Body fat distribution modulates insulin sensitivity in post-menopausal overweight and obese women: a MONET study.

OBJECTIVE: Central fat mass (CFM) correlates with insulin resistance and increases the risk of type 2 diabetes and cardiovascular complications. On the other hand, increased peripheral fat mass (PFM) is associated with higher insulin sensitivity. Thus, we examined the contribution of adipose tissue distribution, as assessed by the PFM/CFM ratio, to insulin sensitivity in overweight and obese postmenopausal women. DESIGN AND METHODS: A total of 124 nondiabetic overweight and obese postmenopausal women underwent an oral glucose tolerance test (OGTT) and a hyperinsulinemic/euglycemic (HI) clamp. Body composition was determined using computed tomography for visceral adipose tissue (VAT) and dual X-ray absorptiometry for fat mass, lean body mass and their respective proportions. Participants were divided by tertiles of the PFM/CFM ratio. RESULTS: Participants with preferential CFM (group 1) had higher fasting insulin levels and insulin area under the curve (AUC) during OGTT, as well as lower glucose infusion rates during the HI clamp, whether it was expressed per kg of body weight (M) or per kg of fat-free mass (Mm), compared with the other two groups. The PFM/CFM ratio also correlated significantly with fasting insulin (r=-0.32, P<0.001), the insulin AUC (r=-0.42 P<0.001), M (r=0.39 P<0.001) and Mm (r=0.37 P<0.001). Using hierarchical regression, we demonstrated that the PFM/CFM ratio was an independent predictor of insulin AUC, M and Mm and that its sequential addition to CFM and VAT improved significantly the predictive value of the model for insulin sensitivity for all variables except fasting insulin. CONCLUSION: The PFM/CFM ratio, which integrates the antagonistic effects of both central and peripheral depots on insulin sensitivity, added substantially to the prediction of insulin sensitivity over VAT and CFM alone.

HOMA or QUICKI: is it useful to test the reproducibility of formulas?

AIM: HOMA and QUICKI are the most widely used indices for assessing insulin sensitivity. Both are based on fasting glucose and insulin measures, and mainly differ by the log transformation of these variables in QUICKI. However, HOMA is less reproducible than QUICKI, and log HOMA does not improve its reproducibility. The aim of this study was to investigate the various mathematical transformations of HOMA and to assess its reproducibility. METHOD: We used data from a clamp study involving 123 non-diabetic overweight and obese postmenopausal women. Fasting insulin and glucose were measured in two visits 15 and 30 days apart. This allowed us to calculate HOMA as (fasting glucose [mmol/L] x fasting insulin [microU/mL])/22.5 and QUICKI as 1/(log fasting glucose [mg/dL]+log fasting insulin [microU/mL]) twice for subjects who were weight-stable between visits. RESULTS: QUICKI had better reproducibility (CV=3.9%) than either HOMA (CV=26.7%) or log HOMA (CV=22.0%). However, log-transforming HOMA using log (glucose x insulin)/log (22.5) and log-transforming HOMA without transforming the constant denominator improved its CV to 6.5% and 5.7%, respectively. CONCLUSION: By modifying the mathematical expression of HOMA, we were able to achieve comparable CVs for QUICKI and HOMA. However, the CV should be used to assess the reproducibility of techniques to measure glucose and insulin, not of mathematical formulas. When evaluating indices for the assessment of insulin sensitivity, the key point is how well they correlate with the 'gold-standard' glucose clamp.

Relationship between the hyperinsulinemic-euglycaemic clamp and a new simple index assessing insulin sensitivity in overweight and obese postmenopausal women.

OBJECTIVE: The purpose of this study was to compare assessment of insulin sensitivity from hyperinsulinemic euglycaemic (HIEG) clamp with indexes derived from fasting and oral glucose tolerance test (OGTT). SUBJECTS AND METHODS: Cross-sectional study with 107 sedentary non-diabetic overweight and obese postmenopausal (BMI=32.4+/-0.4 kg/m(2)) women undergoing both HIEG clamp and OGTT. Pairs of data were analyzed using Pearson correlation and Bland-Altman graphs analysis. Comparison between correlations was made using the method reported by Zar. RESULTS: All the indexes derived from either the OGTT or surrogate indexes were highly correlated with all the clamp-derived formulas (P<0.0001). However, HOMA and QUICKI were generally less correlated than OGTT-derived indexes. Analogically to QUICKI, we calculated a new formula derived from the OGTT measurements of glucose and insulin named simple index assessing insulin sensitivity (SI(is)OGTT)=1/[log(sum glucose t(0-30-90-120)) (mmol/l)+log(sum insulin t(0-30-90-120)) (microUI/ml)]. By using this formula, we found high significant correlations (r's=0.61-0.65; P<0.0001) with the clamp results. Moreover, the correlations of SI(is)OGTT with the clamp data were higher than for other previously published indexes. CONCLUSION: In that large group of non-diabetic overweight and obese postmenopausal women insulin sensitivity index derived from OGTT provided more accurate information than fasting based formula. We propose a new simple index for the assessment of insulin sensitivity from the OGTT data (SI(is)OGTT). The advantage of this new formula over all previously published OGTT-derived indexes of insulin sensitivity is that it is 1) easy to calculate 2) better correlated than other indexes of insulin sensitivity and 3) not affected by the way clamp results are expressed. Further studies are needed to validate SI(is)OGTT index in other populations.

Surrogate indexes vs. euglycaemic-hyperinsulinemic clamp as an indicator of insulin resistance and cardiovascular risk factors in overweight and obese postmenopausal women.

BACKGROUND: There is considerable interest in validating the most convenient method to estimate insulin sensitivity in clinical research protocols that could best indicate cardiovascular risk factors. To address this issue we examined the interrelationships of several cardiovascular risk factors with surrogate indexes such as fasting insulin, the homeostasis model assessment (HOMA), the quantitative insulin sensitivity check index (QUICKI) and the revised QUICKI vs the euglycaemic-hyperinsulinemic (EH) clamp in a non-diabetic overweight or obese postmenopausal female population. DESIGN: Cross-sectional study involving 88 obese postmenopausal women (age: 57.5+/-5.0 yrs; body mass index: 32.52+/-4.4 kg/m2; percent body fat: 46.35+/-4.9%). METHODS: Insulin sensitivity was determined by the EH clamp technique as well as by surrogate indexes such as fasting insulin, HOMA, log HOMA, QUICKI and revised QUICKI. Body composition and body fat distribution were measured using dual energy x-ray absorptiometry and computed tomography, respectively. RESULTS: Correlations between insulin resistance indexes (fasting insulin, revised QUICKI, QUICKI, log HOMA, HOMA) vs glucose disposal were similar (range of r's=0.40 to 0.49), suggesting that no index was superior to another with respect to its relationship with the EH clamp. Correlations between the insulin resistance indexes with plasma lipids were comparable among all indexes, however, systolic blood pressure, visceral fat and C-reactive protein were moderately superior with index vs the EH clamp. CONCLUSION: Surrogate measures of insulin resistance, in particular fasting insulin, are simple tools appropriate for epidemiological studies that can be used as substitutes for the EH clamp to estimate glucose disposal and cardiovascular risk factors in overweight and obese postmenopausal women.

No detrimental effect from chronic exposure to buprenorphine on corticosteroid-binding globulin and corticosensitive immune parameters.

Opioid drugs reportedly regulate the immune system via their effects on the hypothalamic- pituitary-adrenal (HPA) axis. The present study was carried out to assess the effects of chronic exposure to buprenorphine on HPA axis activation, corticosteroid-binding globulin (CBG), the main glucocorticoid (GC) carrier, and the immune system. Results show that buprenorphine, delivered by osmotic pump subcutaneously in C57BL/6 male mice during a 10-day period, caused a marked decrease in total corticosterone (CORT) levels at day 1 of exposure. CORT levels then increased with maximal values observed at day 5 of exposure. After day 5, total CORT levels gradually decreased and returned to control values. No significant changes were observed in CBG protein levels and mRNA expression in the liver. Since CBG levels remained unchanged, the percentage of free CORT values in buprenorphine mice did not differ from control values. Thus, the variations observed in the amount of free CORT were related only to changes measured in total CORT. These endocrine changes did not have a significant impact on the immune parameters measured. Total CD(4)+ and CD(8)+ splenic and thymic populations were not modulated by buprenorphine. However, splenocytes from mice exposed to buprenorphine after 5 days exhibited greater proliferation upon anti-TCR monoclonal antibody stimulation than saline-exposed mice. These results indicate that buprenorphine can be safely used because it did not have significant effects on GC availability for immune corticosensitive cells.

Increased thermogenic response to food and fat oxidation in female athletes: relationship with VO(2 max).

The thermogenic response to food (TRF) and substrate oxidation were studied in 12 endurance-trained and 13 untrained female subjects. Energy expenditure and substrate oxidation were calculated by indirect calorimetry before and for 6 h after an oral test meal and after the same meal given intragastrically on a separate occasion. The TRF was calculated after the oral meal, the obligatory component after the intragastric meal (OTRF), and the facultative component from the difference between the two. VO(2 max) was measured on a treadmill and body composition by underwater weighing. The TRF and OTRF were significantly higher in trained than in untrained subjects: 223 +/- 63 vs. 185 +/- 50 kJ/6 h (P < 0.03) and 174 +/- 38 vs. 131 +/- 37 kJ/6 h (P < 0.01) for the TRF and OTRF in trained vs. untrained subjects, respectively. Multiple regression analysis showed that maximum O(2) consumption (VO(2 max)), but not percentage of body fat, was significantly related to OTRF (r =0.68, P < 0.01). Trained subjects had higher fatty acid oxidation than untrained subjects before (0.6 vs. 0.4 mg. kg(-1). min(-1), P < 0.05) and after the oral meal (13 +/- 6 vs. 8 +/- 4 g/6 h P < 0.05). These results demonstrate that 1) TRF is higher in trained than in untrained women; 2) this is due to a higher cost of nutrient digestion, absorption and storage; 3) the difference is related to higher VO(2 max); and 4) fatty acid oxidation is greater in trained women in both the postabsorptive and postprandial states. These observations suggest that endurance training induces metabolic changes that favor leanness.

Decreased serum insulin-like growth factor-I in burn patients: relationship with serum insulin-like growth factor binding protein-3 proteolysis and the influence of lipid composition in nutritional support.

OBJECTIVES: To test the effects of the amount and type of fat in the nutritional support on serum insulin-like growth factor (IGF)-I concentrations in burn patients and to test the hypothesis that the serum proteolytic activity for insulin-like growth factor binding protein (IGFBP)-3 is a major mechanism for the decreased serum IGF-I observed in these patients. DESIGN: Randomized, double-blind trial of three different nutritional supports and analysis of serum IGF-I, IGFBP-3, and serum IGFBP-3 proteolysis. SETTING: Burn center in a university hospital. PATIENTS: A total of 23 severely burned (>25% total body surface area burned) adult patients. INTERVENTIONS: Patients were randomly assigned to three types of nutritional support differing in the amount of energy derived from fat and the presence or absence of fish oil: Group I (control), 35% fat; Group II, 15% fat; Group III, 15% fat with 50% as fish oil. Nutritional support was both parenteral and enteral and was started within 24 hrs of admission. MEASUREMENTS AND MAIN RESULTS: Serum IGF-I and IGFBP-3 were measured by radioimmunoassay every 3 days for 28 days in 23 severely burned adults. In six patients, IGFBP-3 was measured by ligand binding assay and the serum proteolytic activity for rhIGFBP-3 was measured as well. Serum IGF-I concentration was low in all subjects throughout the study period, but did increase with time (p < .01); significantly higher values were found in Group III (p < .05). Multivariate analysis showed that fish oil and low fat solutions were significantly correlated to serum IGF-I concentrations. Serum IGFBP-3 (radioimmunoassay) was higher than normal throughout the study with no difference between the groups. Between days 4 and 16, IGFBP-3 was cleaved into two fragments in all patients studied, and the molecular weights of the fragments were equal to those observed in the serum of a woman late in pregnancy. During this period of time, serum proteolytic activity for rhIGFBP-3 was >30% in 24 of the 30 samples measured, whereas 20 of the 28 samples measured thereafter were normal (<25%). Serum IGFBP-3 concentration from ligand binding assay was correlated with serum proteolytic capacity in all subjects (mean r2 = 0.77; p < .01) and with serum IGF-I concentrations in five of six subjects (mean r2 = 0.81; p < .01). CONCLUSIONS: In burn injury, serum IGF-I concentrations are sensitive to the amount and type of fat in their nutritional support. The presence of fish oil allowed for a more rapid recovery of serum IGF-I levels. The proteolysis of IGFBP-3 may be an important cause of the decreased serum IGF-I values and the protease(s) responsible for this seem to be similar to those observed in late pregnancy.

Increased burn-induced immunosuppression in lipopolysaccharide-resistant mice.

Severe burns induce a state of immunosuppression, and the inflammatory response after burn injury may play a role in this phenomenon. This study examined the effect of the inflammatory response to endotoxin on burn-induced immunosuppression and oxidative stress. An endotoxin-resistant mouse strain (C3H/HeJ) and a normally responding mouse strain (C3H/HeN) were compared. The mice were separated into three groups of five animals for each experimental day: (1) saline, (2) buprenorphine, and (3) buprenorphine and 20% total body surface area burn. All animals were fed ad libitum. The inflammatory response was studied at 1, 4, 7, 10, and 14 days postburn. Proliferation of activated splenocytes in burn mice was significantly lower on days 7, 10, and 14 for the C3H/HeJ strain and on days 4 and 10 for the C3H/HeN strain. Globally, C3H/HeJ presented stronger immune suppression than C3H/HeN. Oxidative stress parameters (liver malonaldehyde, spleen metabolic activity, and thiol concentrations) were higher in endotoxin-resistant mice than in the control strain. Impairment of the inflammatory response was more pronounced and oxidative stress was greater in endotoxin-resistant burn mice than in normal burn controls. Buprenorphine administration was not related to depression of these immune parameters. The inflammatory response following burn injury may be beneficial to the immune system.

Increased serum-soluble interleukin-2 receptor in burn patients: characterization and effects on the immune system.

The consequences of high serum concentrations of the interleukin (IL)-2 receptor alpha chain (sIL-2Ralpha) in several diseases are poorly understood. The objective of this study was to determine the form of sIL-2Ralpha in burn patients and its biological role. sIL-2Ralpha was measured in 18 severely burned individuals who received nutritional support with a normal or low fat content. sIL-2Ralpha was elevated throughout the study and it was notably lower in patients fed a low fat diet. Serum IL-6 and sIL-2Ralpha significantly correlated (r = 0.74, p < 0.05) in burn patients. The presence of sIL-2Ralpha was associated with a decrease in DR molecules in the CD2(-) and CD11b(+) cells of these patients. Western blot analysis of serum protein with N-terminal or C-terminal specific antibodies indicated that sIL-2Ralpha represents the extracellular domain of this molecule. Patient serum inhibited specifically murine, but not human IL-2-dependent T-cell proliferation. To determine the significance of sIL-2Ralpha, recombinant sIL-2Ralpha was used in different cellular model involving IL-2. sIL-2Ralpha inhibited natural killer cell activity by 50% in the presence of IL-2. The basal proliferation of peripheral blood mononuclear cells was inhibited by sIL-2Ralpha, but phytohemagglutinin-induced proliferation was unaffected by this form of receptor. Interferon (INF)-gamma production induced by OKT-3 on peripheral blood mononuclear cells was not altered by sIL-2Ralpha, but IL-2 induced increase in INF-gamma production was suppressed. The decreasing production of INF-gamma in the presence of IL-4 was significantly increased in the presence of sIL-2Ralpha in media. These results show that the large amount of sIL2-Ralpha circulating in burn patients is related to the inflammatory response. The amount of dietary fat modulates sIL2Ralpha concentration in burn patients, confirming the beneficial effect of low fat administration after burn trauma. Inhibition of T-cell activation in burn patients is not directly related to sIL-2Ralpha, although the presence of sIL-2Ralpha in serum can inhibit some IL-2 mediated response, such as the emergence of TH1 and TH2 cells.

Role of wound healing myofibroblasts on re-epithelialization of human skin.

In human skin, large burned surfaces heal using two concomitant phenomena: re-epithelialization and dermal neoformation. Numerous studies report the role of interactions between keratinocytes and fibroblasts, but the relationship between wound healing myofibroblasts and keratinocytes is not clear, even though these two cell types coexist during healing. We investigated the influence of myofibroblasts on keratinocyte growth and differentiation using an in vitro skin model. A histological study was performed to determine the speed and quality of epithelialization. When the dermis was populated with fibroblasts, a continuous epidermis was formed in 7-10 days. In contrast, with wound healing myofibroblasts or without cell in dermis, the complete reepithelialization never occurred over the 10-day period studied. After 7 further days of epidermal differentiation, histology showed an epidermis more disorganized and expression of basement membrane constituents was reduced when wound healing myofibroblasts or no cells were added in the dermis instead of fibroblasts. These results suggest that wound healing myofibroblasts are not efficient to stimulate keratinocyte growth and differentiation. Treatment of fibroblasts with TGFbeta1 induced an increase of epidermal cell differentiation as seen when myofibroblasts were present. However, this cytokine did not change re-epithelialization rate and induced an increase of basement membrane matrix deposition in opposition to myofibroblasts. Thus, TGFbeta1 action is not sufficient to explain all the different keratinocyte reactions towards fibroblasts and wound healing myofibroblasts. Our conclusion is that myofibroblasts seem to have a limited role in the re-epithelialization process and might be more associated with the increased extracellular matrix secretion.

Improved immune functions with administration of a low-fat diet in a burn animal model.

The purpose of this study was to characterize the impact of a low-fat (LF; 1% fat) diet, a high-fat (HF; 25% fat) diet, and a standard (SD; 5% fat) diet on immune and oxidative parameters in a 20% body surface area burn animal model fed ad libitum for 10 days postinjury. Although the mechanisms are poorly understood, the amount of dietary lipid in nutritional support has been shown to have immunomodulatory effects after burn injury. Burned mice fed the LF diet showed a normal response in activated splenocyte proliferation compared to burned animals that received the SD or HF diet. Animals fed the SD and HF diets presented increased production of nitric oxide and prostaglandin E2 response after burn injury, which is associated with inhibited splenocyte proliferation. The total thiol concentration in spleen cells from burned animals kept on the HF diet was significantly higher than that in unburned animals, while no increase in these oxidative parameters was observed in LF-fed burned animals. Moreover, the LF diet significantly reduced hepatic lipid peroxidation, as measured by malonaldehyde concentration, compared to the other two diets. These results suggest that the administration of a LF diet in mice after a burn injury prevents inhibition of in vitro splenocyte proliferation and reduces the intensity of oxidative stress.

Antiangiogenic effects of the oral administration of liquid cartilage extract in humans.

BACKGROUND: The antiangiogenic properties of shark cartilage extracts have been demonstrated in animal models but there are no data in human subjects. MATERIALS AND METHODS: A placebo or one of two doses of a liquid shark cartilage extract was orally administered daily, from Day 1 to Day 23 of the study protocol, to 29 healthy male volunteers randomized into three groups. On Day 12, a polyvinyl alcohol sponge threaded in a perforated silicone tubing was inserted subcutaneously on the anterior side of the arm and removed on Day 23. Evaluation of endothelial cell density, with factor VIII immunostaining, an indirect measurement of angiogenesis, was performed on histological sections of the implant using a semiquantitative numerical scale ranging from 1 (low density) to 5 (high density). The hydroxyproline content of the sponges was measured by HPLC. RESULTS: The mean endothelial cell density was significantly lower in groups that had received the liquid cartilage extract: grades 2.24 +/- 0.10, 2.47 +/- 0.10, and 3.15 +/- 0.11 for 7 and 21 ml liquid cartilage extract and placebo, respectively (P < 0.01 for both comparisons). No grade 1 was observed in the placebo group, whereas 9 treated subjects received a grade 1. Hydroxyproline content of the sponges did not differ between groups and there was no significant correlation between hydroxyproline content and endothelial cell density in the sponges. CONCLUSIONS: These results demonstrate that the liquid cartilage extract contains an antiangiogenic component bioavailable in humans by oral administration. This is the first report of an inhibition of wound angiogenesis in healthy men.

Decreased corticosteroid-binding globulin in burn patients: relationship with interleukin-6 and fat in nutritional support.

OBJECTIVES: To analyze the effect of low-fat nutritional solutions, with or without fish oil, on serum interleukin (IL)-6, and to explore the relationships between IL-6, corticosteroid-binding globulin (CBG; the main cortisol carrier in plasma), and protein metabolism in severely burned adult patients. DESIGN: Randomized, double-blind study with control and low fat-fed groups. SETTING: Burn center of Hôtel-Dieu Hospital of Montréal. PATIENTS: Thirty-seven men and women with thermal burn injury over >20% of body surface area and no other known medical condition. INTERVENTIONS: Within 24 hrs after admission, nutritional support was started through a gastroenteral tube inserted under endoscopic guidance. The goal for energy intake was calculated using the Curreri formula, and was adjusted with biweekly measurements of resting energy expenditure. Patients were randomly assigned to one of the following groups: control (35% of energy as fat); low fat 1 (15% of energy as fat); and low fat 2 (50% of fat in the form of fish oil). MEASUREMENTS AND MAIN RESULTS: Tumor necrosis factor (TNF)-alpha and TNF-beta, IL-6, CBG, and cortisol free fraction were measured every 3 days for 28 days. Nitrogen balance and urinary 3-methylhistidine excretion were measured daily. IL-6 concentrations were high in all patients, with the highest value (460 +/- 111 units/mL) observed on day 4. Concentrations of IL-6 were higher in control patients than in low fat-fed patients between days 13 and 28, but not between days 1 and 13. Multivariate analysis showed that IL-6, total body surface area burned, and sepsis scores were independent predictors of CBG between days 1 and 13 (n = 170; p<.00001). High IL-6 concentrations were predictors of low CBG concentrations and high cortisol free fractions. There was no relationship between IL-6, nitrogen balance, and 3-methylhistidine excretion. TNF-alpha and TNF-beta activity measurements by biological assay showed no correlation with other factors measured. CONCLUSIONS: a) Low-fat feeding, with or without fish oil, does not change the early production of IL-6 after burn injury; b) serum IL-6 is negatively correlated with CBG, which supports the hypothesis that this cytokine inhibits hepatic CBG production; and c) IL-6 does not appear to directly influence protein metabolism in burn patients.

Muscle strength in individuals with healed burns.

OBJECTIVE: To quantify the long-term effects of burns on muscle strength and to investigate the impact of the initial severity of the trauma on muscle strength. DESIGN: Cross-sectional study comparing individuals with healed burns to nonburned control individuals matched for age, gender, body mass index, and physical activity level. SETTING: Subjects were selected from the data bank of a burn center of a large Montreal teaching hospital and tested in a university laboratory. PATIENTS: Thirty subjects (mean age, 36.3 +/- 11.5 yrs) with second- and third-degree burns covering 15% to 75% of total body surface area (TBSA) (mean, 35.5% +/- 15.9%) were evaluated more than 1 year after discharge (mean, 37.3 +/- 20.4 months; range, 15 to 92 months). Thirty unburned subjects were recruited from the community at large. MAIN OUTCOME MEASURE: Maximal torque, work, and power developed by the elbow and knee flexors and extensors. RESULTS: Subjects with burns of > 30% of TBSA produced significantly less torque, work, and power in the quadriceps than control subjects (15.2% to 20.5% depending on velocity [p < .05]). The ability to develop muscle power at the elbow was also compromised in the severely burned subjects (19.2% in extension and 18.7% in flexion [p = .07]) at the faster velocities. No differences were observed between controls and patients with small burn injuries (TBSA of < 30%). CONCLUSION: Patients who had severe burns (TBSA of > 30%) had weaker muscles even years after the trauma, suggesting either an inability to fully recover or insufficient rehabilitation.

Modulated response to cytokines of human wound healing myofibroblasts compared to dermal fibroblasts.

Myofibroblasts play an important role in normal wound healing. They are present transiently during tissue repair. Their differentiation from fibroblasts and their role in granulation tissues are most likely to be modulated by cytokines. As these cells are derived from normal fibroblasts, their responses to cytokines are assumed to be similar. Until now, however, the difficulties in obtaining and maintaining normal human wound healing myofibroblasts in vitro have hampered comparison. The present study was designed to determine the effect of TGF-beta 1 and IFN-gamma, two cytokines known to modulate fibroblast morphology, on wound healing myofibroblasts and to compare it to fibroblasts. Morphological and phenotypic changes were followed by light and electron microscopy (stress fibers) and immunofluorescence cytochemistry (alpha-SM actin). Functional parameters such as the capacity to synthesize collagen and collagen gel contraction were studied. Both cytokines induced a strong modification of growth rate and phenotypic and morphological parameters in fibroblasts whereas collagen synthesis was slightly changed. Furthermore, TGF-beta 1 increased contractile capacity of fibroblasts whereas IFN-gamma greatly decreased it. In myofibroblasts, TGF-beta 1 and IFN-gamma did not induce any variation of morphology or growth rate. Interestingly, a strong modulation of functional parameters was observed: collagen synthesis was highly modified and, as for fibroblasts, the contractile capacity was altered. However, inhibition of contraction by IFN-gamma was irreversible in myofibroblasts but not in fibroblasts. These results suggest that fibroblastic cells show modulated responses to cytokines according to their stage of differentiation during wound healing.