Fibrotic Patients Research Articles

Identification of MMP28 as a biomarker for the differential diagnosis of idiopathic pulmonary fibrosis.

Background and objectiveIdiopathic Pulmonary Fibrosis (IPF) is a progressive disease of unknown etiology. The diagnosis is based on the identification of a pattern of usual interstitial pneumonia either by high resolution computed tomography and/or histology. However, a similar pattern can be observed in other fibrotic lung disorders, and precise diagnosis remains challenging. Studies on biomarkers contributing to the differential diagnosis are scanty, and still in an exploratory phase. Our aim was to evaluate matrix metalloproteinase (MMP)-28, which has been implicated in abnormal wound healing, as a biomarker for distinguishing IPF from fibrotic non-IPF patients.MethodsThe cell localization of MMP28 in lungs was examined by immunohistochemistry and its serum concentration was measured by ELISA in two different populations. The derivation cohort included 82 IPF and 69 fibrotic non-IPF patients. The validation cohort involved 42 IPF and 41 fibrotic non-IPF patients.ResultsMMP28 was detected mainly in IPF lungs and localized in epithelial cells. In both cohorts, serum concentrations of MMP28 were significantly higher in IPF versus non-IPF (mostly with lung fibrosis associated to autoimmune diseases and chronic hypersensitivity pneumonitis) and healthy controls (ANOVA, p<0.0001). The AUC of the derivation cohort was 0.718 (95%CI, 0.635–0.800). With a cutoff point of 4.5 ng/mL, OR was 5.32 (95%CI, 2.55–11.46), and sensitivity and specificity of 70.9% and 69% respectively. The AUC of the validation cohort was 0.690 (95%CI, 0.581–0.798), OR 4.57 (95%CI, 1.76–12.04), and sensitivity and specificity of 69.6% and 66.7%. Interestingly, we found that IPF patients with definite UIP pattern on HRCT showed higher serum concentrations of MMP28 than non-IPF patients with the same pattern (7.8±4.4 versus 4.9±4.4; p = 0.04). By contrast, no differences were observed when IPF with possible UIP-pattern were compared (4.7±3.2 versus 3.9±3.0; p = 0.43).ConclusionThese findings indicate that MMP28 might be a useful biomarker to improve the diagnostic certainty of IPF.

Impact of IL-27p28 (rs153109) and TNF-α (rs1800629) Genetic Polymorphisms on the Progression of HCV Infection in Egyptian Patients

ABSTRACTBackground: Hepatitis C virus (HCV) is a universal health problem. HCV infection may proceed to liver fibrosis, cirrhosis, and eventually hepatocellular carcinoma (HCC). The latest is the third leading global cause of cancer-related mortality. Cytokines including IL-27 and TNF-α play a major role as a link between innate and adaptive immunity which in turn deduct the outcome of HCV infection.Aim: The present study examined the role of both (-964 A/G) single-nucleotide polymorphism (SNP) of IL-27p28 rs153109 and (-308 G/A) SNP of TNF-α rs1800629 on the progression of HCV infection in genotype 4a infected patients.Patients and Methods: The patients enrolled in the study were divided into three main groups group I: 38 fibrotic patients, group II: 51 cirrhotic patients, and finally group III: 29 HCC patients. Sixteen healthy volunteers were used as controls. IL-27p28 rs153109 and TNF-α rs1800629 genotyping were performed using polymerase chain reaction-restriction fragment length polymorphism assay.Results: There was no statistically significant difference between the studied groups regarding the IL-27p28 genotypes. However, TNF-α (-308) studied polymorphism showed a significant difference between the HCC and fibrosis group (p = 0.00), and also between the cirrhosis and fibrosis group (p = 0.031) revealing that AA genotype is the genotype of risk. Furthermore, the association found between allele frequencies of two studied SNPs and the four studied groups were non-significant.Conclusion: TNF-α rs1800629 polymorphism is a potential genetic-susceptibility factor for HCV related cirrhosis and HCC progression.

Clinical significance of radiological pleuroparenchymal fibroelastosis pattern in interstitial lung disease patients registered for lung transplantation: a retrospective cohort study

BackgroundRadiological pleuroparenchymal fibroelastosis (PPFE) lesion is characterized by pleural thickening with associated signs of subpleural fibrosis on high-resolution computed tomography (HRCT). This study evaluated the clinical significance of radiological PPFE as an isolated finding or associated with other interstitial lung diseases (ILDs) in patients having fibrotic ILDs and registered for cadaveric lung transplantation (LT).MethodsThis retrospective study included 118 fibrotic ILD patients registered for LT. Radiological PPFE on HRCT was assessed. The impact of radiological PPFE on clinical features and transplantation-censored survival were evaluated.ResultsRadiological PPFE was observed in 30/118 cases (25%): definite PPFE (PPFE concentrated in the upper lobes, with involvement of lower lobes being less marked) in 12 (10%) and consistent PPFE (PPFE not concentrated in the upper lobes, or PPFE with features of coexistent disease present elsewhere) in 18 (15%). Of these, 12 had late-onset non-infectious pulmonary complications after hematopoietic stem-cell transplantation and/or chemotherapy (LONIPCs), 9 idiopathic PPFE, and 9 other fibrotic ILDs (idiopathic pulmonary fibrosis, IPF; other idiopathic interstitial pneumonias, other IIPs; connective tissue disease-associated ILD, CTD-ILD, and hypersensitivity pneumonia, HP). Radiological PPFE was associated with previous history of pneumothorax, lower body mass index, lower percentage of predicted forced vital capacity (%FVC), higher percentage of predicted diffusion capacity of carbon monoxide, less desaturation on six-minute walk test, and hypercapnia. The median survival time of all study cases was 449 days. Thirty-seven (28%) received LTs: cadaveric in 31 and living-donor lobar in six. Of 93 patients who did not receive LT, 66 (71%) died. Radiological PPFE was marginally associated with better survival after adjustment for age, sex, %FVC, and six-minute walk distance < 250 m (hazard ratio 0.51 [0.25–1.05], p = 0.07). After adjustment for covariates, idiopathic PPFE and LONIPC with radiological PPFE was associated with better survival than fibrotic ILDs without radiological PPFE (hazard ratio 0.38 [0.16–0.90], p = 0.03), and marginally better survival than other fibrotic ILDs with radiological PPFE (hazard ratio, 0.20 [0.04–1.11], p = 0.07).Conclusionsidiopathic PPFE and LONIPC with radiological PPFE has better survival on the wait list for LT than fibrotic ILDs without radiological PPFE, after adjustment for age, sex, %FVC, and six-minute walk distance.

Activation of ferritinophagy is required for the RNA-binding protein ELAVL1/HuR to regulate ferroptosis in hepatic stellate cells

ABSTRACTFerroptosis is a recently recognized form of regulated cell death that is characterized by lipid peroxidation. However, the molecular mechanisms regulating ferroptosis are largely unknown. In this study, we report that the RNA-binding protein ELAVL1/HuR plays a crucial role in regulating ferroptosis in liver fibrosis. Upon exposure to ferroptosis-inducing compounds, ELAVL1 protein expression was remarkably increased through the inhibition of the ubiquitin-proteasome pathway. ELAVL1 siRNA led to ferroptosis resistance, whereas ELAVL1 plasmid contributed to classical ferroptotic events. Interestingly, upregulated ELAVL1 expression also appeared to increase autophagosome generation and macroautophagic/autophagic flux, which was the underlying mechanism for ELAVL1-enhanced ferroptosis. Autophagy depletion completely impaired ELAVL1-mediated ferroptotic events, whereas autophagy induction showed a synergistic effect with ELAVL1. Importantly, ELAVL1 promoted autophagy activation via binding to the AU-rich elements within the F3 of the 3ʹ-untranslated region of BECN1/Beclin1 mRNA. The internal deletion of the F3 region abrogated the ELAVL1-mediated BECN1 mRNA stability, and, in turn, prevented ELAVL1-enhanced ferroptosis. In mice, treatment with sorafenib alleviated murine liver fibrosis by inducing hepatic stellate cell (HSC) ferroptosis. HSC-specific knockdown of ELAVL1 impaired sorafenib-induced HSC ferroptosis in murine liver fibrosis. Noteworthy, we retrospectively analyzed the effect of sorafenib on HSC ferroptosis in advanced fibrotic patients with hepatocellular carcinoma receiving sorafenib monotherapy. Attractively, ELAVL1 upregulation, ferritinophagy activation, and ferroptosis induction occurred in primary human HSCs from the collected human liver tissue. Overall, these results reveal novel molecular mechanisms and signaling pathways of ferroptosis, and also identify ELAVL1-autophagy-dependent ferroptosis as a potential target for the treatment of liver fibrosis.Abbreviations: ACTA2/alpha-SMA: actin, alpha 2, smooth muscle, aorta; ACTB/beta-actin: actin beta; ARE: AU-rich element; ATG: autophagy related; BDL: bile duct ligation; BECN1: beclin 1; BSO: buthionine sulfoximine; COL1A1: collagen type I alpha 1 chain; ELAVL1/HuR: ELAV like RNA binding protein 1; FDA: fluorescein diacetate; FTH1: ferritin heavy chain 1; GOT1/AST: glutamic-oxaloacetic transaminase 1; GPT/ALT: glutamic–pyruvic transaminase; GPX4: glutathione peroxidase 4; GSH: glutathione; HCC: hepatocellular carcinoma; HSC: hepatic stellate cell; LCM: laser capture microdissection; MAP1LC3B: microtubule associated protein 1 light chain 3 beta; MDA: malondialdehydep; NCOA4: nuclear receptor coactivator 4; PTGS2: prostaglandin-endoperoxide synthase 2; ROS: reactive oxygen species; SQSTM1/p62: sequestosome 1; TBIL: total bilirubin; TEM: transmission electron microscopy; TGFB1: trasforming growth factor beta 1; UTR: untranslated region; VA-Lip-ELAVL1-siRNA: vitamin A-coupled liposomes carrying ELAVL1-siRNA.

EVALUATION OF LIVER FIBROSIS BY NONINVASIVE MARKER IN PATIENTS WITH CHRONIC VIRAL HEPATITIS B

Objectives: To determine the frequency of liver fibrosis by non invasive markerin patients with chronic viral hepatitis B. Study Design: Cross sectional clearly investigate aboutchronic viral hepatitis population. Setting: Liaquat University Hospital Hyderabad. Period: Sixmonths, 09-Jan-2014 to 08-July-2014. Patients and Methods: All the patients of 16-50 years ofage, of either gender with chronic viral hepatitis B infection for more than 6 months duration wereadmitted and evaluated for liver fibrosis through non invasive marker (APRI). The SPSS was usedto manipulate the data. Results: During six month study period, total 140 patients with chronicviral hepatitis B infected patients were evaluated for liver fibrosis. Majority of patients were fromurban areas 112/140 (80%). The mean ±SD for age of patients with chronic viral hepatitis Binfection was 37.95±9.77. The mean age ±SD of hepatic fibrotic patients was 35.72±7.62.The mean ±SD for age of male and female population was 35.83±8.74 and 33.83 ± 6.53respectively. The mean ± SD for APRI score in hepatic fibrotic subjects was 1.31±0.31 while inrelation to liver fibrotic male and female patients it was 0.91±0.21 and 1.00±0.32 respectively.Majority of the subjects were 30-39 years of age and the male population predominant (p=0.02)whereas the liver fibrosis was identified in 89/140 (63.5) [p=<0.01] as far as gender distributionis concerned. Conclusion: APRI may be used as a simple and readily available tool for thediagnosis of significant fibrosis in patients with chronic viral hepatitis B.

CHRONIC VIRAL HEPATITIS B;

Objectives: To determine the frequency of liver fibrosis by non invasive markerin patients with chronic viral hepatitis B. Study Design: Cross sectional clearly investigate aboutchronic viral hepatitis population. Setting: Liaquat University Hospital Hyderabad. Period: Sixmonths, 09-Jan-2014 to 08-July-2014. Patients and Methods: All the patients of 16-50 years ofage, of either gender with chronic viral hepatitis B infection for more than 6 months duration wereadmitted and evaluated for liver fibrosis through non invasive marker (APRI). The SPSS was usedto manipulate the data. Results: During six month study period, total 140 patients with chronicviral hepatitis B infected patients were evaluated for liver fibrosis. Majority of patients were fromurban areas 112/140 (80%). The mean ±SD for age of patients with chronic viral hepatitis Binfection was 37.95±9.77. The mean age ±SD of hepatic fibrotic patients was 35.72±7.62.The mean ±SD for age of male and female population was 35.83±8.74 and 33.83 ± 6.53respectively. The mean ± SD for APRI score in hepatic fibrotic subjects was 1.31±0.31 while inrelation to liver fibrotic male and female patients it was 0.91±0.21 and 1.00±0.32 respectively.Majority of the subjects were 30-39 years of age and the male population predominant (p=0.02)whereas the liver fibrosis was identified in 89/140 (63.5) [p=&lt;0.01] as far as gender distributionis concerned. Conclusion: APRI may be used as a simple and readily available tool for thediagnosis of significant fibrosis in patients with chronic viral hepatitis B.

Systematic review of drug effects in humans and models with surfactant-processing disease.

Fibrotic interstitial pneumonias are a group of rare diseases characterised by distortion of lung interstitium. Patients with mutations in surfactant-processing genes, such as surfactant protein C (SFTPC), surfactant protein A1 and A2 (SFTPA1 and A2), ATP binding cassette A3 (ABCA3) and Hermansky-Pudlak syndrome (HPS1, 2 and 4), develop progressive pulmonary fibrosis, often culminating in fatal respiratory insufficiency. Although many mutations have been described, little is known about the optimal treatment strategy for fibrotic interstitial pneumonia patients with surfactant-processing mutations.We performed a systematic literature review of studies that described a drug effect in patients, cell or mouse models with a surfactant-processing mutation. In total, 73 articles were selected, consisting of 55 interstitial lung disease case reports/series, two clinical trials and 16 cell or mouse studies. Clinical effect parameters included lung function, radiological characteristics and clinical symptoms, while experimental outcome parameters included chemokine/cytokine expression, surfactant trafficking, necrosis and apoptosis. SP600125, a c-jun N-terminal kinase (JNK) inhibitor, hydroxychloroquine and 4-phenylbutyric acid were most frequently studied in disease models and lead to variable outcomes, suggesting that outcome is mutation dependent.This systematic review summarises effect parameters for future studies on surfactant-processing disorders in disease models and provides directions for future trials in affected patients.

Obstructive sleep apnoea in patients with fibrotic diffuse parenchymal lung disease-characterization and treatment compliance assessment.

IntroductionRecent studies have reported a high prevalence of obstructive sleep apnoea (OSA) among patients with diffuse parenchymal lung disease (DPLD), mainly idiopathic pulmonary fibrosis (IPF). Effective OSA treatment appears to have a positive impact on morbidity and mortality in these patients. However, poor compliance to positive airway pressure (PAP) treatment in fibrotic DPLD patients has been reported. The aims of our study were to characterize patients with fibrotic DPLD and OSA and to assess their compliance to PAP treatment.MethodsForty-nine patients with fibrotic DPLD underwent level III polysomnography. Auto-adjusting PAP (APAP) treatment was proposed for those patients with moderate-to-severe OSA and those with mild OSA with daytime sleepiness and/or cardiovascular disease. The APAP treatment compliance was assessed after 1 month of therapy.ResultsThe distribution of the 49 fibrotic DPLD patients included was as follows: 21 with chronic hypersensitivity pneumonitis, 12 with IPF, 10 with connective-tissue associated DPLD, 4 with stage IV sarcoidosis, 1 with idiopathic pleuropulmonary fibroelastosis, and 1 with DPLD-associated vasculitis. Thirty-four (69.4%) of the patients presented with OSA; 22 had mild OSA, and 12 had moderate-to-severe OSA. APAP treatment was prescribed in 17 of the patients. After 1 month of therapy, all patients used APAP more than 70% of the nights for more than 4 h per night.ConclusionWe found a high prevalence of OSA among all of the patients with fibrotic DPLD (not only IPF). Despite certain difficulties, it was possible to achieve good APAP compliance in these patients.

Cardiorespiratory adaptation during 6-Minute Walk Test in fibrotic idiopathic interstitial pneumonia patients who did or did not respond to pulmonary rehabilitation.

Pulmonary rehabilitation (PR) improves performance in the 6-min walk test (6MWT) in a subset of patients with fibrotic idiopathic interstitial pneumonia (f-IIP); however, a large proportion of patients does not respond to PR. To investigate the effects of a PR program on cardiorespiratory responses during a 6MWT and to identify the characteristics of patients who do not show improved performance after PR. An observational study. Patients were recruited from the Competence Centre for Rare Pulmonary Diseases at Lille University Hospital, France and completed an 8-week home-based PR program. A total of 19 patients with f-IIP; 12 with idiopathic pulmonary fibrosis (IPF) and 7 with fibrotic non-specific interstitial pneumonia. Patients underwent spirometry and completed a 6MWT before and after an 8-week PR program. Gas exchange, heart rate, and pulse O2 saturation were measured continuously during the 6MWT. Quality of life, dyspnea, and anxiety/depression were assessed using the Short-Form 36 (SF-36), the baseline/transition dyspnea index (BDI/TDI), and the Hospital Anxiety and Depression Scale (HADS) questionnaires. Patients who did and did not improve the distance walked in the 6MWT by at least 30 m after PR were classified as responders (N.=9) and non-responders (N.=10), respectively. O2 uptake, ventilation rate, and distance covered during the 6MWT were significantly improved only in the responder group (P<0.05). Changes in SF-36, BDI/TDI, and HADS scores did not differ significantly between responders and non-responders. The non-responder group contained significantly more patients with IPF (P<0.05) and experienced greater arterial oxygen desaturation during the 6MWT compared with the responder group. Failure to improve performance in the 6MWT after PR was associated with a diagnosis of IPF, non-improvement in gas exchange, and greater arterial oxygen desaturation. Most f-IIP patients who did not respond to PR were diagnosed with IPF and displayed greater hypoxemia during exercise. Clinical practitioners should seek to determine why patients fail to improve exercise performance after PR and propose an alternative exercise regimen to these patients.

Lifestyle intervention for morbid obesity: effects on liver steatosis, inflammation, and fibrosis

The prevalence of obesity-related nonalcoholic fatty liver disease (NAFLD) is rising. NAFLD may result in nonalcoholic steatohepatitis (NASH), progressing to liver cirrhosis. Weight loss is recommended to treat obesity-related NASH. Lifestyle intervention may improve NASH; however, pertinent trials have so far focused on overweight patients, whereas patients with obesity are at highest risk of developing NAFLD. Furthermore, reports of effects on liver fibrosis are scarce. We evaluated the effect of lifestyle intervention on NAFLD in a real-life cohort of morbidly obese patients. In our observational study, 152 patients underwent lifestyle intervention, with a follow-up of 52 weeks. Noninvasive measures of obesity, metabolic syndrome, liver steatosis, liver damage, and liver fibrosis were analyzed. Treatment response in terms of weight loss was achieved in 85.1% of patients. Dysglycemia and dyslipidemia improved. The proportion of patients with fatty liver dropped from 98.1 to 54.3% ( P < 0.001). Weight loss >10% was associated with better treatment response ( P = 0.0009). Prevalence of abnormal serum transaminases fell from 81.0 to 50.5% ( P < 0.001). The proportion fibrotic patients, as determined by the NAFLD fibrosis score, dropped from 11.8 to 0% ( P < 0.05). Low serum levels of adiponectin correlated with degree of liver damage, i.e., serum liver transaminases ( r = -0,32, P < 0.05). Serum levels of adiponectin improved with intervention. In conclusion, lifestyle intervention effectively targeted obesity and the metabolic syndrome. Liver steatosis, damage and fibrosis were ameliorated in this real-life cohort of morbidly obese patients, mediated in part by changes in the adipokine profile. Patients with weight loss of >10% seemed to benefit most. NEW & NOTEWORTHY We demonstrate new evidence that lifestyle intervention is effective in treating NAFLD in the important group of patients with (morbid) obesity. Although current guidelines on the therapy of NASH recommend weight loss of 5-7%, weight reduction >10% may be favorable in morbid obesity. Serum levels of adipokines correlate with liver damage, which is indicative of their pathogenetic importance in human NASH. Our study adds to the limited body of evidence that NAFLD-associated liver fibrosis may resolve with lifestyle intervention.

High Concentrations of Sodium Chloride Improve Microbicidal Activity of Ibuprofen against Common Cystic Fibrosis Pathogens.

Ibuprofen (IBU-H), a widely used anti-inflammatory, also shows a marked antimicrobial effect against several bacterial species, including those involved in cystic fibrosis such as Pseudomona aeruginosa, methicillin resistant Staphylococcus aureus and Burkholderia cepacia complex. Additionally, our results show significant synergy between water soluble Na-ibuprofen (IBU-Na) and ionic strength. Salt concentrations above 0.5 M modify the zeta potential promoting the action of Na-IBU; thus, with 1 M sodium chloride, IBU-Na is ten times more efficient than in the absence of ionic strength, and the minimum effective contact time is reduced from hours to minutes. In short time periods, where neither IBU-Na nor controls with 1 M NaCl show activity, the combination of both leads to a reduction in the bacterial load. We also analyzed whether the changes caused by salt on the bacterial membrane also promoted the activity of other microbicide compounds used in cystic fibrosis like gentamicin, tobramycin and phosphomycin. The results show that the presence of ionic strength only enhanced the bactericidal activity of the amphipathic molecule of IBU-Na. In this respect, the effect of saline concentration was also reflected in the surface properties of IBU-Na, where, in addition to the clear differences observed between 145 mM and 1 M, singular behaviors were also found, different in each condition. The combination of anti-inflammatory activity and this improved bactericidal effect of Na-IBU in hypertonic solution provides a new alternative for the treatment of respiratory infections of fibrotic patients based on known and widely used compounds.

Autophagy Attenuates Angiotensin II-Induced Pulmonary Fibrosis by Inhibiting Redox Imbalance-Mediated NOD-Like Receptor Family Pyrin Domain Containing 3 Inflammasome Activation

The NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome, which is activated by reactive oxygen species (ROS) and repressed by autophagy, has been identified as a novel agent of pulmonary fibrosis. Angiotensin II (AngII), the bioactive pro-oxidant in the renin-angiotensin system, aggravates lung fibrosis. However, the effect of AngII on NLRP3 inflammasome and autophagy in lung fibrosis remains unknown. This study investigates the potential link between AngII-induced autophagy in the regulation of NLRP3 inflammasome/IL-1β axis in lung fibrosis. In vivo, autophagy and the NLRP3 inflammasome were activated in fibrotic patients and positively correlated with oxidation. Treatment with rapamycin promoted autophagy but inhibited oxidation, NLRP3 inflammasome, and lung fibrosis after bleomycin (BLM) infusion. The autophagy inhibitor 3-methyladenine reduced BLM-induced lung fibrosis and concurrently facilitated NLRP3 inflammasome activation and oxidation in fibroblasts. In vitro, AngII promoted intercellular ROS, hydrogen peroxide, and NADPH oxidase 4 (NOX4) protein levels and reduced the glutathione concentration, thereby leading to NLRP3 inflammasome activation and consequent collagen synthesis. AngII induced autophagy, while VAS2870, NOX4, small-interfering RNA (siRNA), and compound C eliminated AngII-induced LC3B augmentation. Moreover, blocking autophagy with bafilomycin A1 or LC3B siRNA resulted in oxidant accumulation, NLRP3 inflammasome hyperactivation, and collagen deposition. Finally, AngII induced P62/SQSTM1, targeting ubiquitinated apoptosis-associated speck-like protein containing a CARD for degradation, thereby contributing to NLRP3 inflammasome inactivation. Innovation and Conclusion: Autophagy attenuates pulmonary fibrosis by regulating NLRP3 inflammasome activation induced by AngII-mediated ROS via redox balance modulation.

A single-center experience of 1500 lung transplant patients

ObjectiveOver the past 30 years, lung transplantation has emerged as the definitive treatment for end-stage lung disease. In 2005, the lung allocation score (LAS) was introduced to allocate organs according to disease severity. The number of transplants performed annually in the United States continues to increase as centers have become more comfortable expanding donor and recipient criteria and have become more facile with the perioperative and long-term management of these patients. We report a single-center experience with lung transplants, looking at patients before and after the introduction of LAS. MethodsWe retrospectively reviewed 1500 adult lung transplants at a single center performed between 1988 and 2016. Patients were separated into 2 groups, before and after the introduction of LAS: group 1 (April 1988 to April 2005; 792 patients) and group 2 (May 2005 to September 2016; 708 patients). ResultsDifferences in demographic data were noted over these periods, reflecting changes in allocation of organs. Group 1 patient average age was 48 ± 13 years, and 404 subjects (51%) were male. Disease processes included emphysema (52%; 412), cystic fibrosis (18.2%; 144), pulmonary fibrosis (16.1%; 128) and pulmonary vascular disease (7.2%; 57). Double lung transplant (77.7%; 615) was performed more frequently than single lung transplant (22.3%; 177). Group 2 average age was 50 ± 14 years, and 430 subjects (59%) were male. Disease processes included pulmonary fibrosis (46%; 335), emphysema (25.8%; 188), cystic fibrosis (17.7%; 127) and pulmonary vascular disease (1.6%; 11). Double lung transplant (96.2%; 681) was performed more frequently than single lung transplant (3.8%; 27). Overall incidence of grade 3 primary graft dysfunction (PGD) in group 1 was significantly lower at 22.1% (175) than in group 2 at 31.6% (230) (P < .001). Nonetheless, overall hospital mortality was not statistically different between the 2 groups (4.4% vs 3.5%; P < .4). Most notably, survival at 1 year was statistically different at 646 (81.6%) for group 1 and 665 (91.4%) for group 2 (P < .02). ConclusionsPatient demographics over the study period have changed with an increased number of fibrotic patients transplanted. In addition, more aggressive strategies with donor/recipient selection appear to have resulted in a higher incidence of primary graft dysfunction. This does not, however, appear to affect patient survival on index hospitalization or at 1 year. In fact, we have observed a significant improvement in survival at 1 year in the more recent era. This observation suggests that continued expansion of possible donors and recipients, coupled with a more sophisticated understanding of primary graft dysfunction and long-term chronic rejection, can lead to increased transplant volume and prolonged survival.

Effects of pulmonary rehabilitation on daily life physical activity of fibrotic idiopathic interstitial pneumonia patients.

Fibrotic idiopathic interstitial pneumonia patients derived benefit from a pulmonary rehabilitation programme in terms of exercise tolerance, anxiety, depression and quality of life without increasing their daily life physical activity http://ow.ly/WV7U30kgNkU

Simple score to predict risk of hepatocellular carcinoma in chronic hepatitis C patients with advanced fibrosis after pegylated interferon and ribavirin therapy.

PurposeEradication of chronic hepatitis C virus (HCV) after interferon-based therapy and its association with the reduction of risk of hepatocellular carcinoma (HCC) in HCV-infected patients with advanced fibrosis is controversial. The study is aimed to develop a simple scoring model for HCC prediction among advanced fibrotic chronic hepatitis C (CHC) patients after pegylated interferon (pegIFN) and ribavirin (RBV) therapy.Patients and methodsWe enrolled 271 biopsy-proven CHC patients with advanced fibrosis between 2003 and 2016, and divided them into non-HCC (n=211) and HCC (n=60) groups. The median observation duration was 6.0 years (range: 0.9–12.6 years).ResultsThe HCC prevalence after pegIFN and RBV therapy in CHC patients with sustained virologic response (SVR) and without SVR was 14.7% and 32.2%, respectively. Multivariate Cox regression showed age ≥59.5 years old at initiation of therapy (HR: 2.542, 95% CI: 1.390–4.650, P=0.002), pretreatment total bilirubin ≥1.1 mg/dL (HR: 2.630, 95% CI: 1.420–4.871, P=0.002), pretreatment platelet counts <146.5 × 103/μL (HR: 2.751, 95% CI: 1.373–5.511, P=0.004), no achievement of SVR (HR: 2.331, 95% CI: 1.277–4.253, P=0.006), and no diabetes at treatment initiation (HR: 3.085, 95% CI: 1.283–7.418, P=0.012) were significant predictors of HCC development. The scoring model consisted of the five categorical predictors and had an optimal cutoff point of 2.5. The area under receiver operating characteristic (AUROC) of the scoring model was 0.774±0.035 (P<0.001). The sensitivity and specificity of the cutoff value to detect HCC were 81.3% and 57.5%. The 5-year and 10-year cumulative incidence of HCC was 4.9% and 10.0% in patients with simple score ≤2; and 25.9% and 44.6% in patients with simple score ≥3 (P<0.001).ConclusionThe simple clinical-guided score has high discriminatory power for HCC prediction in advanced fibrotic CHC patients after pegIFN and RBV therapy.

Evaluation of Serum Levels of Endothelial Adhesion Molecules: Leukocyte Adhesion Molecule-1 (LAM-1), CD11a/CD18 (LFA-1) and CD11b/CD18 (Mac-1) in Fibrotic Patients

Leukocyte adhesion molecule-1 (LAM-1), CD11a/CD18 (LFA-1) and CD11b/CD18 (Mac-1) are adhesion molecules and constitute important steps in the liver inflammation due to chronic hepatitis C. We measured soluble intercellular adhesion molecule (LAM-1), (LFA-1) and (Mac-1) as well as cholesterol and triglyceride concentrations in the serum of 120 patients with fibrosis. A study was carried out to analyze levels of LAM-1, LFA-1 and Mac-1in fibrotic patients, and find whether increasing with cholesterol and triglycerides. 120 serum samples from fibrotic patients were classified according to levels of Cholesterol and Triglycerides concentration into four groups. Positive LAM-1 samples were found in 90% of patients in first group, 83% in the second group, 73% in the third group and 46% in the fourth group. These levels were significantly higher than their levels in control group (p&lt;0.0001) indicating extremely significant. Level of LAM-1in group (1) was extremely significant compared to group (4) (356 ± 70.5 vs. 209± 5 p &lt; 0.0001 ES). High LFA-1level was found in 76% in first group, 73% in the second group, 70% in the third group, and 40% in the fourth group. The levels of MAC-1 in first group were significantly greater than their levels in control group (p&lt;0.0001), and +ve MAC-1 samples were found in 66% in first group, 53% in the second group, 46% in third group, and 36% in fourth group. AST and ALT were significantly higher in first group, compared to healthy group (95.68 ± 33.32 vs. 31.77 ± 8.11, p &lt; 0.001) for AST and (78.6 ± 29.86 vs. 28.55 ± 7.15 p &lt; 0.001) for ALT indicating very significant relationship, while no significant was detected between the fourth group and healthy individuals (33.56±8.16 vs. 28.55 ± 7.15 p = 0.05 NS). Our study showed a significant increase in levels of LAM-1 and LFA-1 rather than MAC-1 in fibrosis compared to healthy individuals. The results showed the ability to circulate LAM-1 and LFA-1 to predict fibrosis disease and evaluated the relationship between circulating adhesion molecules and fibrotic patients.

Unmet Needs for Palliation in Fibrotic Interstitial Lung Disease.

Chronic fibrotic interstitial lung disease (ILD) forms a substantial proportion of disabling lung diseases and leads to significant morbidity and mortality. The mortality of these patients when admitted to the Intensive Care Unit with acute respiratory worsening requiring mechanical ventilation can reach up to 90%. Indian law does not allow the physician to make the final decision about mechanical ventilation, we are forced to follow the wishes of the family despite knowing the extremely poor outcome of aggressive intervention and invasive ventilation. Patients more often become ventilator dependent and do not gain much regarding the quality of life with mechanical ventilation. Hence, there is a desperate need for palliative support for these patients with advance care planning to reduce the suffering of these patients toward the end of life. The article describes various methods by which the decision making process of mechanical ventilation could be made simpler and acceptable to the patient and the families of fibrotic Interstitial lung disease patients and also the dilemma faced by chest physician in India with virtually no prior end of life planning and no clear guidelines on ventilation when it comes to palliation of patients with advanced ILD.

Termination of re-entrant atrial tachycardia via optogenetic stimulation with optimized spatial targeting: insights from computational models.

Optogenetics has emerged as a potential alternative to electrotherapy for treating heart rhythm disorders, but its applicability for terminating atrial arrhythmias remains largely unexplored. We used computational models reconstructed from clinical MRI scans of fibrotic patient atria to explore the feasibility of optogenetic termination of atrial tachycardia (AT), comparing two different illumination strategies: distributed vs. targeted. We show that targeted optogenetic stimulation based on automated, non-invasive flow-network analysis of patient-specific re-entry morphology may be a reliable approach for identifying the optimal illumination target in each individual (i.e. the critical AT isthmus). The above-described approach yields very high success rates (up to 100%) and requires dramatically less input power than distributed illumination We conclude that simulations in patient-specific models show that targeted light pulses lasting longer than the AT cycle length can efficiently and reliably terminate AT if the human atria can be successfully light-sensitized via gene delivery of ChR2. Optogenetics has emerged as a potential alternative to electrotherapy for treating arrhythmia, but feasibility studies have been limited to ventricular defibrillation via epicardial light application. Here, we assess the efficacy of optogenetic atrial tachycardia (AT) termination in human hearts using a strategy that targets for illumination specific regions identified in an automated manner. In three patient-specific models reconstructed from late gadolinium-enhanced MRI scans, we simulated channelrhodopsin-2 (ChR2) expression via gene delivery. In all three models, we attempted to terminate re-entrant AT (induced via rapid pacing) via optogenetic stimulation. We compared two strategies: (1) distributed illumination of the endocardium by multi-optrode grids (number of optrodes, Nopt =64, 128, 256) and (2) targeted illumination of the critical isthmus, which was identified via analysis of simulated activation patterns using an algorithm based on flow networks. The illuminated area and input power were smaller for the targeted approach (19-57.8mm2 ; 0.6-1.8W) compared to the sparsest distributed arrays (Nopt =64; 124.9±6.3mm2 ; 3.9±0.2W). AT termination rates for distributed illumination were low, ranging from <5% for short pulses (1/10ms long) to ∼20% for longer stimuli (100/1000ms). When we attempted to terminate the same AT episodes with targeted illumination, outcomes were similar for short pulses (1/10ms long: 0% success) but improved for longer stimuli (100ms: 54% success; 1000ms: 90% success). We conclude that simulations in patient-specific models show that light pulses lasting longer than the AT cycle length can efficiently and reliably terminate AT in atria light-sensitized via gene delivery. We show that targeted optogenetic stimulation based on analysis of AT morphology may be a reliable approach for defibrillation and requires less power than distributed illumination.

Targeting secreted cytokine BMP9 gates the attenuation of hepatic fibrosis

Liver fibrosis is overly exuberant wound healing that leads to portal hypertension or liver cirrhosis. Recent studies have demonstrated the functions of bone morphogenetic protein 9 (BMP9) in liver fibrosis, and thus, targeting liver-specific BMP9 abnormalities will become an attractive approach for developing therapeutics to treat liver fibrosis. Here, we reveal that BMP9 serves as a valuable serum diagnostic indicator and efficient therapeutic target to attenuate liver fibrogenesis. Our analysis of biopsies from liver fibrotic patients revealed that higher BMP9 levels accompanied advanced stages of liver fibrosis. In mouse models, recombinant Bmp9 overexpression accelerated liver fibrosis, and adenovirus-mediated Bmp9 knockdown attenuated liver fibrogenesis. Intriguingly, BMP9 directly stimulated hepatic stellate cell activation via the SMAD signaling pathway to enhance hepatic fibrosis. Moreover, an inhibitory monoclonal antibody targeting Bmp9 was efficacious in treatment of mice with liver fibrosis. These observations delineate a novel model in which BMP9 directly drives SMAD/ID1 signaling in hepatic stellate cells, which modulates liver fibrogenesis development. Moreover, the findings unveil a promising surrogate biomarker for the diagnosis of hepatic fibrosis, thereby representing an efficient “BMP9 neutralization” approach in alleviating hepatic fibrosis.

Exertional hypoxemia is more severe in fibrotic interstitial lung disease than in COPD.

Despite its clinical and prognostic significance, few studies have evaluated the severity of exertional oxygen desaturation in fibrotic interstitial lung disease (ILD). Our objectives were to identify clinical and physiological variables that predict the extent of exertional oxygen desaturation in fibrotic ILD and to quantify the severity of desaturation compared to chronic obstructive pulmonary disease (COPD). This retrospective study compared the results of 6-min walk test (6MWT) performed while breathing room air in fibrotic ILD patients and COPD patients eligible for pulmonary rehabilitation. Outcomes included the oxygen saturation (SpO2 ) nadir and the change in SpO2 from rest during a 6MWT. Predictor variables were identified on unadjusted analysis, followed by multivariate analysis to identify independent predictors of desaturation. The study included 134 patients with fibrotic ILD and 274 patients with COPD. The ILD and COPD cohorts had similar age, sex, frequency of major comorbidities, walk distance, baseline SpO2 and baseline Borg dyspnoea scores. DLCO was the strongest predictor of desaturation in both cohorts. Compared to patients with COPD, ILD patients had significantly lower SpO2 nadir values (88.1 ± 6.4 vs 91.0 ± 4.6) and greater decrease in SpO2 from baseline (7.4 ± 5.2 vs 4.5 ± 3.7) after adjusting for demographic features and pulmonary physiology (P < 0.0005), with greater between-group differences at lower DLCO values. Patients with fibrotic ILD have greater oxygen desaturation during 6MWT compared to patients with COPD when adjusting for demographic features and pulmonary physiology. These findings suggest the need for disease-specific studies to evaluate the potential utility of ambulatory oxygen in fibrotic ILD.