higher comorbidity burden. Specifically, they more frequently had asthma, lung cancer, pleural disease, cardiovascular/cerebrovascular disease, and connective tissue disease, whereas emphysema was more common in IPF (all P < 0.05). Over a median follow-up of 44 months (IQR 24-61), IPF patients had a higher cumulative incidence of endpoint events than those with asbestosis. In asbestosis, a usual interstitial pneumonia (UIP) pattern on HRCT predicted disease progression. In IPF, risk factors for progression included hypoxemia, forced vital capacity (FVC) < 80%, and UIP compared with probable UIP. Interestingly, combined emphysema was protective against IPF progression. Mortality in asbestosis was associated with lung cancer, pulmonary hypertension (PH), and atrial fibrillation, whereas in IPF, it was linked to FVC < 80% and PH. Asbestosis and IPF show distinct comorbidity patterns and prognostic drivers. IPF prognosis is mainly determined by fibrosis severity, while asbestosis mortality is driven largely by asbestos-related complications.

Rationale: Disease activity in idiopathic pulmonary fibrosis (IPF) remains highly variable, poorly understood, and difficult to predict. Objectives: To identify a predictor using short-term longitudinal changes in gene expression that forecasts future FVC decline and to characterize involved pathways and cell types. Methods: Seventy-four patients from COMET (Correlating Outcomes with Biochemical Markers to Estimate Time-Progression in IPF) cohort were dichotomized as progressors (≥10% FVC decline) or stable. Blood gene-expression changes within individuals were calculated between baseline and 4 months and regressed with future FVC status, allowing determination of expression variations, sample size, and statistical power. Pathway analyses were conducted to predict downstream effects and identify new targets. An FVC predictor for progression was constructed in COMET and validated using independent cohorts. Peripheral blood mononuclear single-cell RNA-sequencing data from healthy control subjects were used as references to characterize cell type compositions from bulk peripheral blood mononuclear RNA-sequencing data that were associated with FVC decline. Measurements and Main Results: The longitudinal model reduced gene-expression variations within stable and progressor groups, resulting in increased statistical power when compared with a cross-sectional model. The FVC predictor for progression anticipated patients with future FVC decline with 78% sensitivity and 86% specificity across independent IPF cohorts. Pattern recognition receptor pathways and mTOR pathways were downregulated and upregulated, respectively. Cellular deconvolution using single-cell RNA-sequencing data identified natural killer cells as significantly correlated with progression. Conclusions: Serial transcriptomic change predicts future FVC decline. An analysis of cell types involved in the progressor signature supports the novel involvement of natural killer cells in IPF progression.

Idiopathic pulmonary fibrosis (IPF) represents a condition included in the heterogeneous group of interstitial lung diseases without known causes. The recent ATS/ERS/JRS/ALAT guidelines and the white paper published by the Fleischner Society have well-defined diagnosis and management of idiopathic pulmonary fibrosis. Idiopathic pulmonary fibrosis management is complex because it is also influenced by several co-morbidities and complications. The new frontier in idiopathic pulmonary fibrosis is represented by the effort to understand the complex mechanism of the pathogenesis and progression of disease in order to predict several consequences and co-morbidities. In our review, we tried to distinguish co-morbidities from complications of idiopathic pulmonary fibrosis. In each complication, we have reviewed the existing literature and we have emphasized the complex pathobiological pathway which links the progression of idiopathic pulmonary fibrosis to the development of the complication itself. For every co-morbidity, we tried to identify share common risk factors which explain the coexistence of idiopathic pulmonary fibrosis with its co-morbidities. We then analyzed high-resolution computed tomography (CT) aspects of co-morbidities and complications of idiopathic pulmonary fibrosis that the radiologist should be aware of. In this review, we focused on the role of high-resolution CT imaging in the evaluation of co-morbidities and complications in idiopathic pulmonary fibrosis because their early diagnosis and treatment could change the prognosis in patients with idiopathic pulmonary fibrosis. We have also pointed out that in some cases the final combined quantitative CT tools and conventional visual CT score would allow to get an accurate analysis and quantification of disease progression, co-morbidities, and complications of idiopathic pulmonary fibrosis in order to improve staging systems in idiopathic pulmonary fibrosis.

BackgroundIdiopathic pulmonary fibrosis (IPF) is a progressive, chronic interstitial lung disease that is unresponsive to current therapy and often leads to death. However, the rate of disease progression differs among patients. We hypothesized that comparing the gene expression profiles between patients with stable disease and those in which the disease progressed rapidly will lead to biomarker discovery and contribute to the understanding of disease pathogenesis.Methodology and Principal FindingsTo begin to address this hypothesis, we applied Serial Analysis of Gene Expression (SAGE) to generate lung expression profiles from diagnostic surgical lung biopsies in 6 individuals with relatively stable (or slowly progressive) IPF and 6 individuals with progressive IPF (based on changes in DLCO and FVC over 12 months). Our results indicate that this comprehensive lung IPF SAGE transcriptome is distinct from normal lung tissue and other chronic lung diseases. To identify candidate markers of disease progression, we compared the IPF SAGE profiles in stable and progressive disease, and identified a set of 102 transcripts that were at least 5-fold up regulated and a set of 89 transcripts that were at least 5-fold down regulated in the progressive group (P-value≤0.05). The over expressed genes included surfactant protein A1, two members of the MAPK-EGR-1-HSP70 pathway that regulate cigarette-smoke induced inflammation, and Plunc (palate, lung and nasal epithelium associated), a gene not previously implicated in IPF. Interestingly, 26 of the up regulated genes are also increased in lung adenocarcinomas and have low or no expression in normal lung tissue. More importantly, we defined a SAGE molecular expression signature of 134 transcripts that sufficiently distinguished relatively stable from progressive IPF.ConclusionsThese findings indicate that molecular signatures from lung parenchyma at the time of diagnosis could prove helpful in predicting the likelihood of disease progression or possibly understanding the biological activity of IPF.