The Genetic Landscape of Familial Pulmonary Fibrosis.

Up to 20% of idiopathic interstitial lung disease is familial, referred to as familial pulmonary fibrosis (FPF). An integrated analysis of FPF genetic risk was performed by comprehensively evaluating for genetic rare variants (RVs) in a large cohort of FPF kindreds. Whole-exome sequencing and/or candidate gene sequencing from affected individuals in 569 FPF kindreds was performed, followed by cosegregation analysis in large kindreds, gene burden analysis, gene-based risk scoring, cell-type enrichment analysis, and coexpression network construction.

Incidence and Progression of Fibrotic Lung Disease in an At-Risk Cohort.

Relatives of patients with familial interstitial pneumonia (FIP) are at increased risk for pulmonary fibrosis and develop preclinical pulmonary fibrosis (PrePF). We defined the incidence and progression of new-onset PrePF and its relationship to survival among first-degree relatives of families with FIP. This is a cohort study of family members with FIP who were initially screened with a health questionnaire and chest high-resolution computed tomography (HRCT) scan, and approximately 4 years later, the evaluation was repeated.

The Association between Exposures and Disease Characteristics in Familial Pulmonary Fibrosis.

Heterogeneous characteristics are observed in familial pulmonary fibrosis (FPF), suggesting that nongenetic factors contribute to disease manifestations. To determine the relationship between environmental exposures and disease characteristics of FPF, including the morphological characteristics on chest computed tomography (CT) scan, and timing of FPF symptom onset, lung transplantation, or death. Subjects with FPF with an exposure questionnaire and chest CT were selected from a prospective cohort at Vanderbilt.

Case series of pediatric mediastinal granuloma related to histoplasmosis.

Introduction: Mediastinal granuloma (MG) is a postinfectious complication of histoplasmosis that remains a rare diagnosis in the pediatric literature. This case series presents a well phenotyped population to further characterize this disease process.

Methods: Thirty cases of MG in children under 21 years-of-age presenting over a 16-year period were retrospectively analyzed.

Postdeployment Respiratory Syndrome in Soldiers With Chronic Exertional Dyspnea.

After deployment to Southwest Asia, some soldiers develop persistent respiratory symptoms, including exercise intolerance and exertional dyspnea. We identified 50 soldiers with a history of deployment to Southwest Asia who presented with unexplained dyspnea and underwent an unrevealing clinical evaluation followed by surgical lung biopsy. Lung tissue specimens from 17 age-matched, nonsmoking subjects were used as controls.

A Phase I Randomized, Controlled, Clinical Trial of Valganciclovir in Idiopathic Pulmonary Fibrosis.

Human herpesviruses Epstein-Barr virus and cytomegalovirus are frequently detectable in the lungs of patients with idiopathic pulmonary fibrosis (IPF) and could contribute to disease pathogenesis. With the goal of inhibiting herpesvirus replication, we tested the safety and tolerability of adding valganciclovir to standard IPF therapy (pirfenidone). We performed a single-center, Phase I, double-blind, randomized, placebo-controlled trial comparing valganciclovir 900 mg daily with placebo in patients with IPF with serologic evidence of prior Epstein-Barr virus and/or cytomegalovirus infection who were tolerating full-dose pirfenidone (2,403 mg/d).

CD4CTLs in Fibrosing Mediastinitis Linked to .

Although fibrotic disorders are frequently assumed to be linked to T cells, quantitative tissue interrogation studies have rarely been performed to establish this link and certainly many fibrotic diseases do not fall within the type 2/allergic disease spectrum. We have previously linked two human autoimmune fibrotic diseases, IgG4-related disease and systemic sclerosis, to the clonal expansion and lesional accumulation of CD4CTLs. In both these diseases T cell accumulation was found to be sparse.

Expression of a Human Caveolin-1 Mutation in Mice Drives Inflammatory and Metabolic Defect-Associated Pulmonary Arterial Hypertension.

In 2012, mutations in Cav1 were found to be the driving mutation in several cases of heritable pulmonary arterial hypertension (PAH). These mutations replaced the last 21 amino acids of Cav1 with a novel 22-amino-acid sequence. Because previously only Cav1 knockouts had been studied in the context of PAH, examining the effects of this novel mutation holds promise for new understanding of the role of Cav1 in disease etiology.

Single-cell RNA sequencing reveals profibrotic roles of distinct epithelial and mesenchymal lineages in pulmonary fibrosis.

Pulmonary fibrosis (PF) is a form of chronic lung disease characterized by pathologic epithelial remodeling and accumulation of extracellular matrix (ECM). To comprehensively define the cell types, mechanisms, and mediators driving fibrotic remodeling in lungs with PF, we performed single-cell RNA sequencing of single-cell suspensions from 10 nonfibrotic control and 20 PF lungs. Analysis of 114,396 cells identified 31 distinct cell subsets/states.

Sex hormone exposure and reproductive factors in pulmonary arterial hypertension: a case-control study.

Pulmonary arterial hypertension (PAH) is a sexually dimorphic disease that for unknown reasons affects women more than men. The role of estrogens, both endogenous and exogenous, and reproductive factors in this female susceptibility is still poorly understood. It has been strongly suggested that sex hormones may influence the development and progression of the disease.

Development and Progression of Radiologic Abnormalities in Individuals at Risk for Familial Interstitial Lung Disease.

The preclinical natural history of progressive lung fibrosis is poorly understood. Our goals were to identify risk factors for interstitial lung abnormalities (ILA) on high-resolution computed tomography (HRCT) scans and to determine progression toward clinical interstitial lung disease (ILD) among subjects in a longitudinal cohort of self-reported unaffected first-degree relatives of patients with familial interstitial pneumonia. Enrollment evaluation included a health history and exposure questionnaire and HRCT scans, which were categorized by visual assessment as no ILA, early/mild ILA, or extensive ILA.

Current Concepts in the Epidemiology, Diagnosis, and Management of Histoplasmosis Syndromes.

Histoplasmosis is a global disease endemic to regions of all six inhabited continents. The areas of highest endemicity lie within the Mississippi and Ohio River Valleys of North America and parts of Central and South America. As a result of climate change and anthropogenic land utilization, the conditions suitable for are changing, leading to a corresponding change in epidemiology.

variant is associated with visually and quantitatively detected preclinical pulmonary fibrosis.

Background: Relatives of patients with familial interstitial pneumonia (FIP) are at increased risk for pulmonary fibrosis. We assessed the prevalence and risk factors for preclinical pulmonary fibrosis (PrePF) in first-degree relatives of patients with FIP and determined the utility of deep learning in detecting PrePF on CT.

Methods: First-degree relatives of patients with FIP over 40 years of age who believed themselves to be unaffected by pulmonary fibrosis underwent CT scans of the chest.

Resequencing Study Confirms That Host Defense and Cell Senescence Gene Variants Contribute to the Risk of Idiopathic Pulmonary Fibrosis.

Several common and rare genetic variants have been associated with idiopathic pulmonary fibrosis, a progressive fibrotic condition that is localized to the lung. To develop an integrated understanding of the rare and common variants located in multiple loci that have been reported to contribute to the risk of disease. We performed deep targeted resequencing (3.

Genetics and genomics of pulmonary arterial hypertension.

Since 2000 there have been major advances in our understanding of the genetic and genomics of pulmonary arterial hypertension (PAH), although there remains much to discover. Based on existing knowledge, around 25-30% of patients diagnosed with idiopathic PAH have an underlying Mendelian genetic cause for their condition and should be classified as heritable PAH (HPAH). Here, we summarise the known genetic and genomic drivers of PAH, the insights these provide into pathobiology, and the opportunities afforded for development of novel therapeutic approaches.

FHIT, a Novel Modifier Gene in Pulmonary Arterial Hypertension.

Rationale: Pulmonary arterial hypertension (PAH) is characterized by progressive narrowing of pulmonary arteries, resulting in right heart failure and death. BMPR2 (bone morphogenetic protein receptor type 2) mutations account for most familial PAH forms whereas reduced BMPR2 is present in many idiopathic PAH forms, suggesting dysfunctional BMPR2 signaling to be a key feature of PAH. Modulating BMPR2 signaling is therapeutically promising, yet how BMPR2 is downregulated in PAH is unclear.

A potential therapeutic role for angiotensin-converting enzyme 2 in human pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) is a deadly disease with no cure. Alternate conversion of angiotensin II (AngII) to angiotensin-(1-7) (Ang-(1-7)) by angiotensin-converting enzyme 2 (ACE2) resulting in Mas receptor (Mas1) activation improves rodent models of PAH. Effects of recombinant human (rh) ACE2 in human PAH are unknown.

Time for a change: is idiopathic pulmonary fibrosis still idiopathic and only fibrotic?

Idiopathic pulmonary fibrosis (IPF) is a progressive, irreversible, and typically fatal lung disease characterised by subpleural fibrosis, subepithelial fibroblast foci, and microscopic honeycombing. Although understanding of the pathogenic mechanisms continues to evolve, evidence indicates that distal airway and alveolar epithelial cells are central drivers of the disease. In this Viewpoint, we review the history of naming and classifications used to define the disease now referred to as IPF, in the context of understanding the clinical presentation, causes, and pathogenesis of the disease.

Genetics of Pulmonary Arterial Hypertension.

Tremendous progress has been made in understanding the genetics of pulmonary arterial hypertension (PAH) since its description in the 1950s as a primary disorder of the pulmonary vasculature. Heterozygous germline mutations in the gene coding bone morphogenetic receptor type 2 (BMPR2) are detectable in the majority of cases of heritable PAH, and in approximately 20% of cases of idiopathic pulmonary arterial hypertension (IPAH). However, recent advances in gene discovery methods have facilitated the discovery of additional genes with mutations among those with and without familial PAH.

A disease-associated frameshift mutation in caveolin-1 disrupts caveolae formation and function through introduction of a de novo ER retention signal.

Caveolin-1 (CAV1) is an essential component of caveolae and is implicated in numerous physiological processes. Recent studies have identified heterozygous mutations in the gene in patients with pulmonary arterial hypertension (PAH), but the mechanisms by which these mutations impact caveolae assembly and contribute to disease remain unclear. To address this question, we examined the consequences of a familial PAH-associated frameshift mutation in , P158PfsX22, on caveolae assembly and function.

Oestrogen inhibition reverses pulmonary arterial hypertension and associated metabolic defects.

Increased oestrogen is a strong epidemiological risk factor for development of pulmonary arterial hypertension (PAH) in patients, associated with metabolic defects. In addition, oestrogens drive penetrance in mice carrying mutations in bone morphogenetic protein receptor type II (BMPR2), the cause of most heritable PAH. The goal of the present study was to determine whether inhibition of oestrogens was effective in the treatment of PAH in these mice.