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.

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Expression of mutant surfactant protein C (SFTPC) results in endoplasmic reticulum (ER) stress in type II alveolar epithelial cells (AECs). AECs have been implicated as a source of lung fibroblasts via epithelial-to-mesenchymal transition (EMT); therefore, we investigated whether ER stress contributes to EMT as a possible mechanism for fibrotic remodeling. ER stress was induced by tunicamyin administration or stable expression of mutant (L188Q) SFTPC in type II AEC lines. Both tunicamycin treatment and mutant SFTPC expression induced ER stress and the unfolded protein response. With tunicamycin or mutant SFTPC expression, phase contrast imaging revealed a change to a fibroblast-like appearance. During ER stress, expression of epithelial markers E-cadherin and Zonula occludens-1 decreased while expression of mesenchymal markers S100A4 and ␣-smooth muscle actin increased. Following induction of ER stress, we found activation of a number of pathways, including MAPK, Smad, ␤-catenin, and Src kinase. Using specific inhibitors, the combination of a Smad2/3 inhibitor (SB431542) and a Src kinase inhibitor (PP2) blocked EMT with maintenance of epithelial appearance and epithelial marker expression. Similar results were noted with siRNA targeting Smad2 and Src kinase. Together, these studies reveal that induction of ER stress leads to EMT in lung epithelial cells, suggesting possible crosstalk between Smad and Src kinase pathways. Dissecting pathways involved in ER stress-induced EMT may lead to new treatment strategies to limit fibrosis. Idiopathic pulmonary fibrosis (IPF)3 is a fatal lung disease characterized by extensive architectural distortion and progressive parenchymal fibrosis. A substantial body of work supports the concept that alveolar epithelial cells (AECs) play an essential role in the development of IPF, but the specific mechanisms linking AECs to lung fibrosis are not well understood (1). Genetic studies have indicated that mutations in the gene encoding surfactant protein C (SFTPC) can lead to familial interstitial pneumonia, which is the familial form of IPF (2, 3). Mutations in the carboxyl terminal region of the gene result in a product that cannot be processed normally in type II AECs, leading to accumulation of misfolded prosurfactant protein C in the endoplasmic reticulum (ER), ER stress, and activation of the unfolded protein response (UPR) (4). In addition, our group and others (5, 6) have reported that ER stress and UPR activation are found in the alveolar epithelium in lung biopsies from patients with familial interstitial pneumonia in the absence of SFTPC mutation as well as sporadic IPF. Taken together, available data indicate that ER stress may be important in the pathogenesis of IPF; however, the means by which ER stress contributes to lung fibrosis is not currently identified.With ER stress, UPR pathways are activated as a means to help the cell abrogate the untoward effects of protein accumulation in the ER. The three arms of the UPR include processes designed to attenuate protein transla...

PAGE 30974:The same Western blot images were mistakenly used to represent phosphorylated eIF2␣ (peIF2␣) in both RLE6TN cells that had not been transfected (Fig. 1B) and in cells that had been transfected with empty vector or with vectors expressing wild type or mutant surfactant protein C (Fig. 1C). The correct Western blot image for phosphorylated eIF2␣ in transfected cells that we have obtained from a new experiment is shown in the revised Fig. 1C. This change does not affect the interpretation of the results or the conclusions of this work.