Markers of fibrogenesis and basement membrane formation in alcoholic liver disease. Relation to severity, presence of hepatitis, and alcohol intake.

This study investigated the relationships of the serum markers of fibrogenesis and basement membrane formation to the clinical and morphological severity of alcoholic liver disease and to the degree of alcohol abuse. The concentrations of the aminoterminal propeptide of type III collagen, type IV collagen, and laminin were measured from 87 samples representing a wide range of clinical and histological severities of the disease, which were assessed with indices that have been shown to correlate well with the risk of dying within 1 yr. Significant correlations (p less than 0.00001) were found between the markers of connective tissue metabolism and the Combined Clinical and Laboratory Index: (aminoterminal propeptide of type III collagen, rs = 0.82; type IV collagen, rs = 0.82; laminin, rs = 0.81), as well as between these markers and the Combined Morphological Index: (aminoterminal propeptide of type III collagen, rs = 0.70; type IV collagen, rs = 0.68; laminin, rs = 0.64). Whereas the patients with less than 8 mM of alcohol in their morning urine (mild or moderate drinkers) showed a significant (p less than 0.00001) decrease in these markers in a period of 27 +/- 1 wk, the patients with more than 8 mM of urinary alcohol (heavy drinkers) had no improvement. It is proposed that both fibrogenesis and basement membrane formation are associated with disease severity, degree of alcoholic hepatitis, and alcohol intake, which are important determinants of prognosis in alcoholic liver disease.     

Treatment of hypertrophic scars and keloids with a radiofrequency device: a study of collagen effects

BACKGROUND AND OBJECTIVE: To determine the efficacy and safety of the ThermaCool TC radiofrequency system for treatment of hypertrophic and keloid scars and evaluate treatment associated collagen changes. MATERIALS AND METHODS: Six subjects with hypertrophic and four with keloid scars were treated with the ThermaCool device: one-third of the scar received no treatment (control), one-third received one treatment and one-third received two treatments (4-week interval). Scars were graded before and then 12 and 24 weeks after treatment on symptoms, pigmentation, vascularity, pliability, and height. Biopsies were taken from four subjects with hypertrophic scars and evaluated with hematoxylin and eosin (H & E) staining, multiphoton microscopy, and pro-collagen I and III immunohistochemistry. RESULTS: No adverse treatment effects occurred. Clinical and H & E evaluation revealed no significant differences between control and treatment sites. Differences in collagen morphology were detected in some subjects. Increased collagen production (type III > type I) was observed, appeared to peak between 6 and 10 weeks post-treatment and had not returned to baseline even after 12 weeks. CONCLUSION: Use of the thermage radiofrequency device on hypertrophic scars resulted in collagen fibril morphology and production changes. ThermaCool alone did not achieve clinical hypertrophic scar or keloid improvement. The collagen effects of this device should be evaluated further in order to optimize its therapeutic potential for all indications.     

Effect of jaundice and its resolution on wound re-epithelization, skin collagen synthesis, and serum collagen propeptide levels in patients with neoplastic pancreaticobiliary obstruction

BACKGROUND: Wound and anastomotic healing is considered to be delayed in patients with obstructive jaundice. The study was designed to find out whether the healing of experimental suction blister wounds, skin collagen synthesis, and serum procollagen levels are affected by obstructive jaundice, and if biliary drainage may cause any alterations in these processes. PATIENTS AND METHODS: Suction blisters were induced on 24 patients with obstructive jaundice caused by neoplastic pancreaticobiliary obstruction and 17 control patients with the corresponding condition without jaundice, to compare healing parameters and collagen synthesis between the groups. A second set of suction blisters were induced on 13 formerly jaundiced patients after the resolution of jaundice and on 14 control patients, to find out whether drainage or time modifies healing or collagen synthesis. By using this model, it is possible to evaluate the re-epithelization and inflammation on wound healing and to assess the baseline skin collagen synthesis. The healing of suction blisters was followed up by measuring water evaporation and blood flow in the wound. Blister fluids and serum samples were collected to study collagen propeptides. RESULTS: Healing of the blister wound was unaffected by obstructive jaundice. Drainage had no effect on healing. The baseline synthesis of type I and type III collagen in the skin was decreased in jaundiced patients. Biliary drainage improved the synthesis. Serum type III procollagen propeptide levels were elevated in jaundiced patients, but began to normalize after drainage. CONCLUSION: Healing of an experimental blister wound is not disturbed by obstructive jaundice. The decreased baseline skin collagen synthesis is partly restored by the resolution of jaundice. The results indicate that cell protein synthesis is disturbed earlier than cell dynamics in obstructive jaundice. The elevated serum PIIINP levels, which are most likely to be related to early fibrosis in liver, decreased after drainage.     

Synthesis and maturation of type I and type III collagens in endometrial adenocarcinoma

OBJECTIVE: The structure and distribution of type I and type III collagens in the extracellular matrix of malignant endometrium was evaluated for their roles in the development and progression of this neoplasm. STUDY DESIGN: Collagen synthesis and deposition in endometrial adenocarcinomas was determined by immunohistochemical analysis of type I and type III procollagen and verified by computer-assisted morphometry and in situ hybridization. RESULTS: In the stroma of well-differentiated adenocarcinomas increased intracellular collagen synthesis was observed in fibroblastic cells as well as increased extracellular formation of newly synthesized type I and type III procollagen. Collagen maturation was also rapid. In moderately differentiated tumors, destruction and dissolution occurred around invading islets, concomitantly with decreased deposits of both collagens, despite increases in corresponding mRNAs. In poorly differentiated neoplasms, solid epithelial islets coexisted with sparse and distinctly collagen-positive stroma. Poorly differentiated neoplasms also contained tumor cells exhibiting intracellular collagen staining as well as in situ hybridization signals. In highly malignant papillary adenocarcinomas, the tumor cells induced distinctly increased collagen synthesis and deposition of newly synthesized collagen but not the mature cross-linked protein. CONCLUSIONS: In malignancy, compression of surrounding stroma and a fibroproliferative response with increased collagen synthesis and deposition may prevent tumor growth. In more advanced lesions, stromal dissolution may permit tumor spread and in highly malignant lesions an abnormal stroma may promote neoplasm progression.     

Radiological and biochemical resolution of nutritional rickets with calcium

Aims: To determine the response to oral calcium in Nigerian children with rickets. Methods: In a teaching hospital in Western Nigeria, 26 children (13 boys, 13 girls, aged 2–5 years) with confirmed rickets received calcium lactate (2.7 g/day). Results: Within one month of treatment leg pain was relieved and the children were more active. The mean x ray score improved from 3.3 at baseline to 1.7 at three months and 0.9 at six months (arbitrary scoring system, 0–6). Twelve cases were healed radiologically after six months, 11 others improved considerably, two showed no significant improvement, and a non-compliant patient was worse. There was progressive reversal of biochemical features. Median plasma alkaline phosphatase fell from 519 (range 178–1078) to 283 (209–443) IU/l (p = 0.04) in four months, while mean 1,25-dihydroxyvitamin D fell from 473 (251–1057) to 281 (155–481) pmol/l (p = 0.04), and mean plasma calcium increased from 2.26 (1.63–2.54) to 2.37 (2.06–2.54) mmol/l (p = 0.13). Parathyroid hormone fell from 5.3 (0.4–21.5) to 1.7 (0.45–7.4) pmol/l. Type I collagen carboxy terminal cross linked telopeptide was very high at baseline (20 (7.2–103) to 14 (11–24) µg/l) (p = 0.03) and fell promptly to normal. Conclusion: Calcium supplementation alone effected healing of rickets in most of these Nigerian children and may provide sufficient treatment in this environment.     

Effect of short-term antenatal dexamethasone administration on type I collagen synthesis and degradation in preterm infants at birth

To assess the effects of antenatal corticoid administration on foetal collagen metabolism, cord serum concentrations of the aminoterminal propeptide and carboxyterminal telopeptide of type I procollagen (PINP and ICTP), which reflect rates of type I collagen synthesis and degradation, respectively, were measured in 67 consecutive preterm infants with gestational ages ranging from 24 to 32 wk. The samples were divided into three groups, depending on the administration and timing of antenatal corticosteroid treatment for enhancement of foetal lung maturity: cases in which the mothers had received a full 2-dose administration of dexamethasone on consecutive days 1 to 6 d before delivery (n = 23; Complete-Dexa), those who had received only a single dose of dexamethasone less than 24 h before delivery (n = 17; Partial-Dexa) and those who had not received any antenatal steroids (n = 27; No-Dexa). Infants in the Complete-Dexa group had significantly lower median PINP levels than those in the No-Dexa group (3,326 vs 4,028 microg/l; p = 0.036); the median PINP level in the Partial-Dexa group (3,999 microg/l) was close to that of the No-Dexa group. No significant differences in ICTP concentrations were seen between the groups. CONCLUSION: A significant suppression of foetal collagen synthesis but not degradation was found to be associated with antenatal dexamethasone administration. This should be taken into consideration, e.g. when assessing whether to administer repeated or single courses of corticosteroids antenatally in high-risk pregnancies.     

Effect of Sucrose on Collagen Metabolism in Keloid, Hypertrophic Scar, and Granulation Tissue Fibroblast Cultures

Sucrose has been used to treat wounds with excellent results and with minimal abnormal scarring. In this study the effects of sucrose on collagen metabolism in fibroblast culture was evaluated. Sucrose (5.5, 15, or 25 mM) was added to granulation tissue, hypertrophic scar, and keloid fibroblast cultures. mRNA levels and procollagen aminopropeptides for type I and III collagens in cell culture medium were studied. Sucrose decreased mRNA levels for proα1(I) and proα1(III) collagens in fibroblast cultures derived from hypertrophic scar and keloid. In normal granulation tissue fibroblast cultures, 5.5 mM sucrose increased mRNA levels for proα1(I) and proα1(III) collagen, and higher concentrations decreased them. The synthesis of type I collagen decreased dose-dependently in all cell strains, whereas the synthesis of type III collagen decreased only in granulation tissue fibroblasts. To conclude, in vitro high concentrations of sucrose down-regulate both collagen gene expression and synthesis in normal granulation tissue fibroblasts, whereas in fibroblasts derived from abnormal scar sucrose down-regulates only type I collagen gene expression and synthesis, changing the pattern of collagen metabolism toward normal.     

Effect of insulin on serum amino-terminal propeptide of type III procollagen in non-insulin-dependent diabetes mellitus.

The effect of insulin on the serum levels of the amino-terminal propeptide of type III procollagen (PIIINP) was investigated in patients with non-insulin-dependent diabetes mellitus, whose disease was unsatisfactorily controlled by oral drugs. Before insulin therapy the PIIINP values of the patients (3.2 +/- 1.3 micrograms/l, n = 38) varied within the range of healthy subjects (3.1 +/- 0.6 micrograms/l, n = 50, NS). Insulin therapy (6-20 IU at bedtime plus the oral drugs) improved the glycemic control and increased the serum PIIINP during a 4 week (3.1 +/- 0.9 to 3.8 +/- 1.1 micrograms/l, P less than 0.01, n = 8) and an 8 week period (3.2 +/- 1.3 to 3.8 +/- 1.6 micrograms/l, P less than 0.001, n = 22). The values were still elevated after 6 months on insulin (3.5 +/- 1.5 to 4.0 +/- 1.7 micrograms/l, P less than 0.01, n = 12). Placebo-insulin did not alter the concentration of PIIINP (3.1 +/- 0.6 to 2.8 +/- 0.6 micrograms/l, NS, n = 8) whereas the glycemic control improved and body weight decreased. The PIIINP values correlated with fasting insulin before (r = 0.403, P less than 0.05, n = 30) and after the therapy (r = 0.452, P less than 0.001, n = 60). Insulin therapy, while correcting the hormone deficiency and restoring glucose and protein metabolism, seems to activate the synthesis of type III procollagen in patients with NIDDM. This may promote the atherosclerotic process.