Extensive Phenotyping of Individuals at Risk for Familial Interstitial Pneumonia Reveals Clues to the Pathogenesis of Interstitial Lung Disease

Abstract

Rationale: Asymptomatic relatives of patients with familial interstitial pneumonia (FIP), the inherited form of idiopathic interstitial pneumonia, carry increased risk for developing interstitial lung disease.Objectives: Studying these at-risk individuals provides a unique opportunity to investigate early stages of FIP pathogenesis and develop predictive models of disease onset.Methods: Seventy-five asymptomatic first-degree relatives of FIP patients (mean age, 50.8 yr) underwent blood sampling and highresolution chest computed tomography (HRCT) scanning in an ongoing cohort study; 72 consented to bronchoscopy with bronchoalveolar lavage (BAL) and transbronchial biopsies. Twenty-seven healthy individuals were used as control subjects.Measurements and Main Results: Eleven of 75 at-risk subjects (14%) had evidence of interstitial changes by HRCT, whereas 35.2% had abnormalities on transbronchial biopsies. No differences were noted in inflammatory cells in BAL between at-risk individuals and control subjects. At-risk subjects had increased herpesvirus DNA in cell-free BAL and evidence of herpesvirus antigen expression in alveolar epithelial cells (AECs), which correlated with expression of endoplasmic reticulum stress markers in AECs. Peripheral blood mononuclear cell and AEC telomere length were shorter in at-risk individuals than healthy control subjects. The minor allele frequency of the Muc5B rs35705950 promoter polymorphism was increased in at-risk subjects. Levels of several plasma biomarkers differed between at-risk subjects and control subjects, and correlated with abnormal HRCT scans.Conclusions: Evidence of lung parenchymal remodeling and epithelial dysfunction was identified in asymptomatic individuals at risk for FIP. Together, these findings offer new insights into the early pathogenesis of idiopathic interstitial pneumonia and provide an ongoing opportunity to characterize presymptomatic abnormalities that predict progression to clinical disease.

Management of suspected monogenic lung fibrosis in a specialised centre

“…Systematic high-resolution chest CT performed in asymptomatic members of families with FPF revealed ILD in 14-25% [2,16,25]. The most commonly observed anomalies were thickening of septal lines, peribronchovascular thickening, subpleural reticular opacities and ground-glass opacities [2,16,25].…”

“…The most commonly observed anomalies were thickening of septal lines, peribronchovascular thickening, subpleural reticular opacities and ground-glass opacities [2,16,25].…”

“…Transbronchial biopsies from 71 asymptomatic relatives of FPF patients presented histological abnormalities in 26 (36.6%), including interstitial fibrosis (n=12, 16.9%), peribronchiolar fibrosis (n=15, 21.1%), chronic inflammation (n=10, 14.1%), respiratory bronchiolitis (n=2, 2.8%) or granulomas (n=6, 8.5%) [2].…”

“…A genetic predisposition to interstitial lung disease (ILD) is suggested by a 10-fold increase in the prevalence of the disease in families of patients with a diagnosis of idiopathic pulmonary fibrosis (IPF) [1,2]. Genetic studies of familial forms of ILD led to the discovery of mutations in genes implicated in telomere homeostasis (TERT, TERC, RTEL1, PARN, DKC1, TINF2 and NAF1) or surfactant homeostasis (SFTPC, ABCA3 and NFKX2-1) or associated with complex syndromes (COPA, TMEM173, HPS-1 to HPS-8, NF1, FAM111B, NDUFAF6 and GATA2) (table 1 and figure 1) [3][4][5][6][7][8][9][10][11].…”

Mitochondria in the spotlight of aging and idiopathic pulmonary fibrosis

“…Changes in proteostasis lead to an increase of nonfunctional proteins, accumulation of cytotoxic proteins, and/or aggregation of misfolded proteins. In IPF lungs, evidence of altered proteostasis has been found at different levels, including protein misfolding, markers of ER stress (99)(100)(101)(102), defective autophagy, and impaired proteasome activity (103,104) (Table 4). For instance, familial pulmonary fibrosis is associated with several mutations in surfactant A and C genes (105)(106)(107)(108).…”