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Objective To observe the histological change of different waves in treating SD rats of the long-pulse 1064nm Nd:YAG laser and the 560~1200 nm intense pulse light,in order to provide the theory bases of non-ablative rejuvenation.Methods Two waves were used on experimental mice.The dermic thickness and the expression of collagen typesⅠand Ⅲwere detected by HE stain and immunohistochemical methods. Semiquantitative analysis was used to determine the mean of absorbance.Results Thedermal thicknesses and the mean of absorbance of collagen typesⅠandⅢin two different waves were higher than those in common control groups(P<0.05).The effect of Nd:YAG laser groups were higher than IPL groups(P<0.05).The expression of collagen typeⅠwas higher than that of collagen type Ⅲ(P<0.001).Conclusion After Nd:YAG laser or IPL irradiation,the dermal thickness and collagen typesⅠandⅢof SD rats are increased.The effects of Nd:YAG laser are better than those of 560~1 200 nm IPL.The expression of collagen type Ⅲ is obviously more than that of collagen typeⅠin the early,whereas the expression of collagen typeⅠis obviously more than that of collagen type Ⅲin the later.It proves that the mechanism of dermal remodeling of non-ablative skin rejuvenation is mainly correlation with raising range and time of collagen typeⅠ.  相似文献   

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Objective To investigate whether low-protein diet has protective effect on the progression of renal interstitial fibrosis in rats with cyclosporine A (CsA)-induced nephropathy. Methods Eighteen male Sprague-Dawley rats were randomly divided into three groups (6 rats in each group). The rats in control group (C group) received common diet; in model group (M group) low-salt diet; in intervention group (Ⅰ group) low-salt and low-protein diet. After diet adaptation period of one week, the rats in C group received subcutaneous injection of olive oil 1 mg/kg daily for 5 weeks, while M group and Ⅰ group subcutaneous injection of CsA (diluted into 25 g/L with olive oil) 1 ml/kg for 5 weeks. All the rats were sacrificed at the end of the 5th week. The food-intake and body weight were measured daily. The creatinine clearance (Ccr) was examined before rats were sacrificed. The semi-quantitative pathological analysis on kidney sections was performed. The mRNA and protein expression of transforming growth factor-β1 (TGF-βI) and type Ⅰ collagen (Col Ⅰ) in kidney tissue was determined with real time PCR and immunohistochemical staining, respectively. Results The food-intake and body weight of rats in M and I groups were significantly lower than those in C group (P<0.05). Compared with C group, the Ccr levels in M and Ⅰ groups were significantly reduced [(0.65±0.15) ml/min, (0.40+0.13) ml/min vs (1.55±0.29) ml/min, P<0.05], the relative fibrosis areas of kidney interstitium in M and I groups were significantly increased (3.60%±0.46%, 3.26%±0.75% vs 0.44%±0.24%, P<0.05), the mRNA and protein expression of TGF-β1 in M and I group was significantly up-regulated (by 2.6 and 3.1 times in mRNA and by 1.5 and 1.6 times in protein, respectively, P<0.05), and the mRNA and protein expression of Col Ⅰ in M and I groups was also significantly up-regulated (by 3.0 and 3.5 times in mRNA and by 2.3 and 2.1 times in protein, respectively, P<0.05). There were no significant differences between M and I groups in every parameters above-mentioned except the rat body weight and Ccr. Both the body weight and Ccr in Ⅰ group were significantly lower than those in M group (P<0.05). Compared with C group, the urine osmotic pressure in M group and in I group were deceased (for M group, P>0.05; for I group, P<0.05). Compared with C group, the serum cholesterol levels in M and I groups were significantly increased (P<0.05), and the serum phosphorus level in I group was significantly decreased (P<0.05). The levels of serum albumin and serum calcium of all three groups had no statistical differences (P>0.05). Conclusion Low-protein diet has no renoprutective effects on the rat model of cyclosporin A nephropathy, on the contrary, may induce body weight loss.  相似文献   

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Objective To investigate whether low-protein diet has protective effect on the progression of renal interstitial fibrosis in rats with cyclosporine A (CsA)-induced nephropathy. Methods Eighteen male Sprague-Dawley rats were randomly divided into three groups (6 rats in each group). The rats in control group (C group) received common diet; in model group (M group) low-salt diet; in intervention group (Ⅰ group) low-salt and low-protein diet. After diet adaptation period of one week, the rats in C group received subcutaneous injection of olive oil 1 mg/kg daily for 5 weeks, while M group and Ⅰ group subcutaneous injection of CsA (diluted into 25 g/L with olive oil) 1 ml/kg for 5 weeks. All the rats were sacrificed at the end of the 5th week. The food-intake and body weight were measured daily. The creatinine clearance (Ccr) was examined before rats were sacrificed. The semi-quantitative pathological analysis on kidney sections was performed. The mRNA and protein expression of transforming growth factor-β1 (TGF-βI) and type Ⅰ collagen (Col Ⅰ) in kidney tissue was determined with real time PCR and immunohistochemical staining, respectively. Results The food-intake and body weight of rats in M and I groups were significantly lower than those in C group (P<0.05). Compared with C group, the Ccr levels in M and Ⅰ groups were significantly reduced [(0.65±0.15) ml/min, (0.40+0.13) ml/min vs (1.55±0.29) ml/min, P<0.05], the relative fibrosis areas of kidney interstitium in M and I groups were significantly increased (3.60%±0.46%, 3.26%±0.75% vs 0.44%±0.24%, P<0.05), the mRNA and protein expression of TGF-β1 in M and I group was significantly up-regulated (by 2.6 and 3.1 times in mRNA and by 1.5 and 1.6 times in protein, respectively, P<0.05), and the mRNA and protein expression of Col Ⅰ in M and I groups was also significantly up-regulated (by 3.0 and 3.5 times in mRNA and by 2.3 and 2.1 times in protein, respectively, P<0.05). There were no significant differences between M and I groups in every parameters above-mentioned except the rat body weight and Ccr. Both the body weight and Ccr in Ⅰ group were significantly lower than those in M group (P<0.05). Compared with C group, the urine osmotic pressure in M group and in I group were deceased (for M group, P>0.05; for I group, P<0.05). Compared with C group, the serum cholesterol levels in M and I groups were significantly increased (P<0.05), and the serum phosphorus level in I group was significantly decreased (P<0.05). The levels of serum albumin and serum calcium of all three groups had no statistical differences (P>0.05). Conclusion Low-protein diet has no renoprutective effects on the rat model of cyclosporin A nephropathy, on the contrary, may induce body weight loss.  相似文献   

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Objective To investigate whether low-protein diet has protective effect on the progression of renal interstitial fibrosis in rats with cyclosporine A (CsA)-induced nephropathy. Methods Eighteen male Sprague-Dawley rats were randomly divided into three groups (6 rats in each group). The rats in control group (C group) received common diet; in model group (M group) low-salt diet; in intervention group (Ⅰ group) low-salt and low-protein diet. After diet adaptation period of one week, the rats in C group received subcutaneous injection of olive oil 1 mg/kg daily for 5 weeks, while M group and Ⅰ group subcutaneous injection of CsA (diluted into 25 g/L with olive oil) 1 ml/kg for 5 weeks. All the rats were sacrificed at the end of the 5th week. The food-intake and body weight were measured daily. The creatinine clearance (Ccr) was examined before rats were sacrificed. The semi-quantitative pathological analysis on kidney sections was performed. The mRNA and protein expression of transforming growth factor-β1 (TGF-βI) and type Ⅰ collagen (Col Ⅰ) in kidney tissue was determined with real time PCR and immunohistochemical staining, respectively. Results The food-intake and body weight of rats in M and I groups were significantly lower than those in C group (P<0.05). Compared with C group, the Ccr levels in M and Ⅰ groups were significantly reduced [(0.65±0.15) ml/min, (0.40+0.13) ml/min vs (1.55±0.29) ml/min, P<0.05], the relative fibrosis areas of kidney interstitium in M and I groups were significantly increased (3.60%±0.46%, 3.26%±0.75% vs 0.44%±0.24%, P<0.05), the mRNA and protein expression of TGF-β1 in M and I group was significantly up-regulated (by 2.6 and 3.1 times in mRNA and by 1.5 and 1.6 times in protein, respectively, P<0.05), and the mRNA and protein expression of Col Ⅰ in M and I groups was also significantly up-regulated (by 3.0 and 3.5 times in mRNA and by 2.3 and 2.1 times in protein, respectively, P<0.05). There were no significant differences between M and I groups in every parameters above-mentioned except the rat body weight and Ccr. Both the body weight and Ccr in Ⅰ group were significantly lower than those in M group (P<0.05). Compared with C group, the urine osmotic pressure in M group and in I group were deceased (for M group, P>0.05; for I group, P<0.05). Compared with C group, the serum cholesterol levels in M and I groups were significantly increased (P<0.05), and the serum phosphorus level in I group was significantly decreased (P<0.05). The levels of serum albumin and serum calcium of all three groups had no statistical differences (P>0.05). Conclusion Low-protein diet has no renoprutective effects on the rat model of cyclosporin A nephropathy, on the contrary, may induce body weight loss.  相似文献   

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Objective To investigate whether low-protein diet has protective effect on the progression of renal interstitial fibrosis in rats with cyclosporine A (CsA)-induced nephropathy. Methods Eighteen male Sprague-Dawley rats were randomly divided into three groups (6 rats in each group). The rats in control group (C group) received common diet; in model group (M group) low-salt diet; in intervention group (Ⅰ group) low-salt and low-protein diet. After diet adaptation period of one week, the rats in C group received subcutaneous injection of olive oil 1 mg/kg daily for 5 weeks, while M group and Ⅰ group subcutaneous injection of CsA (diluted into 25 g/L with olive oil) 1 ml/kg for 5 weeks. All the rats were sacrificed at the end of the 5th week. The food-intake and body weight were measured daily. The creatinine clearance (Ccr) was examined before rats were sacrificed. The semi-quantitative pathological analysis on kidney sections was performed. The mRNA and protein expression of transforming growth factor-β1 (TGF-βI) and type Ⅰ collagen (Col Ⅰ) in kidney tissue was determined with real time PCR and immunohistochemical staining, respectively. Results The food-intake and body weight of rats in M and I groups were significantly lower than those in C group (P<0.05). Compared with C group, the Ccr levels in M and Ⅰ groups were significantly reduced [(0.65±0.15) ml/min, (0.40+0.13) ml/min vs (1.55±0.29) ml/min, P<0.05], the relative fibrosis areas of kidney interstitium in M and I groups were significantly increased (3.60%±0.46%, 3.26%±0.75% vs 0.44%±0.24%, P<0.05), the mRNA and protein expression of TGF-β1 in M and I group was significantly up-regulated (by 2.6 and 3.1 times in mRNA and by 1.5 and 1.6 times in protein, respectively, P<0.05), and the mRNA and protein expression of Col Ⅰ in M and I groups was also significantly up-regulated (by 3.0 and 3.5 times in mRNA and by 2.3 and 2.1 times in protein, respectively, P<0.05). There were no significant differences between M and I groups in every parameters above-mentioned except the rat body weight and Ccr. Both the body weight and Ccr in Ⅰ group were significantly lower than those in M group (P<0.05). Compared with C group, the urine osmotic pressure in M group and in I group were deceased (for M group, P>0.05; for I group, P<0.05). Compared with C group, the serum cholesterol levels in M and I groups were significantly increased (P<0.05), and the serum phosphorus level in I group was significantly decreased (P<0.05). The levels of serum albumin and serum calcium of all three groups had no statistical differences (P>0.05). Conclusion Low-protein diet has no renoprutective effects on the rat model of cyclosporin A nephropathy, on the contrary, may induce body weight loss.  相似文献   

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Objective To investigate whether low-protein diet has protective effect on the progression of renal interstitial fibrosis in rats with cyclosporine A (CsA)-induced nephropathy. Methods Eighteen male Sprague-Dawley rats were randomly divided into three groups (6 rats in each group). The rats in control group (C group) received common diet; in model group (M group) low-salt diet; in intervention group (Ⅰ group) low-salt and low-protein diet. After diet adaptation period of one week, the rats in C group received subcutaneous injection of olive oil 1 mg/kg daily for 5 weeks, while M group and Ⅰ group subcutaneous injection of CsA (diluted into 25 g/L with olive oil) 1 ml/kg for 5 weeks. All the rats were sacrificed at the end of the 5th week. The food-intake and body weight were measured daily. The creatinine clearance (Ccr) was examined before rats were sacrificed. The semi-quantitative pathological analysis on kidney sections was performed. The mRNA and protein expression of transforming growth factor-β1 (TGF-βI) and type Ⅰ collagen (Col Ⅰ) in kidney tissue was determined with real time PCR and immunohistochemical staining, respectively. Results The food-intake and body weight of rats in M and I groups were significantly lower than those in C group (P<0.05). Compared with C group, the Ccr levels in M and Ⅰ groups were significantly reduced [(0.65±0.15) ml/min, (0.40+0.13) ml/min vs (1.55±0.29) ml/min, P<0.05], the relative fibrosis areas of kidney interstitium in M and I groups were significantly increased (3.60%±0.46%, 3.26%±0.75% vs 0.44%±0.24%, P<0.05), the mRNA and protein expression of TGF-β1 in M and I group was significantly up-regulated (by 2.6 and 3.1 times in mRNA and by 1.5 and 1.6 times in protein, respectively, P<0.05), and the mRNA and protein expression of Col Ⅰ in M and I groups was also significantly up-regulated (by 3.0 and 3.5 times in mRNA and by 2.3 and 2.1 times in protein, respectively, P<0.05). There were no significant differences between M and I groups in every parameters above-mentioned except the rat body weight and Ccr. Both the body weight and Ccr in Ⅰ group were significantly lower than those in M group (P<0.05). Compared with C group, the urine osmotic pressure in M group and in I group were deceased (for M group, P>0.05; for I group, P<0.05). Compared with C group, the serum cholesterol levels in M and I groups were significantly increased (P<0.05), and the serum phosphorus level in I group was significantly decreased (P<0.05). The levels of serum albumin and serum calcium of all three groups had no statistical differences (P>0.05). Conclusion Low-protein diet has no renoprutective effects on the rat model of cyclosporin A nephropathy, on the contrary, may induce body weight loss.  相似文献   

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Objective To discuss the influence of aerosol bioelectricity on the expression of interleukin (IL) -8 and IL-10 in wound healing of burned rats. Methods The deep Ⅱ degree scalding models were established in Sprague Dawley (SD) rats. Rats were randomly divided into experimental group (n1 =20) and control group (n2 =20). The rats in experimental group were treated with aerosol bioelectricity.Samples were collected at the first to eleventh day post-scalding. Immunohistochemistry and image analysis methods were conducted to examine the expression of IL-8 and IL-10 in both experimental and control groups. Results The average wound healing time in experimental group was 7. 00 ± 1. 15 days, and that in control group was 9. 00 ± 1. 34 days. IL-8 and IL-10 were observed mainly in polylmorphonuclear and mononuclear cells in both experimental and control groups on the 1 st day. On the third day, fibroblasts abounded, IL-8 expression was increased evidently and reached a peak. The peak value (6. 73 ± 1. 36) in experimental group was lower significantly than that in control group ( 2. 85 ± 0. 72, P < 0. 01). From the 5th to 11th day, IL-8 expression was declined rapidly. IL-10 was expressed in keratode cells and had the peak value in experimental group (1. 24 ±0. 15) and control group (5. 69 ± 1. 32) on the 3rd day. IL-10 expression was declined gradually from the 5th to 11th days. The expression level of IL-10 in experimental group was significantly higher than in control group from the 3rd day to 11th days post-scalding (P<0. 01). On the 3rd day, both IL-8 and IL-10 in experimental and control groups were expressed abundantly , and there was negative relationship between them (r = - 0. 862, P < 0. 01). Conclusion Aerosol bioelectricity can indicate active cells proliferation through down-regulating the expression of IL-8 and up-regulating the expression of IL-10, accelerating burned wound healing.  相似文献   

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Objective To investigate whether low-protein diet has protective effect on the progression of renal interstitial fibrosis in rats with cyclosporine A (CsA)-induced nephropathy. Methods Eighteen male Sprague-Dawley rats were randomly divided into three groups (6 rats in each group). The rats in control group (C group) received common diet; in model group (M group) low-salt diet; in intervention group (Ⅰ group) low-salt and low-protein diet. After diet adaptation period of one week, the rats in C group received subcutaneous injection of olive oil 1 mg/kg daily for 5 weeks, while M group and Ⅰ group subcutaneous injection of CsA (diluted into 25 g/L with olive oil) 1 ml/kg for 5 weeks. All the rats were sacrificed at the end of the 5th week. The food-intake and body weight were measured daily. The creatinine clearance (Ccr) was examined before rats were sacrificed. The semi-quantitative pathological analysis on kidney sections was performed. The mRNA and protein expression of transforming growth factor-β1 (TGF-βI) and type Ⅰ collagen (Col Ⅰ) in kidney tissue was determined with real time PCR and immunohistochemical staining, respectively. Results The food-intake and body weight of rats in M and I groups were significantly lower than those in C group (P<0.05). Compared with C group, the Ccr levels in M and Ⅰ groups were significantly reduced [(0.65±0.15) ml/min, (0.40+0.13) ml/min vs (1.55±0.29) ml/min, P<0.05], the relative fibrosis areas of kidney interstitium in M and I groups were significantly increased (3.60%±0.46%, 3.26%±0.75% vs 0.44%±0.24%, P<0.05), the mRNA and protein expression of TGF-β1 in M and I group was significantly up-regulated (by 2.6 and 3.1 times in mRNA and by 1.5 and 1.6 times in protein, respectively, P<0.05), and the mRNA and protein expression of Col Ⅰ in M and I groups was also significantly up-regulated (by 3.0 and 3.5 times in mRNA and by 2.3 and 2.1 times in protein, respectively, P<0.05). There were no significant differences between M and I groups in every parameters above-mentioned except the rat body weight and Ccr. Both the body weight and Ccr in Ⅰ group were significantly lower than those in M group (P<0.05). Compared with C group, the urine osmotic pressure in M group and in I group were deceased (for M group, P>0.05; for I group, P<0.05). Compared with C group, the serum cholesterol levels in M and I groups were significantly increased (P<0.05), and the serum phosphorus level in I group was significantly decreased (P<0.05). The levels of serum albumin and serum calcium of all three groups had no statistical differences (P>0.05). Conclusion Low-protein diet has no renoprutective effects on the rat model of cyclosporin A nephropathy, on the contrary, may induce body weight loss.  相似文献   

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Ileus and the macrophage   总被引:2,自引:0,他引:2       下载免费PDF全文
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目的 研究巨噬细胞及粒巨细胞-集落刺激因子(GM-CSF)对大鼠腹壁动脉穿支(deep epigastric perforator,DEP)皮瓣模型的影响.方法 建立SD大鼠DEP皮瓣模型,分别给予大鼠GM-CSF(Ⅰ组)、腹腔巨噬细胞(Ⅱ组)、GM-CSF联合巨噬细胞(Ⅲ组)及乍理盐水(Ⅳ组).术后第7天取皮瓣检测成活而积、组织学观察、微血管密度(MVD)、皮瓣内胶原含量.结果 皮瓣成活率Ⅰ组(53.08%±8.76%)和Ⅱ组(47.95%±4.92%)间无差异,均高于Ⅳ组(43.28%±5.27%)而低于Ⅲ组(61.68%±6.60%),P<0.05.皮瓣MVD Ⅰ组(24.82±4.18)和Ⅱ组(24.30±3.02)间差异无统计学意义,均显著高于Ⅳ组(21.37±2.65),低于Ⅲ组(29.82±4.74).胶原含量Ⅰ组(17.25%±2.85%)高于Ⅳ组(14.41%±2.89%),P<0.05.Ⅱ组(12.69%±3.55%)稍低于Ⅳ组.Ⅲ组(20.31%±3.01%)较Ⅰ组显著增高,P<0.05.结论 重组大鼠GM-CSF和巨噬细胞均能够促进大鼠DEP皮瓣成活,联合应用可发挥协同作用促进皮瓣存活、血管生成以及胶原沉积.  相似文献   

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Alveolar macrophage in the burned rat   总被引:1,自引:0,他引:1  
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The role of the macrophage is an area of emerging interest in tendinopathy and tendon healing. The macrophage has been found to play a key role in regulating the healing process of the healing tendon. The specific function of the macrophage depends on its functional phenotype. While the M1 macrophage phenotype exhibits a phagocytic and proinflammatory function, the M2 macrophage phenotype is associated with the resolution of inflammation and tissue deposition. Several studies have been conducted on animal models looking at enhancing or suppressing macrophage function, targeting specific phenotypes. These studies include the use of exogenous biological and pharmacological substances and more recently the use of transgenic and genetically modified animals. The outcomes of these studies have been promising. In particular, enhancement of M2 macrophage activity in the healing tendon of animal models have shown decreased scar formation, accelerated healing, decreased inflammation and even enhanced biomechanical strength. Currently our understanding of the role of the macrophage in tendinopathy and tendon healing is limited. Furthermore, the roles of therapies targeting macrophages to enhance tendon healing is unclear. Clinical Significance: An increased understanding of the significance of the macrophage and its functional phenotypes in the healing tendon may be the key to enhancing tendon healing. This review will present the current literature on the function of macrophages in tendinopathy and tendon healing and the potential of therapies targeting macrophages to enhance tendon healing.  相似文献   

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Summary Vitamin D3 deficient (D) mice show a depressed inflammatory response and both inflammatory peritoneal macrophages and bone marrow polymorphonuclear leukocytes of D mice exhibit a decreased spontaneous migration under agarose. The impaired phagocytic response of peritoneal macrophages from D mice can be corrected by incubation with 1,25-dihydroxyvitamin D3 and is not affected by interaction with other vitamin D3 metabolites. Transfer of mice from the D to the D+ state results in correction of both the inflammatory and the phagocytic response. Intactness of phagocyte function is thus directly dependent on vitamin D3 metabolism.  相似文献   

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Malnutrition-induced macrophage apoptosis   总被引:7,自引:0,他引:7  
BACKGROUND: Human and murine studies suggest protein-calorie malnutrition (PCM) results in significant host immunosuppression resulting in increased morbidity and mortality. Apoptosis has been implicated as an important mediator in the immunosuppression observed in several disease states. This study was designed to characterize macrophage apoptosis in a murine model of PCM and investigate components that regulate the apoptotic process, such as protein kinase C (PKC) and Bcl-2 activity. METHODS: Swiss-Webster mice (n = 50) were randomly assigned to receive either a control (24% protein) or a PCM diet (0% protein) for 7 days. Peritoneal macrophages were harvested and detection of apoptosis was performed by terminal deoxy-transferase-mediated deoxyuridine triphosphate (dUTP) nick-end labeling (TUNEL) and propidium iodide DNA staining under baseline and pro-apoptotic conditions. Pro-apoptotic conditions included cells treated with tumor necrosis factor-alpha (TNF-alpha) (10 ng/mL), interferon-gamma (IFN-gamma) (10 ng/mL), and a combination of both agents. In addition, levels of PKC activity and expression of Bcl-2 and p53 protein were measured. RESULTS: Peritoneal macrophages from PCM mice had a significantly greater amount of apoptosis at baseline and under stimulated conditions compared with controls. Levels of PCM apoptosis were elevated at baseline by TUNEL staining compared with macrophages from the control group (16.5% +/- 1.4%, versus 4.5% +/- 1.1%, P <.01). In addition, peritoneal macrophages from the malnourished animals were significantly more susceptible to the apoptotic effect of TNF-alpha and the effects of INF-gamma (27.3% +/- 2.1% and 31% +/- 1.4%) compared with control mice (5.5% +/- 0.7% and 7.2% +/- 0.5%, P <.01), respectively. Again, an increase in the baseline apoptosis rate was demonstrated in peritoneal macrophages from PCM mice compared with control fed mice (13.2% +/- 4.4% versus 4.3% +/- 3.1%, P <.01) as measured by propidium iodide staining. The combination of agents, TNF-alpha and INF-gamma, resulted in an additive apoptotic effect in the malnourished host compared with the control animals (43.4% +/- 4.7% versus 10.5% +/- 2.2%, P <.01), respectively. Furthermore, there was a significant decrease in the mean total PKC activity in the malnourished macrophages compared with results in controls (110,000 +/- 8000 versus 60,000 +/- 4000 cpm, P <.01). Similar changes were also observed in PKC cytosolic and membrane activity between both groups. In addition, Bcl-2 protein expression was significantly decreased in PCM animals compared with control animals. CONCLUSIONS: Thus, peritoneal macrophages from PCM mice exhibit significantly greater levels of apoptosis at baseline and when stimulated with pro-apoptotic agents compared with controls. The propensity of macrophages from PCM mice to undergo apoptosis may be attributable in part to decreased PKC activity and Bcl-2 protein expression. These findings may help to explain the associated immune dysfunction observed in malnutrition.  相似文献   

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