Idiopathic pulmonary fibrosis (IPF) is a fibrosing interstitial lung disease associated with aging that is characterized by the histopathological pattern of usual interstitial pneumonia. Although an ...understanding of the pathogenesis of IPF is incomplete, recent advances delineating specific clinical and pathologic features of IPF have led to better definition of the molecular pathways that are pathologically activated in the disease. In this review we highlight several of these advances, with a focus on genetic predisposition to IPF and how genetic changes, which occur primarily in epithelial cells, lead to activation of profibrotic pathways in epithelial cells. We then discuss the pathologic changes within IPF fibroblasts and the extracellular matrix, and we conclude with a summary of how these profibrotic pathways may be interrelated.
Background The treatment of chronic hypersensitivity pneumonitis (cHP) often includes systemic oral corticosteroids, but the optimal pharmacologic management remains unclear. The morbidity associated ...with prednisone has motivated the search for alternative therapies. We aimed to determine the effect of treatment with mycophenolate mofetil (MMF) or azathioprine (AZA) on lung function in patients with cHP. Methods Patients with cHP treated with either MMF or AZA were retrospectively identified from four interstitial lung disease centers. Change in lung function before and after treatment initiation was analyzed using linear mixed-effects modeling (LMM), adjusting for age, sex, smoking history, and prednisone use. Results Seventy patients were included: 51 were treated with MMF and 19 with AZA. Median follow-up after treatment initiation was 11 months. Prior to treatment initiation, FVC and diffusion capacity of the lung for carbon monoxide (D lco ) % predicted were declining at a mean rate of 0.12% ( P < .001) and 0.10% ( P < .001) per month, respectively. Treatment with either MMF or AZA was not associated with improved FVC (0.5% at 1 year; P = .46) but was associated with a statistically significant improvement in D lco of 4.2% ( P < .001) after 1 year of treatment. Results were similar in the subgroup of patients treated with MMF for 1 year; the FVC increased nonsignificantly by 1.3% ( P = .103) and D lco increased by 3.9% ( P < .001). Conclusions Treatment with MMF or AZA is associated with improvements in D lco in patients with cHP. Prospective randomized trials are needed to validate their effectiveness for cHP.
The placenta is the interface between mother and fetus and inadequate function contributes to short and long-term ill-health. The placenta is absent from most large-scale RNA-Seq datasets. We ...therefore analyze long and small RNAs (~101 and 20 million reads per sample respectively) from 302 human placentas, including 94 cases of preeclampsia (PE) and 56 cases of fetal growth restriction (FGR). The placental transcriptome has the seventh lowest complexity of 50 human tissues: 271 genes account for 50% of all reads. We identify multiple circular RNAs and validate 6 of these by Sanger sequencing across the back-splice junction. Using large-scale mass spectrometry datasets, we find strong evidence of peptides produced by translation of two circular RNAs. We also identify novel piRNAs which are clustered on Chr1 and Chr14. PE and FGR are associated with multiple and overlapping differences in mRNA, lincRNA and circRNA but fewer consistent differences in small RNAs. Of the three protein coding genes differentially expressed in both PE and FGR, one encodes a secreted protein FSTL3 (follistatin-like 3). Elevated serum levels of FSTL3 in pregnant women are predictive of subsequent PE and FGR. To aid visualization of our placenta transcriptome data, we develop a web application ( https://www.obgyn.cam.ac.uk/placentome/ ).
Background Combined pulmonary fibrosis and emphysema (CPFE) is increasingly recognized, but its prevalence and prognosis remain unclear. We sought to determine the prevalence, clinical features, and ...prognosis of CPFE in idiopathic pulmonary fibrosis (IPF), using a standardized and reproducible definition. Methods Patients with IPF were identified from two ongoing cohorts. Two radiologists scored emphysema and fibrosis severity on high-resolution CT (HRCT) scans. CPFE was defined as ≥ 10% emphysema on HRCT scan. Clinical characteristics and outcomes of patients with CPFE and IPF and those with non-CPFE IPF were compared with unadjusted analysis and then analysis after adjustment for HRCT fibrosis score. Mortality was compared using competing risks regression to handle lung transplantation. Sensitivity analyses were performed using Cox proportional hazards, including time to death (transplantation censored) and time to death or transplant. Results CPFE criteria were met in 29 of 365 patients with IPF (8%), with high agreement between radiologists (κ = 0.74). Patients with CPFE had less fibrosis on HRCT scans and higher FVC, but greater oxygen requirements ( P ≤ .01 for all comparisons). Findings were maintained with adjustment for fibrosis severity. Inhaled therapies for COPD were used by 53% of patients with CPFE. There was no significant difference in mortality comparing patients with CPFE and IPF to those with non-CPFE IPF (hazard ratio, 1.14; 95% CI, 0.61-2.13; P = .69). Conclusions CPFE was identified in 8% of patients with IPF and is a distinct, clinical phenotype with potential therapies that remain underutilized. Patients with CPFE and IPF and those with non-CPFE IPF have similar mortality.
Agriculture is a major contributor to global greenhouse gas (GHG) emissions and must feature in efforts to reduce emissions. Organic farming might contribute to this through decreased use of farm ...inputs and increased soil carbon sequestration, but it might also exacerbate emissions through greater food production elsewhere to make up for lower organic yields. To date there has been no rigorous assessment of this potential at national scales. Here we assess the consequences for net GHG emissions of a 100% shift to organic food production in England and Wales using life-cycle assessment. We predict major shortfalls in production of most agricultural products against a conventional baseline. Direct GHG emissions are reduced with organic farming, but when increased overseas land use to compensate for shortfalls in domestic supply are factored in, net emissions are greater. Enhanced soil carbon sequestration could offset only a small part of the higher overseas emissions.
The ability of specific histopathologic features to predict mortality or lung transplantation in patients with chronic hypersensitivity pneumonitis (HP) is unknown.
Patients with chronic HP diagnosed ...by surgical lung biopsy were identified from an ongoing longitudinal cohort. The surgical lung biopsy slides were evaluated prospectively by an experienced thoracic pathologist using a standardized checklist to differentiate the major pathologic patterns and score the presence of specific histopathologic features. Cox proportional hazard analysis was used to identify independent predictors of transplant-free survival, and Kaplan-Meier analysis was used to visualize outcomes.
One hundred nineteen patients were identified. Patients with a fibrotic nonspecific interstitial pneumonia (f-NSIP) pattern, bronchiolocentric fibrosis (BF) pattern, or usual interstitial pneumonia (UIP) pattern had significantly worse transplant-free survival than did those with a cellular NSIP (c-NSIP) pattern or peribronchiolar inflammation with poorly formed granulomas (PI-PFG) pattern. No survival difference among patients with an f-NSIP pattern, a BF pattern, or a UIP pattern was found. Fibroblastic foci were identified in a subset of biopsy samples from all pathologic patterns. Peribronchiolar fibrosis was noted in all UIP cases. Independent predictors of time to death or transplantation included the presence of fibroblast foci or dense collagen fibrosis.
Histopathologic patterns of c-NSIP and PI-PFG had a better transplant-free survival than did patterns of UIP, f-NSIP, and BF. The presence of fibroblast foci or dense collagen fibrosis correlated with progression to death or lung transplantation. Identification of fibroblast foci on biopsy samples, regardless of the underlying histopathologic pattern, may be a clinically useful predictor of survival in patients with HP.
Background It is unknown if the radiographic fibrosis score predicts mortality in persistent hypersensitivity pneumonitis (HP) and if survival is similar to that observed in idiopathic pulmonary ...fibrosis (IPF) when adjusting for the extent of radiographic fibrosis. Methods We reviewed records from 177 patients with HP and 224 patients with IPF whose diagnoses were established by multidisciplinary consensus. Two thoracic radiologists scored high-resolution CT (HRCT) scan lung images. Independent predictors of transplant-free survival were determined using a Cox proportional hazards analysis. Kaplan-Meier survival curves were constructed, stratified by disease as well as fibrosis score. Results HRCT scan fibrosis score and radiographic reticulation independently predicted time to death or lung transplantation. Clinical predictors included a history of cigarette smoking, auscultatory crackles on lung examination, baseline FVC, and FEV1 /FVC ratio. The majority of HP deaths occurred in patients with both radiographic reticulation and auscultatory crackles on examination, compared with patients with only one of these manifestations ( P < .0001). Patients with IPF had worse survival than those with HP at any given degree of radiographic fibrosis (hazard ratio 2.31; P < .01). Conclusions Survival in patients with HP was superior to that of those with IPF with similar degrees of radiographic fibrosis. The combination of auscultatory crackles and radiographic reticulation identified patients with HP who had a particularly poor outcome.
Pathologic features of idiopathic pulmonary fibrosis (IPF) include genetic predisposition, activation of the unfolded protein response, telomere attrition, and cellular senescence. The mechanisms ...leading to alveolar epithelial cell (AEC) senescence are poorly understood. MicroRNAs (miRNAs) have been reported as regulators of cellular senescence. Senescence markers including p16, p21, p53, and senescence-associated β-galactosidase (SA-βgal) activity were measured in type II AECs from IPF lungs and unused donor lungs. miRNAs were quantified in type II AECs using gene expression arrays and quantitative RT-PCR. Molecular markers of senescence (p16, p21, and p53) were elevated in IPF type II AECs. SA-βgal activity was detected in a greater percentage in type II AECs isolated from IPF patients (23.1%) compared to patients with other interstitial lung diseases (1.2%) or normal controls (0.8%). The relative levels of senescence-associated miRNAs miR-34a, miR-34b, and miR-34c, but not miR-20a, miR-29c, or miR-let-7f were significantly higher in type II AECs from IPF patients. Overexpression of miR-34a, miR-34b, or miR-34c in lung epithelial cells was associated with higher SA-βgal activity (27.8%, 35.1%, and 38.2%, respectively) relative to control treated cells (8.8%). Targets of miR-34 miRNAs, including E2F1, c-Myc, and cyclin E2, were lower in IPF type II AECs. These results show that markers of senescence are uniquely elevated in IPF type II AECs and suggest that the miR-34 family of miRNAs regulate senescence in IPF type II AECs.
The aim of this study was to determine the prevalence, characteristics and outcomes of patients with unclassifiable interstitial lung disease (ILD) and to develop a simple method of predicting ...disease behaviour. Unclassifiable ILD patients were identified from an ongoing longitudinal cohort. Unclassifiable ILD was diagnosed after a multidisciplinary review did not secure a specific ILD diagnosis. Clinical characteristics and outcomes were compared with idiopathic pulmonary fibrosis (IPF) and non-IPF ILDs. Independent predictors of mortality were determined using Cox proportional-hazards analysis to identify subgroups with distinct disease behaviour. Unclassifiable ILD was diagnosed in 10% of the ILD cohort (132 out of 1370 patients). The most common reason for being unclassifiable was missing histopathological assessment due to a high risk of surgical lung biopsy. Demographic and physiological features of unclassifiable ILD were intermediate between IPF and non-IPF disease controls. Unclassifiable ILD had longer survival rates when compared to IPF on adjusted analysis (hazard ratio 0.62, p = 0.04) and similar survival compared to non-IPF ILDs (hazard ratio 1.54, p = 0.12). Independent predictors of survival in unclassifiable ILD included diffusion capacity of the lung for carbon monoxide (p = 0.001) and a radiological fibrosis score (p = 0.02). Unclassifiable ILD represents approximately 10% of ILD cases and has a heterogeneous clinical course, which can be predicted using clinical and radiological variables.
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