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RationaleAsymptomatic relatives of patients with familial interstitial pneumonia (FIP), the inherited form of idiopathic interstitial pneumonia, carry increased risk for developing interstitial lung disease.ObjectivesStudying these at-risk individuals provides a unique opportunity to investigate early stages of FIP pathogenesis and develop predictive models of disease onset.MethodsSeventy-five asymptomatic first-degree relatives of FIP patients (mean age, 50.8 yr) underwent blood sampling and high-resolution 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 resultsEleven 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.ConclusionsEvidence 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.

Recent evidence suggests that dysfunctional type II alveolar epithelial cells (AECs) contribute to the pathogenesis of idiopathic pulmonary fibrosis (IPF). Based on the hypothesis that disease-causing mutations in surfactant protein C (SFTPC) provide an important paradigm for studying IPF, we investigated a potential mechanism of AEC dysfunction suggested to result from mutant SFTPC expression: induction of endoplasmic reticulum (ER) stress and the unfolded protein response (UPR). We evaluated biopsies from 23 IPF patients (including 3 family members with L188Q SFTPC mutations, 10 individuals with familial interstitial pneumonia without SFTPC mutations, and 10 individuals with sporadic IPF) and sections from 10 control lungs. After demonstrating UPR activation in cultured A549 cells expressing mutant SFTPC, we identified prominent expression of UPR markers in AECs in the lungs of patients with SFTPC mutation-associated fibrosis. In individuals with familial interstitial pneumonia without SFTPC mutations and patients with sporadic IPF, we also found UPR activation selectively in AECs lining areas of fibrotic remodeling. Because herpesviruses are found frequently in IPF lungs and can induce ER stress, we investigated expression of viral proteins in lung biopsies. Herpesvirus protein expression was found in AECs from 15/23 IPF patients and colocalized with UPR markers in AECs from these patients. ER stress and UPR activation are found in the alveolar epithelium in patients with IPF and could contribute to disease progression. Activation of these pathways may result from altered surfactant protein processing or chronic herpesvirus infection. lung; surfactant protein C; usual interstitial pneumonia; unfolded protein response

Chronic inflammation is linked to carcinogenesis in several organ systems. In the lungs, NF-[kappa]B, a central effector of inflammatory responses, is frequently activated in non-small-cell lung cancer, but its role in tumor promotion has not been studied. Several lines of evidence indicate that ethyl carbamate (urethane)-induced lung tumor formation, a prototypical mouse model of multistage lung carcinogenesis, is potentiated by inflammation. We found that mouse strains susceptible to lung tumor formation (FVB, BALB/c) exhibited early NF-[kappa]B activation and inflammation in the lungs after urethane treatment. However, a resistant strain (C57B6) failed to activate NF-[kappa]B or induce lung inflammation. In FVB mice, we identified urethane-induced NF-[kappa]B activation in airway epithelium, as well as type II alveolar epithelial cells and macrophages. Using an inducible transgenic mouse model (FVB strain) to express a dominant inhibitor of NF-[kappa]B specifically in airway epithelial cells, we found that urethane-induced lung inflammation was blocked and tumor formation was reduced by >50%. Selective NF-[kappa]B inhibition resulted in increased apoptosis of airway epithelial cells at 2 weeks after urethane treatment in association with a marked reduction of Bcl-2 expression. These studies indicate that NF-[kappa] apoptosis | cancer | inflammation | airway | adenocarcinoma

Pleural inflammation underlies many pleural diseases, but its pathogenesis remains unclear. Proteinase-activated receptor-2 ([PAR.sub.2]) is a novel seven-transmembrane receptor with immunoregulatory roles. We hypothesized that [PAR.sub.2] is present on mesothelial cells and can induce pleural inflammation. [PAR.sub.2] was detected by immunohistochemistry in all (19 parietal and 11 visceral) human pleural biopsies examined. In cultured murine mesothelial cells, a specific [PAR.sub.2]-activating peptide (SLIGRL-N[H.sub.2]) at 10, 100, and 1,000 [micro]M stimulated a 3-, 42-, and 1,330-fold increase of macrophage inflammatory protein (MIP)-2 release relative to medium control, respectively (P < 0.05 all) and a 2-, 32-, and 75-fold rise over the control peptide (LSIGRL-N[H.sub.2], P < 0.05 all). A similar pattern was seen for TNF-[alpha] release. Known physiological activators of [PAR.sub.2], tryptase, trypsin, and coagulation factor Xa, also stimulated dose-dependent MIP-2 release from mesothelial cells in vitro. Dexamethasone inhibited the [PAR.sub.2]-mediated MIP-2 release in a dose-dependent manner. In vivo, pleural fluid MIP-2 levels in C57BL/6 mice injected intrapleurally with SLIGRL-[NH.sub.2] (10 mg/kg) were significantly higher than in mice injected with LSIGRL-[NH.sub.2] or PBS (2,710 [+ or -] 165 vs. 880 [+ or -] 357 vs. 88 [+ or -] 46 pg/ml respectively; P < 0.001). Pleural fluid neutrophil counts were higher in SLIGRL-[NH.sub.2] group than in the LSIGRL-[NH.sub.2] and PBS groups (by 40- and 26-fold, respectively; P < 0.05). This study establishes that activation of mesothelial cell [PAR.sub.2] potently induces the release of inflammatory cytokines in vitro and neutrophil recruitment into the pleural cavity in vivo. proteinase-activated receptor; pleura

We investigated the requirement for tumor necrosis factor-[alpha], (TNF-[alpha]) and interleukin (IL)-1 receptors in the pathogenesis of the pulmonary and hepatic responses to Escherichia coli lipopolysaccharide (LPS) by studying wild-type mice and mice deficient in TNF type 1 receptor [TNFR1 knockout (KO)] or both TNF type 1 and IL-1 receptors (TNFR1/IL-1R KO). In lung tissue, NF-[kappa]B activation was similar among the groups after exposure to aerosolized LPS. After intraperitoneal injection of LPS, NF-[kappa]B activation in liver was attenuated in TNFR1 KO mice and further diminished in TNFR1/IL-1R KO mice; however, in lung tissue, no impairment in NF-[kappa]B activation was found in TNFR1 KO mice and only a modest decrease was found in TNFR1/IL-1R KO mice. Lung concentrations of KC and macrophage-inflammatory peptide 2 were lower in TNFR1 KO and TNFR1/IL-1R KO mice after aerosolized and intraperitoneal LPS. We conclude that LPS-induced NF-[kappa]B activation in liver is mediated through TNF-[alpha]- and IL-1 receptor-dependent pathways, but, in the lung, LPS-induced NF-[kappa]B activation is largely independent of these receptors. sepsis; macrophage; neutrophil; cytokines; chemokines

Author(s): Hong-Bo Xin [1, 3]; Takaaki Senbonmatsu [2]; Dong-Sheng Cheng [1]; Yong-Xiao Wang [3]; Julio A. Copello [1]; Guang-Ju Ji [3]; Mei Lin Collier [4]; Ke-Yu Deng [3]; Loice H. [...]