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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

Familial forms of human pulmonary arterial hypertension (FPAH) have been linked to mutations in bone morphogenetic protein (BMP) type II receptors (BMPR2s), yet the downstream targets of these receptors remain obscure. Here we show that pulmonary vascular lesions from patients harboring BMPR2 mutations express high levels of tenascin-C (TN-C), an extracellular matrix glycoprotein that promotes pulmonary artery (PA) smooth muscle cell (SMC) proliferation. To begin to define how TN-C is regulated, PA SMCs were cultured from normal subjects and from those with FPAH due to BMPR2 mutations. FPAH SMCs expressed higher levels of TN-C than normal SMCs. Similarly, expression of Prxl, a factor that drives TN-C transcription, was elevated in FPAH vascular lesions and SMCs derived thereof. Furthermore, Prxl and TN-C promoter activities were significantly higher in FPAH vs. normal SMCs. To delineate how BMPR2s control TN-C, we focused on receptor (R)-Smads, downstream effectors activated by wild-type BMPR2s. Nuclear localization and phosphorylation of R-Smads was greater in normal vs. FPAH SMCs. As well, indirect blockade of R-Smad signaling with a kinase-deficient BMP receptor Ib upregulated TN-C in normal SMCs. Because ERK1/2 MAPKs inhibit the transcriptional activity of R-Smads, and because ERK1/2 promotes TN-C transcription, we determined whether ERK1/2 inhibits R-Smad signaling in FPAH SMCs and whether this activity is required for TN-C transcription. Indeed, ERK1/2 activity was greater in FPAH SMCs, and inhibition of ERK1/2 resulted in nuclear localization of R-Smads and inhibition of TN-C. These studies define a novel signaling network relevant to PAH underscored by BMPR2 mutations. pulmonary hypertension; bone morphogenetic protein receptors; extracellular matrix

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

Many cases of primary pulmonary hypertension may be genetic, according to a study of 67 families over a 20-year period. A mutation in the gene for bone morphogenetic protein receptor II was found in several family members with the disease.

The article describes the coding sequences of nested genes kil and eta and prevention of transcription termination by their translation. Bacteriophage P4 immunity control and the effect of kil expression on a bacterial host are examined.

Abstract Background Studies in multiple organ systems have shown cross-talk between signaling through the bone morphogenetic protein receptor type 2 (BMPR2) and estrogen pathways. In humans, pulmonary arterial hypertension (PAH) has a female predominance, and is associated with decreased BMPR2 expression. The goal of this study was to determine if estrogens suppress BMPR2 expression. Methods A variety of techniques were utilized across several model platforms to evaluate the relationship between estrogens and BMPR2 gene expression. We used quantitative RT-PCR, gel mobility shift, and luciferase activity assays in human samples, live mice, and cell culture. Results BMPR2 expression is reduced in lymphocytes from female patients compared with male patients, and in whole lungs from female mice compared with male mice. There is an evolutionarily conserved estrogen receptor binding site in the BMPR2 promoter, which binds estrogen receptor by gel-shift assay. Increased exogenous estrogen decreases BMPR2 expression in cell culture, particularly when induced to proliferate. Transfection of increasing quantities of estrogen receptor alpha correlates strongly with decreasing expression of BMPR2. Conclusions BMPR2 gene expression is reduced in females compared to males in live humans and in mice, likely through direct estrogen receptor alpha binding to the BMPR2 promoter. This reduced BMPR2 expression may contribute to the increased prevalence of PAH in females.