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High recurrence and metastasis of triple-negative breast cancer (TNBC) after operation is a leading cause of breast cancer related death. The pre-metastatic niche (PMN) is an environment in a secondary organ conducive to the metastasis of a primary tumor. Herein, we identify exosomes from autologous breast cancer cells that show effective lung targeting ability. Based on this, we developed the biomimetic nanoparticles (cationic bovine serum albumin (CBSA) conjugated siS100A4 and exosome membrane coated nanoparticles, CBSA/siS100A4@Exosome) to improve drug delivery to the lung PMN. CBSA/siS100A4@Exosome self-assembled nanoparticles formed homogeneous sizes of ~200 nm, protected siRNA from degradation, and showed excellent biocompatibility. Further in vivo studies showed that CBSA/siS100A4@Exosome had a higher affinity toward lung in comparison to the CBSA/siS100A4@Liposome, and exhibited outstanding gene-silencing effects that significantly inhibited the growth of malignant breast cancer cells. Taken together, these results indicate that CBSA/siS100A4@Exosome self-assembled nanoparticles are a promising strategy to suppress postoperative breast cancer metastasis.

Objectives Microbiota dysbiosis in inflammatory bowel disease (IBD) has been widely reported. The gut microbiota connect diet to the metabolism by producing small molecules via diverse metabolic pathways. In this study we aimed to investigate the dietary preferences of IBD patients, and to explore the interactions among gut microbiota composition, dietary components, and metabolites in relation to IBD. Methods Dietary preferences of IBD patients (including those with ulcerative colitis [UC] and Crohn's disease [CD]) and health controls were investigated, and their gut microbiota were analyzed using 16S rRNA gene sequencing and metagenomic analyses of fecal and biopsy samples. The metabolite profiles of the samples were then analyzed using gas and liquid chromatography-mass spectrometry analyses. Results The daily intake of folic acid, niacin, vitamins C and D, calcium, and selenium differed significantly between patients with IBD and healthy controls. A decrease in long-chain (such as arachidic, and oleic acid) and medium-chain fatty acids (sebacic acid and isocaproic acid) as well as bile acid was observed in patients with IBD. Compared with healthy controls, 22 microbial species (including Sulfolobus acidocaldarius, and Clostridium clostridioforme CAG132) in the UC group and 37 microbial species (such as Bacteroides fragilis and Fusobacterium nucleatum) in the CD group were found to be correlated to diet and metabolites. Bacteroides fragilis was enriched in patients with IBD and associated with multi-nutrients, and 21 metabolites including 25-hydroxyvitamin D3 and taurolithocholic acid. Conclusions This study provides an interaction network to identify key micronutrients, microbiota components and metabolites that contribute to IBD.

Metagenomic analyses indicate that streptococcus gallolyticus is enriched at carcinoma in colitis associated colorectal cancer compared with sporadic colorectal cancer. But the particular mechanism of streptococcus gallolyticus in Inflammatory Bowel Disease malignant progression remains undefined yet. We aim to explore the biological carcinogenesis efficacy of streptococcus gallolyticus and its potential mechanism in azoxymethane and dextran sodium sulphate-induced colitis associated colorectal cancer in mice. Oral pretreatment of streptococcus gallolyticus was adopted to evaluate its detrimental effect. The colorectums of experimental C57BL/6 mice were collected and examined for the degree of tumorigenesis. Comparative 16S rRNA sequencing was carried out to observe streptococcus gallolyticus alterations in abundance. We found that streptococcus gallolyticus are enriched in colonic carcinoma compared to adenoma and healthy mice. Pretreatment of Streptococcus gallolyticus aggravated tumor formation, with more colonic obstruction, larger number and diameter of tumor node. Furthermore, Streptococcus gallolyticus selectively recruits tumor-infiltrating myeloid cells but not mast cells, including marrow-derived suppressor cells, tumor-associated macrophages and dendritic cells, which can inhibit competence of T cells. Moreover, several myeloid-cell-derived proinflammatory cytokines (IL-6, IL-1β, IL-8, CCL2, COX-2, TNF-α) were increased with the formation of carcinoma in IBD. Collectively, these data suggest that, through recruitment of tumor-infiltrating immune cells, Streptococcus gallolyticus generate an immune suppressive microenvironment that is conducive for neoplasia progression of Inflammatory Bowel Disease.

The key for better antitumor efficacy is to improve the specificity of antitumor drugs for tumor cells and diminish their cytotoxicity to normal tissues. Targeted nanoparticles as antitumor drug delivery system can resolve this problem. In this study, we prepared folate and TAT (arginine-rich cell-penetrating peptide) modified N-PEG-N'-octyl-chitosan to form the folate/TAT-PEG-OC micelles. Then, the molecular structure, morphology, size distribution and bio-safety of the micelles were characterized. In order to investigate the drug-loading capacity of folate/TAT-PEG-OC micelles, doxorubicin (DOX) was used as model drug to prepare DOX-loaded chitosan micelles. Here, the confocal microscopy was used to evaluate the cellular uptake of DOX/folate/TAT-PEG-OC micelles, while the self-built NIR imaging system was used to evaluate the dynamic behavior of ICG-Der-01/folate/TAT-PEG-OC micelles in vivo. Our results demonstrate that the dual-modified PEG-OC micelles not only have good morphology, uniform size distribution and excellent drug loading capacity, but also show a strong capability for the efficient intracellular uptake and enhanced targeting behaviors in a folate receptor positive tumor model (Bel-7402 human hepatocellular cells). All these results suggest the potential application of folate/TAT-PEG-OC micelles in the targeted diagnosis and therapy to different kinds of folate receptor positive tumors.

Thyroid hormone (TH) is critical for the maintenance of cellular homeostasis during stress responses, but its role in lung fibrosis is unknown. Here we found that the activity and expression of iodothyronine deiodinase 2 (DIO2), an enzyme that activates TH, were higher in lungs from patients with idiopathic pulmonary fibrosis than in control individuals and were correlated with disease severity. We also found that Dio2-knockout mice exhibited enhanced bleomycin-induced lung fibrosis. Aerosolized TH delivery increased survival and resolved fibrosis in two models of pulmonary fibrosis in mice (intratracheal bleomycin and inducible TGF-β1). Sobetirome, a TH mimetic, also blunted bleomycin-induced lung fibrosis. After bleomycin-induced injury, TH promoted mitochondrial biogenesis, improved mitochondrial bioenergetics and attenuated mitochondria-regulated apoptosis in alveolar epithelial cells both in vivo and in vitro. TH did not blunt fibrosis in Ppargc1a- or Pink1-knockout mice, suggesting dependence on these pathways. We conclude that the antifibrotic properties of TH are associated with protection of alveolar epithelial cells and restoration of mitochondrial function and that TH may thus represent a potential therapy for pulmonary fibrosis.

Background COPD is a leading cause of mortality worldwide, and cigarette smoke is a pivotal risk factor. Adenovirus is a common cause of acute exacerbations of COPD and expedites COPD progression. Lung stem/progenitor cells play an important role in the development of COPD, while the relevant mechanism remains elusive. Here, we investigated the number of lung CD31-CD45-Sca-1+ cells and sonic hedgehog (Shh) signaling pathway expression levels in cigarette smoke extract (CSE)-induced emphysema mice, as well as the relevant effects of acute adenovirus infection (AAI). Materials and methods BALB/c mice were treated with CSE by intraperitoneal injection and/or adenovirus endotracheal instillation at different time points for 28 days. Lung function, lung histomorphology, CD31-CD45-Sca-1+ cell count, and expression levels of major components in the Shh signaling pathway in the lungs were measured. Results CSE intraperitoneal injection and adenovirus endotracheal instillation successfully induced emphysema and AAI in mice, respectively. In the lungs of emphysema mice, both the number of CD31-CD45-Sca-1+ cells and expression levels of Shh signaling pathway molecules were reduced. However, AAI increased the number of inhibited CD31-CD45-Sca-1+ cells and activated the suppression of the Shh signaling pathway. Conclusion Both CD31-CD45-Sca-1+ cell numbers and Shh signaling pathway expression levels were downregulated in the lungs of emphysema mice induced by CSE intraperitoneal injection, which likely contributes to the pathogenesis of emphysema. Additionally, these inhibited lung CD31-CD45-Sca-1+ cells and Shh signaling pathway molecules were upregulated during AAI, indicating that they play a protective role in the epithelial repair process after AAI injury.

Bismuth + proton pump inhibitor (PPI) + amoxicillin + levofloxacin is one of the bismuth quadruple therapy regimens widely used for the eradication of H. pylori infection. The recommended dosage of levofloxacin is 500 mg once daily or 200 mg twice daily to eradicate H. pylori infection. The aim of the present open-label, randomized control trial was to compare the effectiveness, safety, and compliance of different dosages of levofloxacin used to cure Helicobacter pylori infection. Eligible patients were randomly assigned to receive esomeprazole, amoxicillin, colloidal bismuth pectin and levofloxacin 500 mg once/day (group A) or levofloxacin 200 mg twice/day (group B) for 14 days. The primary outcome was the eradication rates in the intention-to-treat (ITT) and per protocol (PP) analyses. Overall, 400 patients were enrolled. The eradication rates in group A and group B were 77.5% and 79.5% respectively, in the ITT analysis, and 82.9% and 86.4%, respectively, in the PP analysis. No significant differences were found between two groups in terms of eradication rate, adverse effects or compliance. Oral levofloxacin 200 mg twice daily was similar in efficacy for eradicating H. pylori infection to oral levofloxacin 500 mg once daily but with lower mean total costs.

Pulmonary fibrosis is a progressive and often fatal condition that is believed to be partially orchestrated by macrophages. Mechanisms that control migration of these cells into and within the lung remain undefined. We evaluated the contributions of the semaphorin receptor, plexin C1 (PLXNC1), and the exocytic calcium sensor, synaptotagmin 7 (Syt7), in these processes. We evaluated the role of PLXNC1 in macrophage migration by using Boyden chambers and scratch tests, characterized its contribution to experimentally induced lung fibrosis in mice, and defined the mechanism for our observations. Our findings reveal that relative to control participants, patients with idiopathic pulmonary fibrosis demonstrate excessive monocyte migration and underexpression of PLXNC1 in the lungs and circulation, a finding that is recapitulated in the setting of scleroderma-related interstitial lung disease. Relative to wild type, PLXNC1-/- mouse macrophages are excessively migratory, and PLXNC1-/- mice show exacerbated collagen accumulation in response to either inhaled bleomycin or inducible lung targeted TGF-β1 overexpression. These findings are ameliorated by replacement of PLXNC1 on bone marrow-derived cells or by genetic deletion of Syt7. These data demonstrate the previously unrecognized observation that PLXNC1 deficiency permits Syt7-mediated macrophage migration and enhances mammalian lung fibrosis.-Peng, X., Moore, M., Mathur, A., Zhou, Y., Sun, H., Gan, Y., Herazo-Maya, J. D., Kaminski, N., Hu, X., Pan, H., Ryu, C., Osafo-Addo, A., Homer, R. J., Feghali-Bostwick, C., Fares, W. H., Gulati, M., Hu, B., Lee, C.-G., Elias, J. A., Herzog, E. L. Plexin C1 deficiency permits synaptotagmin 7-mediated macrophage migration and enhances mammalian lung fibrosis.

Objective Fibrocytes are collagen-producing leukocytes that accumulate in patients with systemic sclerosis (SSc; scleroderma)-related interstitial lung disease (ILD) via unknown mechanisms that have been associated with altered expression of neuroimmune proteins. The extracellular matrix (ECM) influences cellular phenotypes. However, a relationship between the lung ECM and fibrocytes in SSc has not been explored. The aim of this study was to use a novel translational platform based on decellularized human lungs to determine whether the lung ECM of patients with scleroderma controls the development of fibrocytes from peripheral blood mononuclear cells. Methods We performed biomechanical evaluation of decellularized scaffolds prepared from lung explants from healthy control subjects and patients with scleroderma, using tensile testing and biochemical and proteomic analysis. Cells obtained from healthy controls and patients with SSc-related ILD were cultured on these scaffolds, and CD45+pro-ColIα1+ cells meeting the criteria for fibrocytes were quantified. The contribution of the neuromolecule netrin-1 to fibrosis was assessed using neutralizing antibodies in this system and by administering bleomycin via inhalation to netrin-1(+/-) mice. Results Compared with control lung scaffolds, lung scaffolds from patients with SSc-related ILD showed aberrant anatomy, enhanced stiffness, and abnormal ECM composition. Culture of control cells in lung scaffolds from patients with SSc-related ILD increased production of pro-ColIα1+ cells, which was stimulated by enhanced stiffness and abnormal ECM composition. Cells from patients with SSc-related ILD demonstrated increased pro-ColIα1 responsiveness to lung scaffolds from scleroderma patients but not enhanced stiffness. Enhanced detection of netrin-1-expressing CD14(low) cells in patients with SSc-related ILD was observed, and antibody-mediated netrin-1 neutralization attenuated detection of CD45+pro-ColIα1+ cells in all settings. Netrin-1(+/-) mice were protected against bleomycin-induced lung fibrosis and fibrocyte accumulation. Conclusion Factors present in the lung matrices of patients with scleroderma regulate fibrocyte accumulation via a netrin-1-dependent pathway. Netrin-1 regulates bleomycin-induced pulmonary fibrosis in mice. Netrin-1 might be a novel therapeutic target in SSc-related ILD.

Cigarette smoking has long been tied to a multitude of poor health outcomes; however, in reproductive biology, smoking has shown several unintuitive findings. Smoking is associated with significantly decreased rates of endometriosis and endometrial cancer. Here, we show that treatment with cigarette smoke extract leads to increased mRNA and protein expression of homeobox A10 (HOXA10) and progesterone receptor (PGR) as well as more rapid decidualization of endometrial stromal cells in vitro. In vivo, mice exposed to cigarette smoke similarly showed increased expression of HOXA10 and PGR in the endometrium. Both HOXA10 and PGR drive endometrial differentiation and are suppressed in endometrial tumors and in endometriosis. The increased expression found upon exposure to cigarette smoke may provide a protective effect, mediating the decreased incidence of endometrial disease among smokers. This mechanism contrasts with the accepted paradigm that the effects of smoking on the uterus are secondary to ovarian alterations rather than direct effects on endometrium as demonstrated here.

Ye Gan1,2, Erica L Herzog2, Richard H Gomer31Department of Medicine, Central South University, Changsha, Hunan, China; 2Department of Medicine, Yale University School of Medicine, New Haven, CT, USA; 3Department of Biology, Texas A&M University, College Station, TX, USAAbstract: Idiopathic pulmonary fibrosis (IPF) is a discrete clinicopathologic entity defined by the presence of usual interstitial pneumonia on high-resolution CT scan and/or open lung biopsy and the absence of an alternate diagnosis or exposure explaining these findings. There are currently no FDA-approved therapies available to treat this disease, and the 5-year mortality is ~80%. The pyridone derivative pirfenidone has been studied extensively as a possible therapeutic agent for use in this deadly disease. This review will present the unique clinical features and management issues encountered by physicians caring for IPF patients, including the poor response to conventional therapy. The biochemistry and preclinical efficacy of pirfenidone will be discussed along with a comprehensive review of the clinical efficacy, safety, and side effects and patient-centered foci such as quality of life and tolerability. It is hoped that this information will lend insight into the complex issues surrounding the use of pirfenidone in IPF and lead to further investigation of this agent as a possible therapy in this devastating disease.Keywords: pirfenidone, fibrosis, clinical trials&nbsp

Epithelial injury, alternative macrophage accumulation, and fibroproliferation coexist in the lungs of patients with idiopathic pulmonary fibrosis (IPF). Chitinase 3-like 1 (CHI3L1) is a prototypic chitinase-like protein that has been retained over species and evolutionary time. However, the regulation of CHI3L1 in IPF and its ability to regulate injury and/or fibroproliferative repair have not been fully defined. We demonstrated that CHI3L1 levels were elevated in patients with IPF. High levels of CHI3L1 are associated with progression--as defined by lung transplantation or death--and with scavenger receptor-expressing circulating monocytes in an ambulatory IPF population. In preterminal acute exacerbations of IPF, CHI3L1 levels were reduced and associated with increased levels of apoptosis. We also demonstrated that in bleomycin-treated mice, CHI3L1 expression was acutely and transiently decreased during the injury phase and returned toward and eventually exceeded baseline levels during the fibrotic phase. In this model, CHI3L1 played a protective role in injury by ameliorating inflammation and cell death, and a profibrotic role in the repair phase by augmenting alternative macrophage activation, fibroblast proliferation, and matrix deposition. Using three-dimensional culture system of a human fibroblast cell line, we found that CHI3L1 is sufficient to induce low grade myofibroblast transformation. In combination, these studies demonstrate that CHI3L1 is stimulated in IPF, where it represents an attempt to diminish injury and induce repair. They also demonstrate that high levels of CHI3L1 are associated with disease progression in ambulatory patients and that a failure of the CHI3L1 antiapoptotic response might contribute to preterminal disease exacerbations.

Accumulating evidence suggests that statins possess anti-inflammatory properties and may decrease C-reactive protein (CRP) levels in plasma. However, no studies have as yet addressed whether or not statins regulate the expression of CRP in human lung epithelial cells (A549). In this study, we determined whether atorvastatin modulates the lipopolysaccharide (LPS)-induced expression of CRP in A549 cells. A549 cells were incubated in Dulbecco's modified Eagle's medium containing LPS in the absence or presence of various concentrations of atorvastatin. After incubation, the medium was collected and the amount of CRP was measured by an enzyme-linked immunosorbent assay. The cells were harvested and CRP messenger ribonucleic acid (mRNA) was analyzed by reverse transcription polymerase chain reaction. Incubation with LPS induced a significant time- and dose-dependent increase in CRP mRNA expression and CRP production in A549 cells, whereas atorvastatin significantly decreased LPS-induced CRP mRNA expression and CRP production in a dose-dependent manner. The present study revealed that A549 cells are capable of LPS-induced CRP expression, and that atorvastatin down-regulates the LPS-induced expression of CRP in cultured A549 cells. Our results suggest that statins ameliorate lung inflammation by regulating CRP production in human lung epithelial cells.

Cigarette smoking leads to female infertility and a decreased incidence of endometriosis. Bone marrow derived stem cells are recruited to uterine endometrium and endometriosis. The effect of cigarette smoking on stem cell recruitment to any organ is uncharacterized. We hypothesized that bone marrow-derived mesenchymal stem cell recruitment to the uterus and differentiation would be diminished by cigarette smoke. We used human mesenchymal stem cells (hMSC) in vitro and a mouse model of cigarette smoke exposure. After myeloablation female C57BL/6J received bone marrow cells from males. Mice were exposed to room air or smoke from unfiltered cigarettes. Immunofluorescence and Y-FISH was performed on uterine sections. In vitro hMSCs were treated with 8-Br-cAMP to induce endometrial cell differentiation with or without cigarette smoke extract (CSE) and decidualization assessed morphologically and by prolactin expression. After 4 weeks the total number of Y-chromosome cells in the uterus was reduced by 68% in the smoke exposed mice. Both leukocytes and bone marrow derived endometrial cells were reduced by 60% and 73%, respectively. Differentiation of bone marrow derived cell to endometrial epithelial cells was reduced by 84%. hMSC treated with CSE failed to show cytological characteristics of decidualization. mRNA levels of the decidualization marker prolactin were decreased by 90% in CSE treated cells. Smoking inhibits both recruitment of bone marrow derived stem cells to uterus and stem cell differentiation. Inhibition of stem cells recruitment may be a general mechanism by which smoking leads to long term organ damage through inability to repair or regenerate multiple tissues.

In this work, a dextran modified PDMS microfluidic ELISA device was fabricated. The dextran functionalization was conducted with a simple, economic and fast flow-through process in a fabricated PDMS microfluidic device, and demonstrated significant enhancement of hydrophilicity and efficient covalent immobilization of proteins on the PDMS microchannel surface. The device was used to simultaneously detect multiple important biomarker IL-5, HBsAg, and IgG, showing a limit of detection of 100 pg mL(-1) and a dynamic range of 5 orders of magnitude, which significantly improved the performance of the reported hydrophobic and plasma-treated hydrophilic PDMS flow-through immunoassay devices. The fabricated PDMS device demonstrated its capability for colorimetric detection of proteins through direct observation by human eyes. Thus, this work not only demonstrates great potential to fabricate an economical and sensitive lab-on-chip system for high throughput screening of various infectious diseases, but also provides an opportunity to develop a portable microfluidic ELISA device via human eye examination for heath point-of-care services.

Immunoassay devices including microarray and microfluidic systems were fabricated with an UV-curable resin by a new economic approach, which can not only simply produce a 3-dimensional (3D) patterned structure, but also simultaneously introduce functional epoxide groups for efficient protein immobilization. The performance of the epoxy resin-based microarray was improved by optimization of printing buffer, probe concentration, and immobilization time, showing a detection dynamic range of 5 orders of magnitude and a limit of detection (LOD) of 10 pg mL(-1) for immunoglobulin G (IgG). The developed microfluidic immunoassay device demonstrates a LOD of 100 pg mL(-1) for IL-5 detection. The device can also be used to colorimetrically detect proteins via naked human eyes for immunoassays. This work provides a simple and inexpensive method to fabricate a sensitive immunoassay device, especially a 3D microfluidic system, which has great potential to develop a portable immunoassay device via human eye detection for point-of-care service and/or high throughput screening of infectious diseases.

A growing body of evidence implicates macrophage migration inhibitory factor (MIF) in tumorigenesis and metastasis. In this study, we investigated whether MIF expression was associated with clinicopathologic features of colorectal carcinoma (CRC), especially in tumors with hepatic metastasis, and whether neutralization of endogenous MIF using anti-MIF therapeutics would inhibit tumor growth and/or decrease the frequency of colorectal hepatic metastases in a mouse colon carcinoma model. The concentration of serum MIF was positively correlated with an increased risk of hepatic metastasis in human patients with CRC (R = 1.25, 95% confidence internal = 1.02–1.52, P = 0.03). MIF was also dramatically upregulated in human colorectal tissue, with 20–40 times as many MIF-positive cells found in the mucosa of patients with CRC than in normal tissue (P < 0.001 ANOVA). Moreover, in those patients with metastatic colorectal cancer in the liver, MIF-positive cells were similarly increased in the diseased hepatic tissue. This increased MIF expression was restricted to diseased tissue and not found in areas of the liver with normal morphology. In subsequent in vitro experiments, we found that addition of recombinant MIF to colonic cell lines significantly increased their invasive properties and the expression of several genes (for example, matrix metalloproteinase 9 and vascular endothelial growth factor) known to be upregulated in cancerous tissue. Finally, we treated mice that had been given CT26 colon carcinoma cell transplants with anti-MIF therapeutics—either the MIF-specific inhibitor ISO-1 or neutralizing anti-MIF antibodies—and observed a significant reduction in tumor burden relative to vehicle-treated animals. Taken together, these data demonstrate that MIF expression was not only correlated with the presence of colorectal cancer but also may play a direct role in cancer development.

Patients who need both capsule endoscopy (CE) and colonoscopy often undergo both examinations on the same day to avoid repeated bowel preparation and fasting. Sedation can relieve pain and is commonly used for colonoscopies but may influence the CE completion rate. To determine whether sedation with propofol influences the completion rate and small-bowel transit time (SBTT) of CE. From July 2014 to December 2014, patients (18–65 years old) who needed both CE and colonoscopy were assessed consecutively for enrollment in our study. Colonoscopies were performed with or without sedation based on patient preferences on the day of capsule ingestion. The completion rate, SBTT, and diagnostic yield of CEs were recorded. Patients’ satisfaction and pain scores were also recorded. Sedation with propofol had no significant effect on CE completion rates (83.3% sedation group vs 81.8% nonsedation group, P = 0.86) but was associated with increased SBTT (403.6 ± 160.3 sedation group vs 334.5 ± 134.4 nonsedation group, P = 0.006). The diagnostic yields in the sedation and nonsedation groups were 69.4% and 65.9%, respectively (P = 0.74). The median satisfaction scores were 8.6 in the sedation group and 3.5 in the nonsedation group (P

Pulmonary hypertension (PH) is a cardiovascular disorder characterized by vasoconstriction and vascular remodeling. Recently, rapidly increasing evidence from various rat models of PH and patients with PH suggest that small GTPase Rho and its downstream effector, Rho-kinase, play a key role in the pathogenesis of PH. Activation of the Rho/Rho-kinase pathway is important for pulmonary endothelial dysfunction, pulmonary vascular smooth muscle cell contractility, proliferation and apoptosis in PH. A greater Rho-kinase expression and an enhanced Rho-kinase activity have been observed in pulmonary arteries of PH rats, such as hypoxia-induced, monocrotaline-induced and genetic spontaneous PH rats. Moreover, Y-27632 or fasudil, the selective Rho-kinase inhibitors, significantly attenuated PH in various pulmonary hypertensive model rats and patients with PH, but did not reduce systemic blood pressure. Therefore, Rho-kinase inhibitors may have therapeutic potential for the treatment of PH.

The above sketches give only a glimpse of some of the things going on in China. There are plenty of problems waiting for us to be solved in the future.

3 signes cardinaux sont les principaux criteres de diagnostic de la lepre: manque de sensibilite de la region affectee, l'epaisseur des nerfs peripheriques associee a des lesions de ces nerfs et presence de Mycobacterium leprae dans les prelevements cutanes

Background Collagen-containing leukocytes (CD45+Col-I+) accumulate in diseased and fibrotic tissues. However, the precise identity of these cells and whether injury is required for their recruitment remain unknown. Using a murine model of pulmonary fibrosis in which an inducible, bioactive form of the human transforming growth factor (TGF)-β1 gene is targeted to the lung, we characterized the cell surface phenotype of collagen-containing CD45+ cells in the lung and tested the hypothesis that apoptotic cell death responses are essential to the accumulation of CD45+Col-I+ cells. Results Our studies demonstrate that CD45+Col-I+ cells appearing in the TGF-β1-exposed murine lung express markers of the monocyte lineage. Inhibition of apoptosis via pharmacological caspase blockade led to a significant reduction in CD45+Col-I+ cells, which appear to accumulate independently of alternatively activated macrophages. There are also increased levels of apoptosis and greater numbers of CD45+Col-I+ in the lung tissue of patients with two distinct forms of fibrotic lung disease, idiopathic pulmonary fibrosis and connective tissue disease-related interstitial lung disease, when compared to lung from healthy normal controls. These findings are accompanied by an increase in collagen production in cultured monocytes obtained from subjects with fibrotic lung disease. Treatment of these cultured cells with the caspase inhibitor carbobenzoxy-valyl-alanyl-aspartyl-[O-methyl]-fluoromethylketone (Z-VAD/fmk) reduces both apoptosis and collagen production in all subjects. Conclusions Interventions that prevent collagen production by monocytes via modulation of caspase activation and of apoptosis may be ameliorative in monocyte-associated, TGF-β1-driven processes such as pulmonary fibrosis.