Role for α3 integrin in EMT and pulmonary fibrosis

Idiopathic pulmonary fibrosis (IPF) is characterized by progressive (myo)fibroblast accumulation and collagen deposition. One possible source of (myo)fibroblasts is epithelial cells that undergo epithelial-mesenchymal transition (EMT), a process frequently mediated by TGF-β. In this issue of the JCI, Kim et al. report that epithelial cell–specific deletion of α3 integrin prevents EMT in mice, thereby protecting against bleomycin-induced fibrosis (see the related article beginning on page 213). The authors propose a novel mechanism linking TGF-β and β-catenin signaling in EMT through integrin-dependent association of tyrosine-phosphorylated β-catenin and pSmad2 and suggest targeted disruption of this interaction as a potential therapeutic approach. Idiopathic pulmonary fibrosis (IPF) is a progressive disorder of unknown etiology characterized by fibroblast accumulation, collagen deposition, and ECM remodeling leading to parenchymal destruction (1). Historically, inflammation has been viewed as central to the pathogenesis of IPF. A recent paradigm shift proposes a model in which injury to the epithelium initiates a proinflammatory and profibrotic cascade, resulting in fibroblast expansion and progressive fibrosis reminiscent of abnormal wound healing (2). Myofibroblasts (activated fibroblasts) are key effector cells in pulmonary fibrosis, being responsible for matrix deposition and structural remodeling. The source of myofibroblasts in IPF remains the subject of debate: in addition to arising from circulating progenitors and resident fibroblasts, myofibroblasts have recently been shown to be derived from alveolar epithelial cells (AECs) through epithelial-mesenchymal transition (EMT) (3, 4).     

Is there an influence of hepatic steatosis on fibrosis and necroinflammation in young patients with chronic viral hepatitis B?

Objectives: Our aim was to investigate the association of liver fibrosis and necroinflammation with HS in untreated young patients with chronic hepatitis B (CHB).

Materials and methods: A retrospective study was conducted in a military hospital in Turkey. A total of 254 subjects with CHB were included in this study. These subjects were divided into two groups: group 1 consisted of patients with hepatic steatosis (HS) according to ultrasonography (USG) and group 2 consisted of non-HS subjects. Sociodemographic, biochemical, histopathological, virological and USG results were recorded for both groups retrospectively. Statistical analysis was performed using SPSS 22.0.

Results: The prevalence of HS was found to be 11.4%. A significant statistical difference was found between group 1 and group 2 regarding the fibrosis degree (p = 0.045). No statistically significant difference was noted between two groups for age, levels of ALT, AST, HBeAg, HBV-DNA levels, HAI scores, diagnosis age and duration of CHB. No difference was noted between the grade of HS and variables. A positive correlation was found between fibrosis groups and the grade of HS (p = 0.012, r = 0.158) and between HAI groups and the grade of HS (p = 0.029, r = 0.137).

Conclusion: The prevalence of steatosis was not higher in patients with CHB. HS is associated with advanced hepatic fibrosis, but not viral liver disease.     

Hyaluronic acid improves “pleasantness” and tolerability of nebulized hypertonic saline in a cohort of patients with cystic fibrosis

Introduction  

Inhaled hypertonic saline improves lung function and decreases pulmonary exacerbations in people with cystic fibrosis. However, side effects such as cough, narrowing of airways and saltiness cause intolerance of the therapy in 8% of patients. The aim of our study was to compare the effect of an inhaled solution of hyaluronic acid and hypertonic saline with hypertonic solution alone on safety and tolerability.     

Cystic fibrosis and lung transplantation — Determination of the survival benefit

INTRODUCTION: Cystic fibrosis is a well acknowledged indication for lung transplantation; however, the optimal timing for transplantation remains debatable. Liou et al. described a score for calculating 5-year probability of survival for patients with cystic fibrosis and concluded that only patients with a probability of survival < 30% gained a survival benefit from transplantation; those between 30% and 50% had equivocal survival effects from transplantation and those > 50% suffered negative effects. The aim of the present study was to determine the validity and applicability of this model. METHODS: Data from patients with cystic fibrosis transplanted between January 1995 and July 2001 were retrospectively reviewed. Survival score according to Liou was calculated from data collected before transplantation. Patients were classified according to 5-year probability of survival (group 1: < 30%, group 2: 30%-50%, groups 3-5: > 50%). Actuarial survival rates were calculated separately for each group and compared with the predicted probability of survival. RESULTS: During the observation period 27 patients were transplanted for cystic fibrosis. Three patients had to be excluded from further analysis because of incomplete pretransplant data. Fifteen patients were classified as group 1 and nine patients as group 2. No patients were eligible for groups 3 to 5. There were nine female patients and six males in group 1, mean age 22.1 +/- 4.9 years. Mean survival time was 918 +/- 787 days; 1-, 3- and 5-year survival rates were 66.6%. Three male patients and six females were classified as group 2, mean age 26.2 +/- 12.2 years. Mean survival time for this group was 701 +/- 617 days, and 1-, 3- and 5-year survival rates were 66.6%. CONCLUSION: We found that only patients with a 5-year probability of survival < 50% had been transplanted. For patients in groups 1 and 2 we report identical 5-year survival rates of 66.6%. According to our experience, cystic fibrosis patients with a 5-year probability of survival < 30% and also those between 30% and 50% gain a clear survival benefit from bilateral lung transplantation.     

ΔF508 CFTR protein expression in tissues from patients with cystic fibrosis

Heterologous expression of the cystic fibrosis transmembrane conductance regulator (CFTR) provided evidence that the major cystic fibrosis (CF) mutation DeltaF508 leads to defective protein folding in the endoplasmic reticulum, which prevents its processing and targeting to the cell surface. In this study, we investigated endogenous CFTR expression in skin biopsies and respiratory and intestinal tissue specimens from DeltaF508 homozygous and non-CF patients, using immunohistochemical and immunoblot analyses with a panel of CFTR antibodies. CFTR expression was detected at the luminal surface of reabsorptive sweat ducts and airway submucosal glands, at the apex of ciliated cells in pseudostratified respiratory epithelia and of isolated cells of the villi of duodenum and jejunum, and within intracellular compartments of intestinal goblet cells. In DeltaF508 homozygous patients, expression of the mutant protein proved to be tissue specific. Whereas DeltaF508 CFTR was undetectable in sweat glands, the expression in the respiratory and intestinal tracts could not be distinguished from the wild-type by signal intensity or localization. The tissue-specific variation of DeltaF508 CFTR expression from null to apparently normal amounts indicates that DeltaF508 CFTR maturation can be modulated and suggests that determinants other than CFTR mislocalization should play a role in DeltaF508 CF respiratory and intestinal disease.     

Management of spontaneous and iatrogenic retroperitoneal haemorrhage: conservative management,endovascular intervention or open surgery?

Background: Retroperitoneal haematoma is a rare clinical entity with variable aetiology, which is increasing in incidence mainly due to complications related to interventional procedures. There is no general consensus as to the best management plan for patients with retroperitoneal haematoma. Methods: A literature review was undertaken using MEDLINE, all relevant papers on retroperitoneal haemorrhage or haematoma were used. Results: The diagnosis is often delayed as symptoms are nonspecific. Retroperitoneal haematoma should be suspected in patients with significant groin, flank, abdominal, back pain or haemodynamic instability following an interventional procedure. Spontaneous haemorrhage usually occurs in patients who are anticoagulated. Multi‐slice CT and arteriography are important for diagnosis. Most haemodynamically stable patients can be managed with fluid resuscitation, correction of coagulopathy and blood transfusion. Endovascular treatment involving selective intra‐arterial embolisation or the deployment of stent‐grafts over the punctured vessel is attaining an increasingly important role. Open repair of retroperitoneal bleeding vessels should be reserved for cases when there is failure of conservative or endovascular measures to control the bleeding. Open repair is also required if endovascular facilities or expertise is unavailable and in cases where the patient is unstable. If treated inappropriately, the mortality of patients with retroperitoneal haematoma remains high. Conclusion: There is a lack of level I evidence for the best management plans for retroperitoneal haematoma, and evidence is based on small cohort series or isolated case reports. Conservative management should only be reserved for patients who are stable. Interventional radiology with intra‐arterial embolisation or stent‐grafting is the treatment of choice. Open surgery is now rarely required.     

Laparoscopic retroperitoneal lymphadenectomy in the management of low‐stage testicular cancer: Technique and results

Retroperitoneal lymph node dissection (RPLND) is still the most sensitive and specific method for detection of lymph node metastases of testicular cancer. Because of its invasiveness and morbidity the acceptance of open RPLND has decreased significantly resulting in a diagnostic deficit. To reduce morbidity and to increase the acceptance of RPLND, laparoscopy has been introduced. Meanwhile, clinical data with long‐term follow‐ups are available demonstrating the technical feasibility and oncological safety of laparoscopic RPLND. Studies comparing laparoscopy and open surgery could show advantages for the laparoscopic approach concerning blood loss, intraoperative complications and operative time. Antegrade ejaculation can be preserved in the majority of patients. In conclusion, laparoscopic RPLND is a safe method for the management of low‐stage germ cell tumors with minimal invasiveness and excellent clinical results. With an increasing number of urologists trained in laparoscopy and an increasing number of published data, it may become a standard approach for low‐stage nonseminomatous testicular cancer.     

Heat shock proteins in fibrosis and wound healing: Good or evil?

Heat shock proteins (HSPs) are key regulators of cell homeostasis, and their cytoprotective role has been largely investigated in the last few decades. However, an increasing amount of evidence highlights their deleterious effects on several human pathologies, including cancer, in which they promote tumor cell survival, proliferation and drug resistance. Therefore, HSPs have recently been suggested as therapeutic targets for improving human disease outcomes. Fibrotic diseases and cancer share several properties; both pathologies are characterized by genetic alterations, uncontrolled cell proliferation, altered cell interactions and communication and tissue invasion. The discovery of new HSP inhibitors that have been shown to be efficacious against certain types of cancers has given rise to a new field of research that investigates the activity of these compounds in other incurable human diseases such as fibrotic disorders. The aim of this review is to discuss new findings regarding the involvement of HSPs in the pathogenesis of organ fibrosis and to note recent discoveries that indicate that HSPs could be important therapeutic targets to improve the current dismal outcome of fibrotic diseases.     

Bleomycin and IL-1β–mediated pulmonary fibrosis is IL-17A dependent

Idiopathic pulmonary fibrosis (IPF) is a destructive inflammatory disease with limited therapeutic options. To better understand the inflammatory responses that precede and concur with collagen deposition, we used three models of pulmonary fibrosis and identify a critical mechanistic role for IL-17A. After exposure to bleomycin (BLM), but not Schistosoma mansoni eggs, IL-17A produced by CD4⁺ and γδ⁺ T cells induced significant neutrophilia and pulmonary fibrosis. Studies conducted with C57BL/6 il17a^−/− mice confirmed an essential role for IL-17A. Mechanistically, using ifnγ^−/−, il10^−/−, il10^−/−il12p40^−/−, and il10^−/−il17a^−/− mice and TGF-β blockade, we demonstrate that IL-17A–driven fibrosis is suppressed by IL-10 and facilitated by IFN-γ and IL-12/23p40. BLM-induced IL-17A production was also TGF-β dependent, and recombinant IL-17A–mediated fibrosis required TGF-β, suggesting cooperative roles for IL-17A and TGF-β in the development of fibrosis. Finally, we show that fibrosis induced by IL-1β, which mimics BLM-induced fibrosis, is also highly dependent on IL-17A. IL-17A and IL-1β were also increased in the bronchoalveolar lavage fluid of patients with IPF. Together, these studies identify a critical role for IL-17A in fibrosis, illustrating the potential utility of targeting IL-17A in the treatment of drug and inflammation-induced fibrosis.Despite distinct etiological and clinical features, most chronic fibrotic disorders have in common a persistent irritant that sustains the production of growth factors, proteolytic enzymes, angiogenic factors, and fibrogenic cytokines (Wilson and Wynn, 2009). Together, these factors stimulate the deposition of connective tissue elements that progressively remodel normal tissue architecture. Although initially beneficial, tissue repair processes become pathogenic when they are not regulated, resulting in substantial deposition of extracellular matrix (ECM) components and development of scar tissue. In some diseases, like idiopathic pulmonary fibrosis (IPF), aberrant healing may lead to organ failure and death (Meltzer and Noble, 2008). Indeed, IPF and other chronic fibrotic lung diseases are associated with high morbidity and mortality and are generally refractory to existing pharmacological therapy (Shah et al., 2005). Therefore, better characterization of the molecular and immunological mechanisms of fibrosis is needed to identify new therapeutic modalities for these diseases.Although a variety of cytokines, chemokines, and growth factors are important regulators of fibrosis, we identified a critical role for IL-13 in the development of fibrosis in schistosomiasis, a chronic liver disease caused by the parasitic helminth Schistosoma mansoni (Chiaramonte et al., 1999). Since then, IL-13 has been shown to exhibit fibrotic activity in a variety of diseases and tissues, including models of chronic asthma (Blease et al., 2001), skin fibrosis (Aliprantis et al., 2007), and bronchiolitis obliterans (Keane et al., 2007). A few recent studies have also suggested a role for IL-13 in bleomycin (BLM)-induced pulmonary fibrosis, a well-studied model of IPF (Jakubzick et al., 2003; Fichtner-Feigl et al., 2006). It has been suggested that IL-13 triggers fibrosis by inducing and activating TGF-β (Lee et al., 2001). Nevertheless, the mechanism of action of TGF-β in the development of pulmonary fibrosis remains controversial (Kaviratne et al., 2004; Varga and Pasche, 2008). Although it has been suggested that TGF-β contributes to BLM-induced inflammation and fibrosis by stimulating fibroblast proliferation and collagen-producing myofibroblasts (Cutroneo et al., 2007), recent studies also identified a critical role for TGF-β in the development of IL-17A–producing CD4⁺ T cells (Bettelli et al., 2006; Veldhoen et al., 2006), which regulate the pathogenesis of a variety of autoimmune and inflammatory diseases (Bettelli et al., 2008). Similarly, IL-1β can stimulate IL-17A production (Sutton et al., 2009), and IL-1β is a critical mediator of pulmonary fibrosis (Gasse et al., 2007). To date, however, a link between IL-17A–driven inflammation and pulmonary fibrosis has not been established.The aim of the current study was to characterize the mechanisms of pulmonary fibrosis and to determine whether IL-17A in particular plays an important regulatory role. To do this, three distinct model systems were used, including S. mansoni egg-induced pulmonary fibrosis, BLM-induced pulmonary fibrosis, and the recently described IL-1β–driven fibrosis (Gasse et al., 2007). We report here that S. mansoni egg-mediated fibrosis is IL-13 dependent, as il13^−/− mice developed minimal fibrosis compared with WT mice. In marked contrast, BLM-induced pulmonary fibrosis was independent of IL-13 at early time points. Instead, studies with il17a^−/− mice revealed a critical role for IL-17A. Using IL-10^gfp reporter mice and newly generated IL-10 and IL-17A double cytokine-deficient animals, we determined that CD4⁺ cell-derived IL-10 is required to limit the production and frequency of IL-17A⁺CD4⁺ and IL-17A⁺γδ⁺ T cells, thus preventing the development of severe IL-17A–driven fibrosis. We also show that IL-17A is essential for the development of fibrosis in response to IL-1β, thus extending recent studies that described an early innate role for IL-1β in pulmonary fibrosis (Gasse et al., 2007). Together, these studies demonstrate that fibrotic tissue remodeling is induced by distinct cytokine-dependent mechanisms, with the effector cytokines IL-13 and IL-17A playing central roles. Moreover, these findings suggest that TGF-β and proinflammatory mediators like IL-1β promote fibrosis by up-regulating the production of IL-17A, thus identifying IL-17A blockade as a potential treatment for fibrotic diseases like IPF.     

Membranoproliferative glomerulonephritis in patients with cystic fibrosis: coincidence or comorbidity? A case series

Cystic fibrosis (CF) is perceived as a childhood illness. However, with advances in medical science, patients are enjoying lives extending well into adulthood. This article reviews two cases of membranoproliferative glomerulonephritis (MPGN) in adults with CF. One patient with severe CF pulmonary disease had concomitant renal failure during hospitalization for a pulmonary exacerbation. Subsequent evaluations, including complement levels, were consistent with MPGN. The second patient had been recently diagnosed with colon cancer and was found to be suffering from acute renal failure. Diagnostic evaluation likewise confirmed the MPGN diagnosis. Immunologic associations linking CF and MPGN, including derangements in the complement system and the effects of superantigen production, are reviewed.     

HAART attenuates liver fibrosis in patients with HIV/HCV co-infection: fact or fiction?

Since highly active antiretroviral therapy (HAART) has significantly improved survival in patients with HIV, liver disease from hepatitis C virus (HCV) infection is now an important cause of morbidity and mortality in such a cohort. Studies assessing liver fibrosis in an HIV/HCV cohort are beset with methodological flaws and heterogeneity of the study population, precluding definite conclusions. Nonetheless, recent data (albeit from retrospective studies) do suggest that HAART can attenuate liver fibrosis in the co-infected cohort with fibrosis progression rates comparable to the mono-infected patients. This is especially true for those patients whose HIV was diagnosed after 1996 and for whom HAART is associated with successful viral suppression. The mechanism/s underlying this favourable course of events however remain speculative but could be related to immune restoration-induced changes in inflammatory and fibrogenic cytokines or to a direct effect of HAART on hepatic fibrosis. Therefore with the current available evidence it seems unjustifiable to defer HAART in those that need it because of concerns regarding potential hepatotoxicity as the benefits (both from the HIV and HCV viewpoint) probably outweigh any potential risks. Nonetheless, this issue can only be unequivocally resolved by better designed prospective studies.     

Does hepatic vein transit time performed with contrast-enhanced ultrasound predict the severity of hepatic fibrosis?

Previously published data suggest a hepatic vein transit time (HVTT) threshold of more than 24 s can distinguish mild to moderate from advanced fibrosis. In this study, we attempted to validate HVTT as a noninvasive index of hepatic fibrosis. Patients were scanned using real-time, pulse-inversion mode following bolus injections of the contrast agent Definity. HVTT was correlated with the degree of fibrosis obtained from contemporaneous liver biopsy. The study population included 40 patients with chronic liver disease and five healthy volunteers. Mean HVTT correlated with histologic grade as follows: absence/minimal fibrosis (n = 18), 25.6 ± 11.8 s; moderate fibrosis (n = 17), 21.5 ± 5.9 s; and severe fibrosis (n = 8), 20.9 ± 5.5 s, (p = .615). Poor sensitivity (57%) and specificity (43%) prevent validation of the previously published HVTT threshold as a surrogate marker of hepatic fibrosis. Further work investigating the different interaction of Definity, SonoVue and Levovist with the reticulo-endothelial system may help explain the discrepant results reported here.     

The comparison of effects of rapid opiate detoxification with ketamine complex and with tramadol and naltrexone under general anesthesia with propofol

Objective To release the heroin addicts‘ sufferings,we made rapid opiate detoxification by injecting naloxine under the general anesthesia.Method 160 volunteers were divided at randon into two groups:Group A were performed under the combined anesthesia with propofol,midazolam and kelamine.Group B were performed under the combined anesthesia with propofol with midazolam and tramadol.The vital signs were recorded and the withdrawal syndrome of the volunteers were assessed during the whole process.Result All of the withdrawal symptoms scores 24 hours after ROD in group B were lower than its pre-treatment;The symptoms of the thirs,tsleeping disturbance,nausea and vomiting,skeletal muscular pains and anorexia scores in group A were also lower than its pre-treatment;and no too much differeence belween group A and group B.But tearing,anxiety and diarrhea scores in group A were almost the same as the pre-treatment and higher than group B.Both groups received of the naloxone treatment smoothly,and remained in the hospital for about 3 days.Conclusion The effect of rapid opiate detoxification of naltrexone with the ketamine or tramadol under anesthesia is obvious.The tramadol is better than others.