Association between noninvasive fibrosis markers and cardio-vascular organ damage among adults with hepatic steatosis

Evidence suggests that advanced fibrosis, as determined by the noninvasive NAFLD fibrosis score (NFS), is a predictor of cardiovascular mortality in individuals with ultrasonography-diagnosed NAFLD. Whether the severity of histology (i.e., fibrosis stage) is associated with more pronounced cardiovascular organ damage is unsettled. In this study, we analyzed the clinical utility of NFS in assessing increased carotid intima-media thickness (cIMT), and left ventricular mass index (LVMI). In this cross-sectional study NFS, cIMT and LVMI were assessed in 400 individuals with ultrasonography-diagnosed steatosis. As compared with individuals at low probability of liver fibrosis, individuals both at high and at intermediate probability of fibrosis showed an unfavorable cardio-metabolic risk profile having significantly higher values of waist circumference, insulin resistance, high sensitivity C-reactive protein (hsCRP), fibrinogen, cIMT, and LVMI, and lower insulin-like growth factor-1 (IGF-1) levels. The differences in cIMT and LVMI remained significant after adjustment for smoking and metabolic syndrome. In a logistic regression model adjusted for age, gender, smoking, and diagnosis of metabolic syndrome, individuals at high probability of fibrosis had a 3.9-fold increased risk of vascular atherosclerosis, defined as cIMT.0.9 mm, (OR 3.95, 95% CI 1.12–13.87) as compared with individuals at low probability of fibrosis. Individuals at high probability of fibrosis had a 3.5-fold increased risk of left ventricular hypertrophy (LVH) (OR 3.55, 95% CI 1.22–10.34) as compared with individuals at low probability of fibrosis. In conclusion, advanced fibrosis, determined by noninvasive fibrosis markers, is associated with cardiovascular organ damage independent of other known factors

Deficiency of NOX1 or NOX4 Prevents Liver Inflammation and Fibrosis in Mice through Inhibition of Hepatic Stellate Cell Activation.

Reactive oxygen species (ROS) produced by nicotinamide adenine dinucleotide phosphate oxidase (NOX) play a key role in liver injury and fibrosis. Previous studies demonstrated that GKT137831, a dual NOX1/4 inhibitor, attenuated liver fibrosis in mice as well as pro-fibrotic genes in hepatic stellate cells (HSCs) as well as hepatocyte apoptosis. The effect of NOX1 and NOX4 deficiency in liver fibrosis is unclear, and has never been directly compared. HSCs are the primary myofibroblasts in the pathogenesis of liver fibrosis. Therefore, we aimed to determine the role of NOX1 and NOX4 in liver fibrosis, and investigated whether NOX1 and NOX4 signaling mediates liver fibrosis by regulating HSC activation. Mice were treated with carbon tetrachloride (CCl4) to induce liver fibrosis. Deficiency of either NOX1 or NOX4 attenuates liver injury, inflammation, and fibrosis after CCl4 compared to wild-type mice. NOX1 or NOX4 deficiency reduced lipid peroxidation and ROS production in mice with liver fibrosis. NOX1 and NOX4 deficiency are approximately equally effective in preventing liver injury in the mice. The NOX1/4 dual inhibitor GKT137831 suppressed ROS production as well as inflammatory and proliferative genes induced by lipopolysaccharide (LPS), platelet-derived growth factor (PDGF), or sonic hedgehog (Shh) in primary mouse HSCs. Furthermore, the mRNAs of proliferative and pro-fibrotic genes were downregulated in NOX1 and NOX4 knock-out activated HSCs (cultured on plastic for 5 days). Finally, NOX1 and NOX4 protein levels were increased in human livers with cirrhosis compared with normal controls. Thus, NOX1 and NOX4 signaling mediates the pathogenesis of liver fibrosis, including the direct activation of HSC

Diagnostic value of two dimensional shear wave elastography combined with texture analysis in early liver fibrosis.

BACKGROUND: Staging diagnosis of liver fibrosis is a prerequisite for timely diagnosis and therapy in patients with chronic hepatitis B. In recent years, ultrasound elastography has become an important method for clinical noninvasive assessment of liver fibrosis stage, but its diagnostic value for early liver fibrosis still needs to be further improved. In this study, the texture analysis was carried out on the basis of two dimensional shear wave elastography (2D-SWE), and the feasibility of 2D-SWE plus texture analysis in the diagnosis of early liver fibrosis was discussed. AIM: To assess the diagnostic value of 2D-SWE combined with textural analysis in liver fibrosis staging. METHODS: This study recruited 46 patients with chronic hepatitis B. Patients underwent 2D-SWE and texture analysis; Young\u27s modulus values and textural patterns were obtained, respectively. Textural pattern was analyzed with regard to contrast, correlation, angular second moment (ASM), and homogeneity. Pathological results of biopsy specimens were the gold standard; comparison and assessment of the diagnosis efficiency were conducted for 2D-SWE, texture analysis and their combination. RESULTS: 2D-SWE displayed diagnosis efficiency in early fibrosis, significant fibrosis, severe fibrosis, and early cirrhosis (AUC \u3e 0.7, P \u3c 0.05) with respective AUC values of 0.823 (0.678-0.921), 0.808 (0.662-0.911), 0.920 (0.798-0.980), and 0.855 (0.716-0.943). Contrast and homogeneity displayed independent diagnosis efficiency in liver fibrosis stage (AUC \u3e 0.7, P \u3c 0.05), whereas correlation and ASM showed limited values. AUC of contrast and homogeneity were respectively 0.906 (0.779-0.973), 0.835 (0.693-0.930), 0.807 (0.660-0.910) and 0.925 (0.805-0.983), 0.789 (0.639-0.897), 0.736 (0.582-0.858), 0.705 (0.549-0.883) and 0.798 (0.650-0.904) in four liver fibrosis stages, which exhibited equivalence to 2D-SWE in diagnostic efficiency (P \u3e 0.05). Combined diagnosis (PRE) displayed diagnostic efficiency (AUC \u3e 0.7, P \u3c 0.01) for all fibrosis stages with respective AUC of 0.952 (0.841-0.994), 0.896 (0.766-0.967), 0.978 (0.881-0.999), 0.947 (0.835-0.992). The combined diagnosis showed higher diagnosis efficiency over 2D-SWE in early liver fibrosis (P \u3c 0.05), whereas no significant differences were observed in other comparisons (P \u3e 0.05). CONCLUSION: Texture analysis was capable of diagnosing liver fibrosis stage, combined diagnosis had obvious advantages in early liver fibrosis, liver fibrosis stage might be related to the hepatic tissue hardness distribution

Lung Cancer in Pulmonary Fibrosis: Tales of Epithelial Cell Plasticity

Lung epithelial cells exhibit a high degree of plasticity. Alterations to lung epithelial cell function are critically involved in several chronic lung diseases such as pulmonary fibrosis. Pulmonary fibrosis is characterized by repetitive injury and subsequent impaired repair of epithelial cells, which leads to aberrant growth factor activation and fibroblast accumulation. Increased proliferation and hyper- and metaplasia of epithelial cells upon injury have also been observed in pulmonary fibrosis; this epithelial cell activation might represent the basis for lung cancer development. Indeed, several studies have provided histopathological evidence of an increased incidence of lung cancer in pulmonary fibrosis. The mechanisms involved in the development of cancer in pulmonary fibrosis, however, remain poorly understood. This review highlights recently uncovered molecular mechanisms shared between lung cancer and fibrosis, which extend the current evidence of a common trait of cancer and fibrosis, as provided by histopathological observations. Copyright (C) 2011 S. Karger AG, Base

Genetic partitioning of interleukin-6 signalling in mice dissociates Stat3 from Smad3-mediated lung fibrosis

Idiopathic pulmonary fibrosis (IPF) is a fatal disease that is unresponsive to current therapies and characterized by excessive collagen deposition and subsequent fibrosis. While inflammatory cytokines, including interleukin (IL)-6, are elevated in IPF, the molecular mechanisms that underlie this disease are incompletely understood, although the development of fibrosis is believed to depend on canonical transforming growth factor (TGF)-β signalling. We examined bleomycin-induced inflammation and fibrosis in mice carrying a mutation in the shared IL-6 family receptor gp130. Using genetic complementation, we directly correlate the extent of IL-6-mediated, excessive Stat3 activity with inflammatory infiltrates in the lung and the severity of fibrosis in corresponding gp130757F mice. The extent of fibrosis was attenuated in B lymphocyte-deficient gp130757F;µMT−/− compound mutant mice, but fibrosis still occurred in their Smad3−/− counterparts consistent with the capacity of excessive Stat3 activity to induce collagen 1α1 gene transcription independently of canonical TGF-β/Smad3 signalling. These findings are of therapeutic relevance, since we confirmed abundant STAT3 activation in fibrotic lungs from IPF patients and showed that genetic reduction of Stat3 protected mice from bleomycin-induced lung fibrosis

Not All Children with Cystic Fibrosis Have Abnormal Esophageal Neutralization during Chemical Clearance of Acid Reflux.

PurposeAcid neutralization during chemical clearance is significantly prolonged in children with cystic fibrosis, compared to symptomatic children without cystic fibrosis. The absence of available reference values impeded identification of abnormal findings within individual patients with and without cystic fibrosis. The present study aimed to test the hypothesis that significantly more children with cystic fibrosis have acid neutralization durations during chemical clearance that fall outside the physiological range.MethodsPublished reference value for acid neutralization duration during chemical clearance (determined using combined impedance/pH monitoring) was used to assess esophageal acid neutralization efficiency during chemical clearance in 16 children with cystic fibrosis (3 to <18 years) and 16 age-matched children without cystic fibrosis.ResultsDuration of acid neutralization during chemical clearance exceeded the upper end of the physiological range in 9 of 16 (56.3%) children with and in 3 of 16 (18.8%) children without cystic fibrosis (p=0.0412). The likelihood ratio for duration indicated that children with cystic fibrosis are 2.1-times more likely to have abnormal acid neutralization during chemical clearance, and children with abnormal acid neutralization during chemical clearance are 1.5-times more likely to have cystic fibrosis.ConclusionSignificantly more (but not all) children with cystic fibrosis have abnormally prolonged esophageal clearance of acid. Children with cystic fibrosis are more likely to have abnormal acid neutralization during chemical clearance. Additional studies involving larger sample sizes are needed to address the importance of genotype, esophageal motility, composition and volume of saliva, and gastric acidity on acid neutralization efficiency in cystic fibrosis children

Role of TGFbRII in myeloid cell mediated regenerative processes and fibroplasia

Tissue repair and fibrosis are controlled by the interaction of different cell lineages, their soluble factors and matrix signals. Recently, macrophages have been found to be crucial for proper tissue repair. In particular, the role of Transforming growth factor-β1 (TGF-β1) has been extensively studied during tissue repair and fibrosis. Fibrosis is characterized by excessive production and deposition of extracellular matrix, as well as immune cell infiltration. Macrophages are one of the main sources of TGF-β1. So far, studies on the mechanisms of tissue repair and fibrosis have mainly focused on macrophages or TGF-β1 individually. However, the specific function of TGF-β1 on macrophages in tissue repair and fibrosis still needs to be elucidated. To understand the macrophage specific role of TGFβ1-TGFβRII signaling in tissue repair and fibrosis, we generated a mouse model, which lacks TGFβRII in myeloid cells (TGFβRIIfl/fl/LysMCre). We observed that during mechanical tissue injury TGFβRII signaling in macrophages contributes to wound contraction, possibly by cross—talk between macrophages and fibroblasts. The attenuated wound contraction was accompanied by impaired myofibroblast differentiation and collagen deposition. However, the loss of TGFβRII signaling in macrophages did not lead to reduced expression of TGF- β1, which we proposed as one of the primary mechanisms in wound tissue underlying reduced myofibroblast formation observed in TGFβRIIfl/fl/LysMCre mice. Generation of cutaneous fibrosis by bleomycin injection for two and four weeks resulted in reduced fibrosis in TGFβRIIfl/fl/LysMCre mice, compared to control mice. The mechanisms leading to this phenotype were associated with reduced infiltration of immune cells, reduced deposition of collagen and diminished production of inflammatory mediators such as IL-1β, TNF-α and osteopontin-1 at the early stage of fibrosis formation. At the later stage, the expression of inflammatory mediators in TGFβRIIfl/fl/LysMCre mice was not altered compared to control mice, possibly due to compensatory mechanisms. Our data leads to the hypothesis that the reduced fibrosis is caused by the reduced expression of inflammatory mediators and accumulation of immune cells at the early stage of fibrosis in TGFβRIIfl/fl/LysMCre mice. Our results provide new insights into the crucial role of macrophage specific TGFβRII signaling in tissue repair and fibrosis

Sequential Wnt Agonist then Antagonist Treatment Accelerates Tissue Repair and Minimizes Fibrosis

Tissue fibrosis compromises organ function and occurs as a potential long-term outcome in response to acute tissue injuries. Currently, lack of mechanistic understanding prevents effective prevention and treatment of the progression from acute injury to fibrosis. Here, we combined quantitative experimental studies with a mouse kidney injury model and a computational approach to determine how the physiological consequences are determined by the severity of ischemia injury, and to identify how to manipulate Wnt signaling to accelerate repair of ischemic tissue damage while minimizing fibrosis. The study reveals that Wnt-mediated memory of prior injury contributes to fibrosis progression, and ischemic preconditioning reduces the risk of death but increases the risk of fibrosis. Furthermore, we validated the prediction that sequential combination therapy of initial treatment with a Wnt agonist followed by treatment with a Wnt antagonist can reduce both the risk of death and fibrosis in response to acute injuries

How do adults with cystic fibrosis cope following a diagnosis of diabetes?

The official published version of the article can be obtained from the link below.Aim. This paper is a report of a study examining the experience of adults with cystic fibrosis in adapting to the diagnosis of diabetes, a second chronic illness. Background. Diabetes is a common complication of cystic fibrosis; the onset signifies the development of a second chronic illness. Both cystic fibrosis and diabetes are complex conditions, which require daily treatment schedules as part of their management. However, it is unclear how people already living with cystic fibrosis respond to the diagnosis of diabetes. Method. A qualitative method was chosen to obtain an ‘insider’ experience of adjusting to a second chronic illness. Semi-structured interviews were conducted in 2004 with 22 adults with cystic fibrosis-related diabetes. The data were analysed using interpretative phenomenological analysis. Findings. Four recurring themes were identified: emotional response to diagnosis of diabetes, looking for an understanding, learning to live with diabetes, and limiting the impact of diagnosis. Having cystic fibrosis appeared helpful in limiting the impact of the diagnosis of diabetes. Juggling conflicting dietary demands of cystic fibrosis and diabetes coupled with the lack of practical professional advice available was seen as one of the biggest challenges in adapting to diabetes. Conclusion. Healthcare professionals need increased awareness of diabetes amongst adults with cystic fibrosis and provide adequate support and structured evidence-based education throughout the course of the illness, particularly in relation to diet. Nevertheless, patients’ familiarity with regular daily routines and problem-solving attitudes, already developed in the context of cystic fibrosis, may be drawn on to limit the impact of diabetes