Lethal burn-induced bacterial translocation: role of genetic resistance

Since genetic factors may influence outcome after trauma or during infection, the current experiments were performed to examine the resistance of three genetically different mouse strains to burn-induced bacterial translocation. Outbred ICR, inbred Balb/c, and inbred C57/B1 mice, with a normal or disrupted (monoassociated with Escherichia coli C25) GI tract microflora, were subjected to sham or actual 25% body burns. In Balb/c, but not ICR mice, replacing the normal intestinal microflora with E. coli C25 converted the thermal injury from a nonlethal (0% mortality) to a lethal (68% mortality) injury. The increased mortality of the burned Balb/c mice monoassociated with E. coli C25 was associated with a higher incidence (p less than 0.05) and magnitude (p less than 0.05) of E. coli C25 translocation from the GI tract. The C57/B1 mice were intermediate between the Balb/c and ICR strains, in that C57/B1 mice monoassociated with E. coli C25 had a higher mortality and greater E. coli C25 translocation than mice with a normal microflora after thermal injury. Thus the composition of the intestinal microflora as well as the genetic background of the host influence the susceptibility of the host to burn-induced bacterial translocation and survival.     

Endotoxin induces bacterial translocation and increases xanthine oxidase activity

Previously, we documented that endotoxin induces bacterial translocation from the gut and that inhibition or inactivation of xanthine oxidase activity reduces endotoxin-induced bacterial translocation. Consequently, experiments were performed to correlate endotoxin-induced bacterial translocation with changes in intestinal mucosal structure and xanthine dehydrogenase and oxidase activity. Segments of the jejunum, ileum, cecum, proximal colon, distal colon, and liver were harvested from ICR mice 24 hr after IP administration of E. coli 0111:B4 endotoxin (0.1 mg). Xanthine dehydrogenase and oxidase activities were measured in these samples and correlated with intestinal morphology. Bacteria translocated from the intestines to extraintestinal organs in 70% of the mice receiving endotoxin, while the organs of control mice were sterile (p less than 0.01). Endotoxin injured primarily the ileal and cecal mucosa and increased ileal and hepatic xanthine dehydrogenase and cecal oxidase activities (p less than 0.05). These results suggest that xanthine oxidase-induced mucosal damage plays a role in endotoxin-induced bacterial translocation.     

A study of the relationship among survival, gut-origin sepsis, and bacterial translocation in a model of systemic inflammation.

Several factors, including uncontrolled inflammation, gut barrier failure, and sepsis, have been implicated in the development of multiple organ failure. To investigate the relative importance and interrelationships among some of these factors, increasing doses of the inflammatory agent zymosan were used to induce a systemic inflammatory state in mice. At nonlethal doses (0.1 and 0.5 mg/g body weight), zymosan caused injury to the intestinal mucosa, increased intestinal xanthine oxidase activity, and promoted bacterial translocation in a dose-dependent fashion. Inhibition or inactivation of xanthine oxidase activity was effective in reducing mucosal injury and bacterial translocation when zymosan was injected at 0.1 mg/g but not at 0.5 mg/g body weight. At a dose of 1 mg/g, the lethal effects of zymosan appeared to be related to gut-origin sepsis, since cefoxitin (1 mg/g) reduced the seven-day mortality rate from 100% to 20% (p less than 0.01). However, at a zymosan dose of 2 mg/g, antibiotics did not improve survival. Zymosan thus induced gut barrier failure and systemic infection in a dose-dependent fashion. Additionally, the mechanism of zymosan-induced bacterial translocation and the relationship of gut-origin sepsis to survival appeared to be related to the magnitude of the inflammatory insult (the dose of zymosan).     

Endotoxin-induced bacterial translocation: a study of mechanisms

Previously, we documented that nonlethal doses of endotoxin cause the translocation (escape) of bacteria from the gut to systemic organs. The purpose of this study was to determine which portion(s) of the endotoxin molecule induces bacterial translocation and to examine the role of xanthine oxidase activity in the pathogenesis of endotoxin-induced bacterial translocation. Nonlethal doses of Salmonella endotoxin preparations (wild type, Ra, or Rb), containing the terminal portion of the core polysaccharide, induced bacterial translocation, whereas those preparations lacking the terminal-3 sugars (Rc, Rd, Re, or lipid A) did not induce bacterial translocation. Additionally, only those endotoxin preparations that induced bacterial translocation injured the gut mucosa, increased ileal xanthine dehydrogenase and oxidase activity, and disrupted the normal ecology of the gut flora, resulting in overgrowth with enteric bacilli. Inhibition of xanthine oxidase activity by allopurinol prevented endotoxin (Ra)-induced mucosal injury and reduced the incidence of bacterial translocation from 83% to 30% (p less than 0.01). These results suggest that endotoxin-induced bacterial translocation requires the presence of the terminal core lipopolysaccharide moiety and that xanthine oxidase-generated oxidants are important in the pathogenesis of endotoxin-induced mucosal injury and bacterial translocation.     

Effect of stress and trauma on bacterial translocation from the gut

Previously, we established that bacteria contained within the gut can cross the GI mucosal barrier and spread systemically, a process termed bacterial translocation. Three models were used to extend this work: cold exposure (up to 16 hr at 4 degrees C), a nontissue injury stress model; femoral fracture-amputation, a trauma model; and thermal injury (30% third-degree burn), a trauma model with retained necrotic tissue. CD-1 mice either with a normal GI microflora or who were monoassociated with Escherichia coli C-25 were subjected to sham or actual stress or trauma. The animals were sacrificed at various times postinsult and the ceca, mesenteric lymph nodes (MLN), spleens, and livers were quantitatively cultured. Neither the incidence nor the magnitude of bacterial translocation was increased in the cold-exposed animals compared to control mice. The incidence of bacterial translocation to the systemic organs was higher in the animals with a normal flora receiving femoral fracture amputation (11%) (P less than 0.02) than in animals receiving a thermal injury (1%) or sham-injured control mice (0%). In contrast, the incidence of translocation to the liver or spleen was higher in burned mice monoassociated with E. coli C-25 (60%) (P less than 0.01) than in E. coli monoassociated mice sustaining femoral fracture amputation (17%). Stress alone (cold exposure) does not promote bacterial translocation; however, trauma, especially in combination with retained necrotic tissue, promotes bacterial translocation. Thus bacteria colonizing the gut can invade systemic organs after trauma, especially when the normal ecology of the gut flora has been disrupted.     

Skin wounds in the MRL/MPJ mouse heal with scar

Adult MRL/MpJ mice regenerate cartilage during repair of through-and-through ear punch wounds. However, the ability of this mouse strain to heal isolated cutaneous wounds by regeneration or with scar is unknown. The purpose of this study was to characterize the rate of reepithelialization and collagen architecture in dermal wounds from MRL/MpJ mice compared with C57bl/6 and Balb/c strains. Full-thickness incisional (5 mm) and excisional (2 mm diameter) skin wounds were made on the dorsum of 7-week-old MRL/MpJ, C57bl/6, and Balb/c mice. Ear punch wounds were made simultaneously on each animal. Reepithelialization was complete by 48 hours for incisional skin wounds in each strain. All excisional wounds showed incomplete reepithelialization at 24, 48, and 72 hours. At 14 days, all skin wounds had grossly healed. In contrast to the ear wounds made in C57bl/6 and Balb/c mice, MRL/MpJ ear wounds were completely healed by day 28. Dorsal skin wound sections at 14 and 28 days revealed dense collagen deposition and similar degrees of fibrosis between the three strains of mice. In conclusion, in contrast to wound healing in the ear, MRL/MpJ mouse dorsal cutaneous wounds heal similarly to C57bl/6 and Balb/c mice with dermal collagen deposition and scar formation.     

Hemorrhagic shock-induced bacterial translocation is reduced by xanthine oxidase inhibition or inactivation

Experiments were performed to determine whether bacterial translocation (BT) after hemorrhagic shock is due to a reperfusion injury mediated by xanthine oxidase-derived oxidants. Rats were subjected to 30 minutes of shock (30 mm Hg) followed by reinfusion of shed blood. Twenty-four hours after hemorrhage and reinfusion, the mesenteric lymph node, liver, and spleen were harvested from each animal for bacterial culture, and the ileum and cecum were examined histologically. Sham-shocked (control) rats were instrumented, but blood was not withdrawn. The incidence of BT was higher in the shocked rats (61%) than in the sham-shocked animals (7%) (p less than 0.01). Allopurinol (50 mg/kg, administered orally), a competitive inhibitor of xanthine oxidase, reduced the incidence of shock-induced BT to 14% (p = 0.02). Similarly, rats fed a tungsten-supplemented molybdenum-free diet, which inactivates xanthine oxidase, reduced shock-induced BT to 10% (p = 0.02). The histologic damage cause by hemorrhagic shock was prevented by blocking xanthine oxidase activity. Thus hemorrhagic shock-induced bacterial translocation from the gut appears to be mediated by oxidants generated by activation of the xanthine oxidase system.     

Localization and changes of diamine oxidase during cardiopulmonary bypass in rabbits

BACKGROUND: We previously observed increased serum diamine oxidase activity during clinical cardiopulmonary bypass, indicating small intestinal mucosal ischemia followed by bacterial translocation. MATERIALS AND METHODS: In seven female rabbits undergoing cardiopulmonary bypass for 1 h, we analyzed the localization of diamine oxidase immunohistochemically, and measured its activity in serum and abdominal organs before and after cardiopulmonary bypass (CPB). RESULTS: Preoperatively, diamine oxidase activity and immunoreactivity were high in the small intestine, localized to villus tips. Serum activity increased significantly after CPB, whereas small intestinal diamine oxidase decreased with mucosal injury. CONCLUSIONS: In this model serum diamine oxidase activity appeared to reflect CPB induced intestinal mucosal injury.     

Staphylococcus aureus antigens induce IgA-type glomerulonephritis in Balb/c mice

BACKGROUND: Staphylococcus aureus (S. aureus) is a common, normal pathogenic flora that colonizes mucosal tissues. We previously reported that glomerulonephritis occurs during methicillin-resistant S. aureus infection, and demonstrated polyclonal elevation of serum immunoglobulin A (IgA) and IgG levels and various histological findings, such as mesangial extracapillary and endocapillary proliferation. To investigate the pathogenic roles of S. aureus antigens, we induced IgA-type glomerulonephritis in mice by immunization with antigens derived from S. aureus, as a model of human IgA nephropathy (IgAN). METHODS: Balb/c mice (Th2 dominant type) and C57BL/6 mice (Th1 dominant type) were immunized biweekly for 4 months with antigens derived from S. aureus mixed with Freund's incomplete adjuvant. RESULTS: Mesangial proliferative glomerulonephritis with IgA, IgG and complement 3 (C3) depositions were observed in all Balb/c mice. Although C3 depositions and cell proliferation in the mesangial area were also seen in C57BL/6 mice, they were not correlated with urinary findings. In Balb/c mice, S. aureus antigens were detected in glomeruli using affinity-purified human anti-S. aureus antibodies, but there was no staining in C57BL/6 mice. The antibodies reacted with several S. aureus antigens, based on Western blot analysis, and the main 30-35 kDa band differed in intensity in Balb/c and C57BL/6 mice. In addition, increased transforming growth factor beta (TGF-beta) messenger RNA (mRNA) expression was seen in Balb/c mice compared to C57BL/6 mice. CONCLUSIONS: S. aureus antigens including, in particular, a 30-35 kDa protein and the host genetic background could play important roles in IgA-like glomerulonephritis pathogenesis.     

Thermal injury promotes bacterial translocation from the gastrointestinal tract in mice with impaired T-cell-mediated immunity

We have shown previously that after thermal trauma viable bacteria will cross the intact gastrointestinal mucosa (bacterial translocation) to invade the mesenteric lymph nodes and other organs if the normal indigenous microflora is disrupted, allowing bacterial overgrowth. To determine whether T-cell-mediated immunity (T-CMI) was important in preventing translocation after thermal injury in animals with an intact normal flora, conventional (+/+), athymic (nu/nu), and heterozygous (nu/+) mice receiving a 30% third-degree burn were killed at various intervals after burn and their organs cultured. Bacterial translocation did not occur in control or burned specific pathogen-free mice with intact T-CMI but did occur in athymic mice with deficient T-CMI. Both the incidence of positive organs and the numbers of translocated bacteria per gram of organ were increased after thermal injury. Bacterial overgrowth was not responsible for these findings, since the levels of cecal enteric bacteria were not different between the burned and nonburned groups. Since translocation occurred to a greater extent in athymic burned mice than control athymic mice, it appears that a thermal injury promotes translocation by impairing other host defense systems in addition to the T-CMI.     

大鼠门静脉高压症及梗阻性黄疸时细菌移位与黄嘌呤脱氢酶和黄嘌呤氧化酶的关系

目的探讨大鼠门静脉高压症（porta; ju[ertemsopm,PH）及梗阻性黄疸（obstructive jaundioe,OJ）时,细菌移位（bacterial translocation,BT）与黄嘌呤氧化酶（xanthine oxidase,XO）、黄嘌呤脱氢酶（xanthine dehydrogenase,XD）之间的关系。方法将雄性SD大鼠60只随机分为对照组（A组）,胆总管结扎组（B组）和门静脉缩窄组（C组）,每组20只。术后第3周取肠系膜淋巴结、脾、肝组织及门静脉、腔静脉血细菌培养,测定门静脉压力（free portal pressure,FPP）,及肠XO,XD活性水平。结果B组及C组细菌移位率明显高于对照组（P〈0．01）,对照组为12％,B组和C组分别为28％和54％;B组和C组空肠XO水平活性明显高于对照组（P〈0．01）,B组和C组门静脉压力也较对照组升高。细菌移位率与XO活性成正相关（r=0．603）。XD活性水平无显著差异。结论门静脉高压症及梗阻性黄疸时可发生细菌移位,可能与肠黏膜屏障被破坏通透性增强有关,肠壁XO水平活性增强引起肠黏膜屏障通透性增高有助于细菌移位发生。     

Hemorrhagic shock-induced bacterial translocation: the role of neutrophils and hydroxyl radicals

We previously documented a relationship between xanthine oxidase activation, intestinal injury, and bacterial translocation (BT) in rats subjected to hemorrhagic shock. The current experiments were performed to determine the relative roles of hydroxyl radicals and neutrophils in the pathogenesis of shock-induced mucosal injury and BT. The incidence of BT was higher in the shocked rats (30 mm Hg for 30 min) than the sham-shock controls (87% vs 12.5%; p less than 0.01). Administration of the hydroxyl radical scavenger, dimethyl sulfoxide (DMSO), or the iron chelator, deferoxamine, reduced the incidence of BT from 87% to 20% and 40%, respectively (p less than 0.05). DMSO and deferoxamine appear to prevent shock-induced BT by blunting the magnitude of shock-induced mucosal injury. In contrast, neutrophil depletion did not prevent BT or protect the intestinal mucosa in shocked rats. Instead, the incidence of systemic spread of translocating bacteria past the mesenteric lymph nodes to the livers and spleens of the shocked rats was higher in the neutrophil-depleted rats (56%) than in any other group (p less than 0.01). Thus, shock-induced BT and intestinal injury appear to be mediated by oxidants (.OH) derived from xanthine oxidase, rather than granulocytes.     

不同品系小鼠间皮肤移植致敏后抗供体特异性抗体的变化特点研究

目的 比较不同品系小鼠间皮肤移植致敏后抗供体特异性抗体（DSA）的变化特点。 方法 将小鼠分为Balb/c→C57BL/6皮肤移植组（6对）和Balb/c→C3H皮肤移植组（6对）。皮肤移植后收集d0、d2、d4、d7、d13、d17、d28、d35、d42、d49、d56时间点血清并检测DSA-IgG和DSA-IgM。 结果 小鼠皮肤移植致敏后1周内DSA-IgG水平升高不明显,1~4周内IgG水平持续快速增长,4~8周IgG水平处于高峰平台稳定。皮肤移植后8周内DSA-IgM无明显变化。Balb/c→C57BL/6皮肤移植组DSA-IgG水平明显低于Balb/c→C3H组,两组在d2、d17、d28、d35、d42、d49和d56时间点的IgG水平差异有统计学意义（均为P < 0.05）,两组DSA-IgM在各时间点比较差异无统计学意义（均为P>0.05）。 结论 利用Balb/c→C3H适当提前皮肤移植后的肾移植手术时间,或改用免疫反应性更弱的Balb/c→C57BL/6组合有望建立排斥反应更弱的移植肾AMR模型。     

Role of gut-derived endotoxaemia and bacterial translocation in rats after thermal injury: effects of selective decontamination of the digestive tract

This study was performed to investigate: (1) the role of gut-derived endotoxin/bacterial translocation in the pathogenesis of sepsis, and (2) the possible effects of selective decontamination of the digestive tract (SDD) on mortality in rats following 40 per cent full-thickness scald injury. In the SDD-treated group, Enterobacteriaceae and yeasts were eradicated from the caecal mucosa, while the mucosal flora consisting of mainly anaerobes was well preserved, within 3 days. The incidence of bacterial translocation to the mesenteric lymph nodes (MLN) and viscerae was significantly lowered on postburn days 1, 3 and 5 (P < 0.05−0.01). Meanwhile, pretreatment with SDD resulted in reductions of the faecal endotoxin levels in different segments of intestinal tract to less than 0.5 per cent (0.04 – 0.45 per cent) of the untreated control; there was also a significant attenuation of the elevation of endotoxin concentrations in both portal and systemic blood. Intestinal diamine oxidase (DAO) activity returned to baseline on day 5 in rats receiving SDD but not in controls. The 5-day survival rate in the SDD-treated group was elevated by 26.7 per cent as compared with controls (P < 0.05). These data suggested that endotoxin/bacterial translocation took place early and commonly, which in turn contributed to postburn sepsis and mortality. SDD was effective in preventing gut origin endotoxaemia and bacterial translocation, and improving the survival rate in rats following severe thermal injuries.     

Human C1 esterase inhibitor attenuates murine mesenteric ischemia/reperfusion induced local organ injury

BACKGROUND: Complement activation contributes to ischemia and reperfusion (IR)-initiated organ injury. C1 inhibitor (C1 Inh) inhibits the earliest steps of the classical and the mannose binding lectin pathways. MATERIALS AND METHODS: To determine whether C1 Inh prevented tissue injury, we performed intestinal IR experiments in BALB/c and C57BL/6 mice. RESULTS: We found that C1 Inh limits mucosal injury in the two strains in a dose dependent manner. Tissue damage was associated with the accumulation of functional polymorphonuclear cells, which was reduced following C1 Inh treatment. Constitutive nitric oxide synthase activity correlated with the development of injury in the C57BL/6 but not in the BALB/c mouse. CONCLUSIONS: These findings emphasize the importance of complement activation in ischemia/reperfusion and highlight the potential therapeutic use of C1 Inh in limiting or preventing damage caused by IR.     

Enteric bacteria and their antigens may stimulate postoperative peritoneal adhesion formation

BACKGROUND: Intraabdominal sepsis causes exuberant inflammation, which results in dense adhesions. Translocation of enteric bacteria and/or their antigens after laparotomy may therefore also affect peritoneal healing by promoting local release of proinflammatory cytokines. Our hypothesis was that targeted counter therapy could be beneficial if such contamination was to augment postoperative adhesion formation. METHODS: Two endotoxin-hyposensitive mouse strains (C3H/HeJ and C57BL/10ScCr) and their syngeneic counterparts (C3H/HeN and C57BL10/ScSn, respectively) underwent reproducible adhesion-inducing operation (AIO) (n=10/group) with sacrifice and blinded adhesion grading 14 days later. In addition, CD-1 mice were gavaged with fluorescein isothiocyanate labeled-lipopolysaccharide (FITC-LPS) prior to either AIO or sham laparotomy and had both peritoneal macrophages and circulating monocytes assessed by flow cytometry afterward. The cytokine-release response of resident peritoneal cells to LPS stimulation was assessed in vitro (murine peritoneal mast cell cultures) and in vivo (unoperated CD-1 mice administered LPS intraperitoneally [10 & 50 microg/mouse]). Finally, CD-1 mice (n=10/group) had AIO and received either bactericidal/permeability increasing protein (rBPI, 2 mg/mouse) or vehicle solution in the early postoperative period with assessment of adhesion formation 2 weeks later. RESULTS: Both HeJ and ScCr mice had less adhesions than their controls (P=.0015 and .0001, respectively, Mann Whitney U test). FITC-LPS uptake by peritoneal macrophages was striking after AIO. Intraperitoneal LPS provoked significant local vascular endothelial growth factor (VEGF) release as did the process of AIO. In vitro, LPS induced significant interleukin-(IL)-6 release from isolated mast cells. Intraperitoneal administration of rBPI to CD-1 mice early after AIO markedly attenuated subsequent adhesion formation (P=.0003). CONCLUSIONS: Peritoneal adhesion formation is exacerbated by peritoneal contamination due to translocation after laparotomy and may be attenuated by therapeutic antagonism.     

Effect of blood transfusions from different H-2 donors on immune responses in mice

We studied the effect of blood transfusions (BT) from different H-2 donors on the induction of suppressor cells (SC) and of MLC inhibitory activity in serum in a drug-unmodified mouse model. Balb/c (H-2d) mice were transfused at weekly intervals with whole blood from donors of three strains using two transfusion protocols. In protocol I, blood was transfused first from C3H/HeJ (C3H) (H-2k), then C57Bl (H-2b), and then SJL (H-2s) strain mice, and in protocol II the order of blood donors was reversed. Spleen cells and serum samples were obtained from the transfused mice one and two weeks after the last BT. In both transfusion protocols, the kinetics of responses of cells from recipient transfused mice to cells from the blood donors in MLC were similar to those of cells from nontransfused mice. The peak responses of cells from transfused mice were consistently lower than those of cells from nontransfused mice. In cell-mixing experiments, radiosensitive SC capable of inhibiting responses of Balb/c mice to cells from all three blood donors in MLC could be demonstrated one week after the last transfusion in both protocols. Two weeks after the last BT, SC were demonstrable only against the first (C3H) blood donor in protocol I, and against all three blood donors in protocol II. Serum obtained one week after transfusion in protocol I inhibited responses of Balb/c mice to stimulator lymphocytes from all three blood donors in MLC. Serum obtained two weeks after BT, however, inhibited responses of recipient mice only to the first blood donor. In contrast, in protocol II, serum obtained both one and two weeks after BT did not cause inhibition of responses of cells from Balb/c mice to blood donor cells in MLC. Similar results were obtained when Balb/c mice were transfused at weekly intervals with whole blood from either C3H or from SJL mice. The data suggest that the induction of SC and/or MLC-inhibitory activity in the serum after BT is dependent on the H-2 type of the first blood donor.     

Protein malnutrition predisposes to inflammatory-induced gut-origin septic states.

The development of an uncontrolled inflammatory response has been implicated in the pathogenesis of adult respiratory distress syndrome and multiple-organ failure. Because zymosan activates complement and induces a systemic inflammatory response, the effect of zymosan on intestinal structure and barrier function was measured in normally nourished (NN) and protein malnourished (PM) mice. Normally nourished and protein malnourished (up to 21 days) mice challenged intraperitoneally with zymosan (0.1 mg/g body weight) were killed 24 hours after zymosan challenge and their organs cultured for translocating bacteria. Zymosan-induced bacterial translocation was limited to the mesenteric lymph nodes of the NN mice, whereas translocating bacteria spread from the gut to the liver, spleen, and blood stream (p less than 0.05) in the PM mice. Zymosan-induced bacterial translocation appeared to be related primarily to the combination of mucosal injury and a disruption of the gut flora ecology in the PM mice and to mucosal injury in the NN mice. The extent of mucosal injury was greater the longer the mice were protein malnourished before zymosan challenge. The effect of zymosan on survival was measured in separate groups of mice. At a dose of 0.1 mg/g body weight, no deaths occurred in NN mice or in 7-day PM mice. However 20% of the 14-day PM mice and 80% of the 21-day PM mice receiving zymosan died. Thus PM predisposes to mucosal damage and the development of potentially lethal gut origin septic state during periods of systemic inflammation.     

Endotoxin promotes the translocation of bacteria from the gut

Experiments were performed in mice to determine whether endotoxin could cause bacteria normally colonizing the gut to spread systemically, a process termed bacterial translocation. Endotoxin given intraperitoneally promoted bacterial translocation in a dose-dependent fashion from the gut to the mesenteric lymph node (MLN). The incidence of bacterial translocation to the MLN was similar whether the endotoxin was administered intramuscularly or intraperitoneally, although the number of bacteria colonizing the MLN was greater with intraperitoneal endotoxin. The incidence and magnitude of endotoxin-induced bacterial translocation were similar between CD-1 and C3H/HeJ (endotoxin-resistant) mice, indicating that bacterial translocation is not prevented by genetic resistance to endotoxin. Thus, it appears that the gut may serve as a reservoir for bacteria causing systemic infections during endotoxemia.     

The diabetogenic effects of streptozotocin in mice are prolonged and inversely related to age

Single "subdiabetogenic" doses of streptozotocin (SZ), when given to young male CD-1 mice, produced a delayed onset of hyperglycemia dependent on the dose of SZ and on the age of the mice. The effect was markedly reduced or absent in older mice given the same dose of SZ per kg of body weight. Histologic examination of the pancreas of these animals revealed that SZ induced greater damage to the islets of the young mice compared with older mice. In addition to the characteristic findings of a decrease in insulin-containing cells and an increase in glucagon- and pancreatic polypeptide-containing cells there was evidence of new islet formation. Delayed-onset hyperglycemia was also induced in young inbred DBA/2J, C57BL/KsJ, and SWR/J mice with single SZ doses as well as with alloxan in young CD-1 mice, indicating that the effect was not specific for CD-1 mice not for SZ as the agent inducing beta-cell injury. The induction of beta-cell autoimmunity did not appear to be important in the delayed diabetogenic effect of SZ, since insulitis was rare and followed the onset of hyperglycemia when seen, and islet cell autoantibodies were not found. Rather, SZ induced more beta-cell destruction in young animals than in older mice, and the continued somatic growth of the former suggests that the delayed hyperglycemia was due to an out-growing of a reduced insulin supply. That mild to severe diabetes could be induced by the same dose of SZ/kg, depending only on the age of the mice when SZ was given, may have implications for understanding the apparent heterogeneity of human diabetes mellitus.