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PubMed1977

Studies on cystic fibrosis using isoelectric focusing. IV. Distinction between ciliary dyskinesia activity in cystic fibrosis and asthmatic sera and association of cystic fibrosis protein with the activity in cystic fibrosis serum.

The cystic fibrosis protein (CFP) and ciliary dyskinesia activities (CDA) in sera from CF homozygotes, heterozygote carriers, and individuals with bronchial asthma have been partially purified. Concurrently, the CDA's in sera from patients with cystic fibrosis (CF) or bronchial asthma were shown to be different substances by ion-exchange or gel permeation chromatographic procedures. Sephadex G-200 chromatography indicated that the CF-CDA eluted with a protein fraction of molecular weight (MW) 68,000-150,000 and that the asthma CDA was found in a protein fraction of MV greater than 150,000. The two activities could also be separated by DEAE-cellulose chromatography. Prior acidification of whole normal, CF homozygote, obligate heterozygote, or asthmatic sera to pH 3.7 using EDTA, followed by fractionation of Sephadex G-200 removed all the CDA's from fractions of highermolecular weight and shifted the activities to a protein fraction of MW 1,100-13,700. This procedure afforded a 200-fold purification of the CDA's in sera from patients with asthma or CF. EDTA treatment, however, also generated a CDA in previously nonreactive normal sera. Subsequent fractionation of the various active G-200 fractions on Bio-Gel P10 allowed for the separation of three separate activities (Bio-Gel Fractions I, II-IV, and V). Fraction I was shown to represent the activity in sera from patients with asthma and was determined to be C3a (MW 9,000). Fraction I was also found in normal, CF, and carrier sera and therefore is not a specific CDA. Fraction II-IV is thought to represent a CF-specific CDA (MW 5,000) since it could not be demonstrated in either normal or asthmatic sera but was found in sera of obligate heterozygotes. Fraction III-IV also did not react with antisera to human C3a. Fraction V was generated from all serum types upon acidification of the serum with EDTA and is thought to be a nonspecific CDA. Bio-Gel P10 filtration of Sephadex G-200 fractions provided 823-fold and 650-fold purification of the asthmatic and CF CDA's, respectively. Concurrent analysis of column fractions for CDA's by bioassay and for CFP by electrofocusing showed CFP only in fractions that contained the CF-CDA. Combined analyses employing acid disc gel electrophoresis, isoelectric focusing, and EDTA treatment of active CF-immunoglobulin (Ig) G and Sephadex G-200 column fractions, followed by Bio-Gel P10 chromatography, provided evidence that CFP was associated with the CF-CDA. It is unknown as yet whether CFP itself is responsible for the CF-CDA activity.

Asthma↗
PubMed1996

Fibroblast radiosensitivity in vitro and lung fibrosis in vivo: comparison between a fibrosis-prone and fibrosis-resistant mouse strain.

Radiation-induced pneumonitis and fibrosis in the lung after treatment to the thoracic cavity for malignant disease currently limit the maximum tolerated dose to that region. It has been suggested that heterogeneity in susceptibility to radiation-induced fibrosis exists in the population, implying that the lung tolerance dose is defined by a sensitive subset of the patient population. Studies of radiotherapy patients have indicated that the survival at 2 Gy (SF2) of cultured skin fibroblasts correlates with the incidence and severity of postirradiation damage in a number of tissues, suggesting that this assay may be a useful predictor of late tissue effects. The goal of the studies presented here was to determine if the radiosensitivity of fibroblasts in vitro isolated from mouse lungs was correlated with the severity of radiation-induced fibrosis in the lungs of two inbred strains of mice previously shown to differ markedly in their susceptibility to radiation-induced lung fibrosis: the C3Hf/Kam strain, classified as fibrosis-resistant, and the C57BL/6J strain, classified as fibrosis-prone. Quantitative measurements of lung fibrosis after irradiation were compared to SF2 values for fibroblasts of skin and lung cultured from each strain. Lung fibrosis was quantified, using computerized image analysis, as the percentage of fibrosis on Masson's Trichrome-stained lung sections from both strains after single doses of radiation to the thorax. For the measurements of SF2, fibroblasts plated at the second passage and grown to confluence were given single doses of radiation ranging from 0 to 6 Gy. Survival curves were constructed and SF2 values obtained from a linear-quadratic fit to the data. The radiosensitivity of fibroblasts from the lung and skin of SCID mice was determined and served as a positive control. The percentage of radiation-induced lung fibrosis was significantly different between the two strains, 5.1% and 0.2% in the C57 strain and C3H strain, respectively. Follow-up of long-term survivors (two mice) from the C3H strain did not change this conclusion. However, the lung fibroblast SF2 for the C57BL/6J strain (fibrosis-prone), 0.50 +/- 0.03, was not statistically different from the C3Hf/Kam strain (fibrosis-resistant), 0.55 +/- 0.07. These data indicate that in vitro radiosensitivity of lung fibroblasts as assayed by survival at 2 Gy does not correlate with the development of lung fibrosis in this mouse model. The SF2 for lung fibroblasts from SCID mice was 0.10. Similar SF2 values were obtained for both the C3Hf/Kam mouse lung and skin fibroblasts, 0.55 and 0.56, respectively, and C57BL/6J mouse lung and skin fibroblasts, 0.50 and 0.52, respectively, indicating that the radiosensitivity of fibroblasts isolated from lung and skin within a strain is the same.

Animals↗
PubMed2000

Prophylactic antibiotics for cystic fibrosis.

BACKGROUND: Patients with cystic fibrosis are sometimes prescribed antibiotics to take continuously on a prophylactic (preventative) basis. This approach is most commonly used in infants where the objective is to reduce pulmonary infection with Staphylococcus aureus and prevent lung damage. This approach may also be used in older patients. This review evaluates the evidence for the effectiveness of this approach and considers potential adverse effects. OBJECTIVES: To compare continuous oral antibiotic prophylaxis with no prophylaxis (short courses of oral antibiotics given as clinically indicated) in patients with cystic fibrosis. This review considers both the effectiveness of prophylaxis (bacteria isolated from the respiratory tract, requirement for additional antibiotic treatment, lung function, survival) and the adverse effects. SEARCH STRATEGY: The Cochrane Cystic Fibrosis and Genetic Disorders Group clinical trials register was used. This comprises references identified from a comprehensive search of electronic databases, as well as hand searching relevant journals and conference abstracts. Companies manufacturing anti-staphylococcal antibiotics were also approached for unpublished data. Date of the most recent search of the Group's specialised register: November 1999. SELECTION CRITERIA: All randomised or pseudo-randomised trials where continuous oral prophylactic antibiotics, given for a period of at least one year, were compared to intermittent antibiotic therapy given "as required." Cystic fibrosis patients of any disease severity were considered. DATA COLLECTION AND ANALYSIS: Trials were assessed for eligibility, methodological quality and data extraction by two reviewers (AS & SW). The following outcomes were assessed: lung function; nutrition (weight standard deviation score); survival; requirement for additional antibiotic treatment; isolates of pathogens from the respiratory tract; occurrence of adverse reactions to prophylactic antibiotics. MAIN RESULTS: Only two studies, totalling 66 patients (over half of whom were infants), were suitable for inclusion in the review. A reduced prevalence of Staphylococcus aureus in the respiratory secretions was seen in children receiving anti-staphylococcal antibiotic prophylaxis, although no effect was seen on other common pathogens. This is associated with a reduced requirement for additional courses of oral antibiotics and fewer hospital admissions in the first two years of life in patients receiving prophylaxis. No effect on infant lung function has been shown after one year of prophylactic treatment. Data are not available on adverse effects of the interventions. As the duration of the studies reviewed has been of two years or less, conclusions cannot be drawn about the long term effects of prophylaxis on acquisition of Pseudomonas aeruginosa and survival. REVIEWER'S CONCLUSIONS: Anti-staphylococcal antibiotic prophylaxis may be of benefit when commenced early in infancy and continued up to two years of age. There is insufficient evidence from this review to say whether use in older children, or adults, or for periods of over two year is beneficial.

Adult↗
PubMed2001

Presence of cystic fibrosis-related diabetes mellitus is tightly linked to poor lung function in patients with cystic fibrosis: data from the European Epidemiologic Registry of Cystic Fibrosis.

Data derived from a cross-sectional analysis of 7,566 patients stratified into six age groups were used to compare lung function, body mass index (BMI), and weight for age in patients with and without cystic fibrosis-related diabetes mellitus (CFDM). The presence of CFDM was tightly linked to poor lung function, regardless of age. The mean value of FEV(1) % predicted in the age groups < 10, 10-< 15, 15-< 20, 20-< 25, 25-< 30, and 30 years or older were 87%, 77%, 69%, 58%, 55%, and 53% in the nondiabetic cystic fibrosis (CF) patients as compared to 79%, 66%, 55%, 49%, 46%, and 44% in the diabetic CF patients. BMI and weight for age were also lower in diabetic than nondiabetic CF patients in all age groups, except for BMI in the youngest patients. The difference in lung function and in nutritional parameters between diabetic and nondiabetic CF patients was not linked to presence or absence of any specific pathogen in the lower respiratory tract. These results confirm and extend those of earlier studies in smaller numbers of patients, and they clearly identify CFDM as a powerful determinant of severe lung disease and reduced survival in patients with CF and diabetes mellitus.

Adolescent↗
PubMed2000

Two mild cystic fibrosis-associated mutations result in severe cystic fibrosis when combined in cis and reveal a residue important for cystic fibrosis transmembrane conductance regulator processing and function.

The number of complex cystic fibrosis transmembrane conductance regulator (CFTR) genotypes identified as having double-mutant alleles with two mutations inherited in cis has been growing. We investigated the structure-function relationships of a severe cystic fibrosis (CF)-associated double mutant (R347H-D979A) to evaluate the contribution of each mild mutation to the phenotype. CFTR mutants expressed in HeLa cells were analyzed for protein biosynthesis and Cl(-) channel activity. Our data show that R347H is associated with mild defective Cl(-) channel activity and that the D979A defect leads to misprocessing. The mutant R347H-D979A combines both defects for a dramatic decrease in Cl(-) current. To decipher the molecular mechanism of this phenotype, single and double mutants with different charge combinations at residues 347 and 979 were constructed as charged residues were involved in this complex genotype. These studies revealed that residue 979, located in the third cytoplasmic loop, is critical for CFTR processing and Cl(-) channel activity highlighting the role of charged residues. These results have also important implications for CF, as they show that two mutations in cis can act in concert to alter dramatically CFTR function contributing to the wide phenotypic variability of CF disease.

Cystic Fibrosis↗
PubMed1999

Abnormal expression of the cystic fibrosis transmembrane regulator in chronic sinusitis in cystic fibrosis and non-cystic fibrosis patients.

Cystic fibrosis (CF) patients commonly suffer from chronic sinusitis. Mutations of a single gene, the cystic fibrosis transmembrane conductance regulator (CFTR) gene, have been associated with CF. Functional CFTR protein is localized to the apical cell membrane, while dysfunctional CFTR is commonly found in the cytoplasm. We undertook a preliminary immunocytochemical study of CFTR subcellular localization in CF and non-CF pediatric and adult patients using a newly developed murine monoclonal antibody, TAM. Immunostaining was evaluated for subcellular localization (cytoplasmic versus membranous) and for epithelial layer (basal versus luminal). Analysis of the predominant CFTR distribution patterns demonstrated significant differences in adult versus pediatric groups independent of whether the latter were CF or non-CF (p<.0001 and p<.008, respectively), and no significant difference between the 2 pediatric groups (p = .70). This suggests that the pathophysiology of pediatric sinusitis differs from that of adult sinusitis at the level of secretion production.

Adolescent↗
PubMed2006

Proteomic analysis of nasal cells from cystic fibrosis patients and non-cystic fibrosis control individuals: search for novel biomarkers of cystic fibrosis lung disease.

Potential biological markers for cystic fibrosis (CF) lung disease were identified by comparative proteomics profiling of nasal cells from deletion of phenylalanine residue 508 (F508del)-homozygous CF patients and non-CF controls. From the non-CF 2-DE gels, 65 spots were identified by MS, and a reference 2-DE map was thus established. The majority of those correspond to ubiquitously expressed proteins. Consistent with the epithelial origin of this tissue, some of the identified proteins are epithelial markers (e.g. cytokeratins, palate lung and nasal epithelium clone protein (PLUNC), and squamous cell carcinoma antigen 1). Comparison of this protein profile with the one similarly obtained for CF nasal cells revealed a set of differentially expressed proteins. These included proteins related to chronic inflammation and some others involved in oxidative stress injury. Alterations were also observed in the levels of cytoskeleton proteins, being probably implicated with cytoskeleton organization changes described to occur in CF-airways. Lower levels were found for some mitochondrial proteins suggesting an altered mitochondrial metabolism in CF. Differential expression was also found for two more enzymes that have not been previously associated to CF. Further studies will clarify the involvement of such proteins in CF pathophysiology and whether they are targets for CF therapy.

Adolescent↗
PubMed1977

Pseudomonas aeruginosa infection in cystic fibrosis. Bactericidal effect of serum from normal individuals and patients with cystic fibrosis on P. aeruginosa strains from patients with cystic fibrosis or other diseases.

P. aeruginosa strains originating from the respiratory tract of patients with cystic fibrosis (CF) and patients with other diseases (non-CF) were analysed with regard to their sensitivity to the bactericidal activity of human serum. P. aeruginosa strains isolated from CF patients were more sensitive than strains from non-CF patients to the bactericidal activity of normal human serum. The bactericidal activity was heatlabile. As regards the sensitivity to normal human serum, mucoid and non-mucoid variants were not found to differ. Strains originating from chronically infected CF patients with many precipitins against these bacteria did not differ with respect to serum sensitivity from strains originating from intermittently colonized CF patients without P. aeruginosa precipitins. Compared with normal sera, CF sera showed similar or higher bactericidal activity against a panel of P. aeruginosa strains. In this respect, any difference between CF sera with precipitins and CF sera without precipitins against P. aeurginosa was not found. Sera from three CF patients chronically infected with P. aeruginosa, and with many precipitins against these bacteria, showed a selective inability in bactericidal activity against the patients' own P. aeruginosa isolate possibly reflecting the presence of "bactericidal blocking" antibodies.

Adolescent↗
PubMed2000

Newborn screening for cystic fibrosis.

BACKGROUND: This review was performed to test the hypothesis that presymptomatic diagnosis, for example by newborn screening, and early treatment may prevent or reduce irreversible organ damage and thereby improve outcome and quality of life in patients with cystic fibrosis. OBJECTIVES: To determine whether there is evidence that early diagnosis of cystic fibrosis by means of neonatal screening, followed by current treatment, improves survival and long term morbidity, without unacceptable adverse effects. SEARCH STRATEGY: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Trials Register. Additional studies were identified by one of the reviewers from handsearching conference proceedings not included in the Cochrane Register. Pharmaceutical companies manufacturing screening tests for cystic fibrosis were also contacted to identify any trials of neonatal screening for cystic fibrosis. Date of the most recent search of the Group's specialised register: November 1999. SELECTION CRITERIA: All randomised or pseudorandomised controlled trials, published and unpublished, comparing screening followed by early treatment to clinical diagnosis and later treatment in patients with cystic fibrosis. DATA COLLECTION AND ANALYSIS: Four reviewers independently assessed trial eligibility and methodological quality and two of these reviewers independently extracted data. MAIN RESULTS: Two trials involving a total of 1,124,483 neonates met inclusion criteria. A total of 210 patients with cystic fibrosis aged from zero to 11 years with a maximum follow-up of eleven years are included. Concealment of allocation was unclear in both studies. Sequence generation was adequate in one study and unclear in the other. Method to ascertain cases was similar in one study and not similar in the other. An intention-to-screen-analysis was possible in one study, but could not be made due to lack of data and was not performed in the other. Differences in study design, variation in outcomes reported and their summary measures precluded calculation of pooled screening estimates. Only data from one study could be analysed in this review. This study reported a reduced risk of weight and height below the fifth percentile among screened patients (odds ratio control compared with screened group for: weight 6.16, 95% Confidence Interval (CI) 2.44, 15.57 and height 5.03, 95% CI 1. 63, 15.63). Adverse effects among parents in the screened and control populations were examined, but it is difficult to assess how meaningful these results are as the timing of the administration of the questionnaire to each group was not clear. Estimation of direct medical costs of screening suggested it was cheaper to diagnose cystic fibrosis by screening rather than other methods. The costing methods used however were not fully described and costs have not been related to effect. REVIEWER'S CONCLUSIONS: There are few randomised controlled trials assessing the effectiveness of neonatal screening in cystic fibrosis. From the data available at this time, there is little evidence suggesting benefit from screening for cystic fibrosis in the neonatal period, although there is similarly little evidence of harm. This systematic review has identified the need for individual patient data from both included studies. Although we have not been able to perform a meta-analysis, this review provides a summary of all the information currently available from randomised controlled trials on the effectiveness of neonatal screening for cystic fibrosis.

Cystic Fibrosis↗
PubMed1999

Predicting the risk of cystic fibrosis with echogenic fetal bowel and one cystic fibrosis mutation.

OBJECTIVE: To assess fetal risk for cystic fibrosis when echogenic bowel and one cystic fibrosis mutation are detected. METHODS: A hypothetical cohort of 1000 women with singleton pregnancies and echogenic fetal bowel during the second trimester was used to determine the probability of cystic fibrosis when one cystic fibrosis transmembrane conductance regulator mutation was detected. The risk of cystic fibrosis was calculated using the range of prevalence of cystic fibrosis in fetuses with echogenic bowel reported in the literature. Risk calculations for fetuses of Ashkenazi Jewish, Northern European, African-American, Hispanic, and Asian descent accounted for carrier frequencies and mutation detection rates specific to each ethnic group. RESULTS: As the assumed prevalence of cystic fibrosis increases from 1-25%, the probability that a white fetus with one mutation and echogenic fetal bowel actually has cystic fibrosis increases from 4.8% to 62.5%. Assuming a 2% risk of cystic fibrosis with echogenic fetal bowel, an Ashkenazi Jewish fetus and an Asian fetus with echogenic bowel and one mutation have a 3.1% and 72% risk of cystic fibrosis, respectively. The probability of cystic fibrosis in a nonwhite fetus is between those two extremes. CONCLUSION: The probability of cystic fibrosis after detection of echogenic bowel and one cystic fibrosis mutation varied among ethnic groups. Even at the highest prevalence of cystic fibrosis, most white fetuses will not have cystic fibrosis. In nonwhite populations almost half of these fetuses will have cystic fibrosis, even at the lowest prevalence of cystic fibrosis.

Cystic Fibrosis↗
PubMed2000

Hepatic fibrosis and cytochrome P450: experimental models of fibrosis compared to AHR knockout mice.

Hepatic fibrosis is characterized by abnormal collagen deposition resulting from increased collagen synthesis and decreased collagen degradation. Cytochrome P450 mediates major drug metabolizing enzyme activity in the liver and this activity is reduced in hepatic fibrosis. In this study we assess cytochrome P450 and CYP 1A mRNA in livers of animals that have been induced to hepatic fibrosis using the heterologous serum induced model of fibrosis in rats compared to controls. Fibrosis was confirmed by assessing the collagen in liver sections as quantified by Sirius red/Fast green staining, a quantitative measure of fibrosis as well as by visualization of the hepatic fibrosis. Collagen levels in the liver sections of heterologous serum induced fibrotic rats was increased by 33% compared to controls and a typical fibrotic pattern was seen. Messenger RNA was prepared from heterologous serum induced fibrotic rats and compared to controls. CYP 1A2 was assessed using a specific probe and the CYP 1A2 level was significantly reduced in the heterologous serum induced fibrotic rats compared to controls. These results further suggest that cytochrome P450 is reduced in the presence of hepatic fibrosis. Thus, in three well established experimental models of hepatic fibrosis which had clearly developed hepatic fibrosis (as shown by Sirius red/Fast green staining), cytochrome P450 mediated enzyme activity, or specifically, CYP 1A messenger RNA is decreased. We then investigated a transgenic mouse, deficient in the arylhydrocarbon hydroxylase receptor (AHR), which has undetectable levels of CYP 1A messenger RNA. We quantitated the collagen in liver sections obtained from AHR knockout mice compared to controls, as an indication of the presence of hepatic fibrosis. Collagen concentration was significantly increased by 53% (P<0.0005) in sections from Ahr-/- (knockout) mice compared to wild-type controls. Collagen in livers of the Ahr+/- heterozygous mice was not different from wild-type controls. The increase in collagen concentration in liver sections is an indication of fibrosis in Ahr-/- mice. Collagen protein deposition was also elevated in liver sections from bile duct ligated rats (by 44%) compared to sham operated controls, was elevated in liver sections from heterologous serum induced fibrosis in rats (33%) compared to controls, and was elevated in liver sections from yellow phosphorous induced hepatic fibrosis (74%) compared to vehicle treated controls. In conclusion, these results indicate that cytochrome P450 and specific subtypes of P450, the CYP 1A subgroup, are significantly reduced in three experimental models of hepatic fibrosis when there is evidence of increased collagen deposition in the livers. These results also indicate that mice that are deficient in CYP 1A have elevated levels of hepatic collagen protein, an indication of hepatic fibrosis.

Journal Article↗
PubMed2000

Nebulised hypertonic saline for cystic fibrosis.

BACKGROUND: The lung disease in cystic fibrosis is characterised by impaired mucociliary clearance, recurrent bronchial infection and airway inflammation. Hypertonic saline has been shown to enhance mucociliary clearance in-vitro and this may act to lessen the destructive inflammatory process in the airways. OBJECTIVES: To determine if nebulised hypertonic saline treatment improved lung function, exercise tolerance, quality of life and decreased the incidence of exacerbations of respiratory infections in patients with cystic fibrosis. SEARCH STRATEGY: Studies were identified from the Cochrane Cystic Fibrosis and Genetic Disorders Group trials register. Titles and abstracts were reviewed to identify all controlled trials. Review articles and bibliographies identified from this process were surveyed for additional citations & RCTs. Identification of unpublished work was obtained from abstract books from the three major Cystic Fibrosis conferences (International Cystic Fibrosis Conference, The European Cystic Fibrosis Conference and the North American Cystic Fibrosis Conference). Trial authors were contacted for additional information when only abstracts were available to review. Date of the most recent search of the Group's specialised register: November 1999. SELECTION CRITERIA: All controlled trials that assessed the effect of hypertonic saline compared to placebo or other mucolytic therapy, for any duration or dose regimen in subjects with cystic fibrosis of any age or severity were reviewed. Studies in languages other than English were included. DATA COLLECTION AND ANALYSIS: All identified trials were independently reviewed by both reviewers & all data collected. Trial quality was scored by the Cochrane assessment of allocation concealment & the Jadad scale of methodological quality. MAIN RESULTS: Twelve controlled trials of hypertonic saline were identified. Seven trials met the inclusion criteria; these involved 143 subjects with an age range of 6 to 46 years. Of these, six were published studies and one in abstract form. The durations of the trials were limited to immediate effects on mucociliary clearance to a maximum of three weeks. In two studies, involving thirty five subjects, a score for the feeling of cleared chest was made using visual analogue scales. This analysis showed a weighted mean difference of -0.98 (95% confidence Interval -1.6, -0.34), favouring hypertonic saline over isotonic saline. In two trials with 22 subjects hypertonic saline improved mucociliary clearance as measured by isotope clearance from the lungs in 90 minutes demonstrating a weighted mean difference of -11.3 (95% confidence Interval -18.6, -4.0), and as area under the clearance time curve; weighted mean difference of -212 (95%CI -272, -152), also favouring hypertonic saline over isotonic saline. Lung function as measured by improvement in FEV1 was observed in one study of 27 subjects. The percentage increase in FEV1 at two weeks increased by a mean 15.0% with hypertonic saline and 2.8% with isotonic saline (p=0.004). Adverse events were adequately described in only one trial and none were serious. REVIEWER'S CONCLUSIONS: Nebulised hypertonic saline improves mucociliary clearance immediately after administration which may have a longer term beneficial effect in cystic fibrosis. The maximum time data were recorded for was only three weeks. Most of the patients had mild to moderate lung disease and the effect on severe lung disease remains unclear. Further studies of hypertonic saline should be carried out to determine the effect on pulmonary function tests, quality of life, frequency of exacerbations of respiratory disease and efficacy comparisons with nebulised deoxyribonuclease, with larger numbers and for longer duration. At this stage there is insufficient evidence to support the use of hypertonic saline in routine treatment for patients with cystic fibrosis.

Administration, Inhalation↗
PubMed2006

Correlation between TIMP-1 expression and liver fibrosis in two rat liver fibrosis models.

AIM: To evaluate serum TIMP-1 level and the correlation between TIMP-1 expression and liver fibrosis in immune-induced and CCL4-induced liver fibrosis models in rats. METHODS: Immune-induced and CCL4-induced liver fibrosis models were established by dexamethasone (0.01 mg) and CCL4 respectively. Serum TIMP-1 level was detected with ELISA, while histopathological grade of liver biopsy was evaluated. Spearman rank-correlation test was used to analyse the difference of the correlation between the TIMP-1 expression and hepatic fibrosis in the two fibrosis models. Furthermore, in situ hybridization was used to determine the expression difference of TIMP-1 mRNA in the two models. RESULTS: Positive correlation existed between serum TIMP-1 level of immune induced group and the histopathological stages of fibrosis liver of corresponding rats (Spearman rank-correlation test, r(s) = 0.812, P < 0.05), and the positive in situ hybridization signal of TIMP-1 mRNA was strong. In CCL4-induced liver fibrosis model, the correlation between the serum TIMP-1 level and the severity of hepatic fibrosis was not statistically significant(Spearman rank-correlation test, r(s) = 0.229, P > 0.05). And compared with immune-induced model, the positive in situ hybridization signal of TIMP-1 mRNA was weaker, while the expression variation was higher in hepatic fibrosis of the same severity. CONCLUSION: The correlations between TIMP-1 expression and liver fibrosis in two rat liver fibrosis models are different. In immune-induced model, serum TIMP-1 level could reflect the severity of liver fibrosis, while in CCL4-induced model, the correlation between the serum TIMP-1 level and the severity of hepatic fibrosis was not statistically significant.

Animals↗
PubMed2002

Cytokine regulation of periportal fibrosis in humans infected with Schistosoma mansoni: IFN-gamma is associated with protection against fibrosis and TNF-alpha with aggravation of disease.

Hepatic periportal fibrosis, which affects 5-10% of subjects infected by Schistosoma mansoni, is caused by the T cell-dependent granuloma that develop around schistosome eggs. Experimental models of infection have shown that granuloma and fibrosis are tightly regulated by cytokines. However, it is unknown why advanced periportal fibrosis occurs only in certain subjects. The goal of the present study was to evaluate the cytokine response of S. mansoni-infected subjects with advanced liver disease in an attempt to relate susceptibility to periportal fibrosis with an abnormal production of cytokines that regulate granuloma and fibrosis. Fibrosis was evaluated by ultrasound on 795 inhabitants of a Sudanese village in which S. mansoni is endemic: advanced periportal fibrosis was observed in 12% of the population; 35% of the affected subjects exhibited signs of portal hypertension. Age (odds ratio (OR), 11.5), gender (OR, 4.2), and infection levels (OR, 2.2) were significantly (p < or = 0.01) associated with hepatic fibrosis. Cytokines produced by egg-stimulated blood mononuclear cells from 99 subjects were measured (75 with no or mild fibrosis; 24 subjects with advanced fibrosis). Multivariate analysis of cytokine levels showed that high IFN-gamma levels were associated with a marked reduction of the risk of fibrosis (p = 0.01; OR, 0.1); in contrast, high TNF-alpha levels were associated with an increased risk (p = 0.05; OR, 4.6) of periportal fibrosis. Moreover, infection levels were negatively associated with IFN-gamma production. These results with observations in experimental models strongly suggest that IFN-gamma plays a key role in the protection of S. mansoni-infected patients against periportal fibrosis, whereas TNF-alpha may aggravate the disease.

Adult↗
PubMed2006

[Serum fibrosis markers in diagnosing liver fibrosis].

OBJECTIVE: To evaluate the clinical value of serum fibrosis markers hyaluronic acid (HA), type IV collagen (CIV), type III procollagen N peptide (PIIIP) and laminin (LN) in the diagnosis of liver fibrosis. METHODS: Detection of the serum levels of these markers including HA, CIV, PIIIP, LN was carried out in 50 patients with chronic hepatitis B and 18 healthy persons. Liver biopsy was performed in all patients. The relationship between the markers and liver fibrosis stage was analyzed and the diagnostic value of the markers in liver fibrosis stage evaluated with receiver operating curve. RESULTS: The correlation between serum HA, CIV, PIIIP and histologically assessed grade of inflammatory activity was weak (r = 0.430, 0.382 and 0.300, respectively, P < 0.05). The correlation between serum HA, CIV and histologically assessed stage of liver fibrosis were moderate (r = 0.614, 0.708, respectively, P < 0.05). The increase in serum HA, CIV was correlated with the progression of liver fibrosis. Based on receiver operating curve, the value of using serum HA to differentiate patients with early cirrhosis (S4) from those without cirrhosis (S0-S3) was greater than that of serum CIV, PIIIP and LN (the areas under the curves = 0.967 vs 0.932, 0.659, 0.403), while the ability of serum CIV to predict liver fibrosis (S1-S4) was superior to that of serum HA, PIIIP and LN (areas under the curves = 0.853 vs 0.680, 0.536, 0.487). Serum LN was found to show limited changes in different pathologic grade and stage. The combined detection of HA and CIV has higher specificity than that of a single marker. CONCLUSIONS: Serum fibrosis markers can be helpful in diagnosis of liver fibrosis even in its early stage, but can not discriminate accurately the stage of fibrosis as accurately as the histological assessment. The combination of fibrosis markers is more valuable than single marker. New fibrosis markers and combination of noninvasive markers are the future trend in liver fibrosis research.

Adult↗
PubMed1996

Histopathologic study of coexistent pathologic states in pancreatic fibrosis in patients with chronic alcohol abuse: two distinct pathologic fibrosis entities with different mechanisms.

The distribution and clinicopathologic features of pancreatic fibrosis were studied histopathologically in 137 autopsy cases of chronic alcohol abuse. Fibrosis was observed in 90 of the cases and was classified as perilobular sclerosis (PS) and intralobular sclerosis (IS). Fibrosis of the PS type was irregular and sometimes patchy and extended into the intralobular area in advanced cases. In some advanced cases, complete replacement of the pancreatic tissue by extensive fibrosis was seen. Fibrosis of the IS type was uniformly distributed. The tissues in some cases showed prominently periacinar fibrosis. In these cases, the pancreatic parenchyma had not been completely replaced by extensive fibrosis. Clinicopathologic comparisons revealed the following results: accompanying liver cirrhosis was greater in the IS than in the PS of fibrosis. However, a higher frequency of protein plugs, pancreatic stones, extensive fibrosis replacement, peripancreatic fibrosis, splenic vein involvement, choledochus involvement, pseudocyst, and ductal hyperplasia was found in the PS type compared to the IS type. In conclusion, the findings on the perilobular and intralobular distribution of fibrosis and differences in various components or accompanying diseases in pancreatic fibrosis suggest that this entity shows two distinct pathologic patterns with differing mechanisms.

Adult↗