Although airway epithelial cells provide important barrier and host defense functions, a crucial role for these cells in development of acute lung inflammation and injury has not been elucidated. We investigated whether NF-κB pathway signaling in airway epithelium could decisively impact inflammatory phenotypes in the lungs by using a tetracycline-inducible system to achieve selective NF-κB activation or inhibition in vivo. In transgenic mice that express a constitutively active form of IκB kinase 2 under control of the epithelial-specific CC10 promoter, treatment with doxycycline induced NF-κB activation with consequent production of a variety of proinflammatory cytokines, high-protein pulmonary edema, and neutrophilic lung inflammation. Continued treatment with doxycycline caused progressive lung injury and hypoxemia with a high mortality rate. In contrast, inducible expression of a dominant inhibitor of NF-κB in airway epithelium prevented lung inflammation and injury resulting from expression of constitutively active form of IκB kinase 2 or Escherichia coli LPS delivered directly to the airways or systemically via an osmotic pump implanted in the peritoneal cavity. Our findings indicate that the NF-κB pathway in airway epithelial cells is critical for generation of lung inflammation and injury in response to local and systemic stimuli; therefore, targeting inflammatory pathways in airway epithelium could prove to be an effective therapeutic strategy for inflammatory lung diseases.
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.
Characteristics of early and late effusions differ significantly, suggesting a different pathogenesis of the effusions. Patients who develop a symptomatic pleural effusion after CABG should undergo a therapeutic thoracentesis; however, further investigations are warranted only in patients who have pleural fluid characteristics different from those described.
NF-kB is a critical transcription factor for the production of many inflammatory cytokines. It is activated in the airway epithelium of human asthmatics and in mice after allergic stimulation. To examine the role of NF-kB activation in allergic inflammation we generated transgenic mouse lines that allowed for the inducible stimulation of NF-kB in airway epithelial cells. After allergic sensitization with ovalbumin and alum, mice were challenged daily with ovalbumin aerosols and NF-kB was activated in airway epithelium by administration of doxycycline. Enhancement of airway epithelial NF-kB expression alone did not lead to increased airway responsiveness to methacholine. However induction of epithelial NF-kB during allergic inflammation caused airway hyperresponsiveness, increased airway neutrophilic and lymphocytic inflammation and goblet cell hyperplasia. Accompanying the exaggerated inflammation was an increase in the cytokines, G-CSF, IL-15, and KC. Interestingly, the counter regulatory interleukin, IL-10, was suppressed by NF-kB activation. The epithelial NF-kB dependent modulation of these cytokines provides a plausible explanation for the increased inflammation seen with overexpression of NF-kB. Modulation of airway epithelial NF-kB activation enhances the airway hyperresponsiveness and mucus secretion found in the mouse lung during allergic inflammation. NF-kB represents a potential target for pharmacologic intervention in human asthma.
Pleural inflammation underlies many pleural diseases, but its pathogenesis remains unclear. Proteinaseactivated receptor-2 (PAR 2) is a novel seven-transmembrane receptor with immunoregulatory roles. We hypothesized that PAR 2 is present on mesothelial cells and can induce pleural inflammation. PAR 2 was detected by immunohistochemistry in all (19 parietal and 11 visceral) human pleural biopsies examined. In cultured murine mesothelial cells, a specific PAR 2-activating peptide (SLIGRL-NH2) at 10, 100, and 1,000 M stimulated a 3-, 42-, and 1,330-fold increase of macrophage inflammatory protein (MIP)-2 release relative to medium control, respectively (P Ͻ 0.05 all) and a 2-, 32-, and 75-fold rise over the control peptide (LSIGRL-NH 2, P Ͻ 0.05 all). A similar pattern was seen for TNF-␣ release. Known physiological activators of PAR 2, tryptase, trypsin, and coagulation factor Xa, also stimulated dosedependent MIP-2 release from mesothelial cells in vitro. Dexamethasone inhibited the PAR 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 2 (10 mg/kg) were significantly higher than in mice injected with LSIGRL-NH 2 or PBS (2,710 Ϯ 165 vs. 880 Ϯ 357 vs. 88 Ϯ 46 pg/ml, respectively; P Ͻ 0.001). Pleural fluid neutrophil counts were higher in SLIGRL-NH 2 group than in the LSIGRL-NH2 and PBS groups (by 40-and 26-fold, respectively; P Ͻ 0.05). This study establishes that activation of mesothelial cell PAR 2 potently induces the release of inflammatory cytokines in vitro and neutrophil recruitment into the pleural cavity in vivo.proteinase-activated receptor; pleura THE PLEURAL SPACE IS INVADED by pathogens from time to time.
We present an independent assessment of the health and water sustainability of the East River (Dongjiang) in South China, which is the source of nearly 80% of Hong Kong's water supply. Field measurements show that the water quality in the upper and middle reaches is generally good and well exceeds the drinking quality standard, with high bio-diversity. The streamflow of the East River Basin is satisfactorily simulated using both the distributed MIKE-SHE model and the lumped HSPF model. With an average streamflow of 760 m3/s, the River is able to satisfy the current water demand. Using the HSPF model, the water quality is found to have deteriorated in recent years. In addition to water supply, the River also supports a variety of needs such as hydro-power generation, waste assimilation, navigation, habitat for aquatic life, and expulsion of sea water intrusion. Using the projected need of 150 m3/s for water supply, the instream flow requirement based on hydrological and water quality simulation is estimated to be 467 m3/s in 2010. This suggests that the water sustainability of the East River requires alternative strategies, which may include integrated water resources management, provision of better wastewater treatment, and water and soil conservation.
In Fluent, the 3-D RNG k–ε mathematical model is employed to compute water and air mixture pipe flow. The dissolved oxygen convectionaεnd diffusion model is established to simulate the concentration distribution of dissolved oxygen with user defined scalar method. Velocity, pressure and dissolved oxygen concentration are computed. Then, dissolved oxygen concentration and pressure are compared with the data of physical model, and they agree with each other approximately, showing it is valid and reliable to compute the mixture pipe flow and dissolved oxygen concentration with the model .Furthermore, under a specific condition, velocity, pressure and dissolved oxygen concentration of water and air mixture pipe flow are computed and their characteristics are analyzed.
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