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 but not malnutrition promotes bacterial translocation of the gut flora in burned mice

Previously we have shown that under certain conditions, bacteria can pass through the intact epithelial mucosa to the mesenteric lymph nodes (MLN), liver, spleen, and bloodstream to cause infection, a process termed bacterial translocation. To extend these studies, we determined the influence of protein malnutrition and endotoxemia on bacterial translocation in burned (25% TBSA) and unburned mice. The results of these experiments documented that protein malnutrition did not promote bacterial translocation from the gut in either burned or unburned animals, although it did disrupt the normal indigenous gut flora. In contrast, a nonlethal dose of endotoxin (IP) promoted bacterial translocation to the mesenteric lymph nodes in burned and unburned mice, but only in burned mice did the bacteria translocate from the gut to other systemic organs (p less than 0.01). Furthermore, the mortality rate of mice receiving only endotoxin or burn was less than 10%, while the combination of endotoxin plus a thermal injury increased the mortality rate to 100% (p less than 0.01). These studies support the concept that bacteria may translocate from the gut to other organs and be a potential source of lethal infections after thermal injury.     

Role of bacterial adherence and the mucus barrier on bacterial translocation: effects of protein malnutrition and endotoxin in rats.

OBJECTIVE: The purpose of the study was to investigate the potential relations between mucosal bacterial adherence, intestinal mucus and mucin content, and bacterial translocation. SUMMARY BACKGROUND DATA: The attachment of bacteria to mucosal surfaces is the initial event in the pathogenesis of most bacterial infections that originate at mucosal surfaces, such as the gut. The intestinal mucus layer appears to function as a defensive barrier limiting micro-organisms present in the intestinal lumen from colonizing enterocytes. Consequently, studies focusing on the biology of bacterial adherence to the intestinal mucosa likely are to be important in clarifying the pathogenesis of gut origin sepsis. METHODS: To explore the relations between intestinal bacterial adherence, mucus bacterial binding, and bacterial translocation, two models were used. One (protein malnutrition) in which profound alterations in intestinal morphology occurs in the absence of significant translocation and one (endotoxin challenge) in which bacterial translocation occurs and intestinal morphology is relatively normal. RESULTS: Protein malnutrition was not associated with bacterial translocation and measurement of enteroadherent, mucosally associated bacterial population levels documented that the total number of gram-negative enteric bacilli adherent to the ileum and cecum was less in the protein-malnourished rats than in the normally nourished animals (p < 0.01). Furthermore, there was an inverse relation between the duration of protein malnutrition and bacterial adherence to the intestinal mucosa (r = 0.62, p < 0.002). In contrast, after endotoxin challenge, the level of enteroadherent bacteria was increased and bacterial translocation was observed. The binding of Escherichia coli to immobilized ileal mucus in vitro was decreased significantly in protein-malnourished rats, whereas E. coli binding to insoluble ileal mucus was increased in the rats receiving endotoxin. CONCLUSIONS: This study indicates that the adherence of bacteria to the intestinal mucosal surface is an important factor in bacterial translocation, that intestinal mucus modulates bacterial adherence, and that increased levels of mucosally associated bacteria are associated with a loss intestinal barrier function to bacteria.     

Effect of starvation, malnutrition, and trauma on the gastrointestinal tract flora and bacterial translocation

We have previously shown, in an animal model, that viable indigenous bacteria will cross the intact gastrointestinal (GI) mucosa and spread systemically, a process termed bacterial translocation, if the normal bacterial ecology of the gut was sufficiently disrupted to allow bacterial overgrowth or if the animals were severely immunosuppressed. Starvation or protein malnutrition disrupts the normal indigenous GI tract microflora and impairs host antibacterial defenses. Consequently, we tested the effect of the combination of starvation or protein malnutrition plus burn trauma in promoting bacterial translocation from the GI tract. Bacterial translocation was measured by quantitatively culturing the mesenteric lymph nodes, spleens, livers, blood, and peritoneal cavities of normal or burned (30% of total body surface area) CD1 mice deprived of food for three days or fed a low-protein (0.03%) diet. The effect of starvation or protein malnutrition on the gut microflora was determined by quantitatively measuring the levels of bacteria present in the ceca. Both starvation and protein malnutrition increased the cecal levels of gram-negative enteric bacilli and decreased the levels of lactobacilli and strict anaerobes. Surprisingly, neither starvation nor protein malnutrition promoted bacterial translocation, even though these animals lost over 20% of their body weight and the ecology of the gut microflora was disrupted. In fact, the protein-malnourished animals exhibited lower incidences of bacterial translocation than normally nourished animals when both groups were monoassociated with Escherichia coli C-25 or monoassociated and burned. Thus, it appears that protein malnutrition does not promote bacterial translocation, even when combined with burn trauma.     

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.     

Hemorrhagic shock induces bacterial translocation from the gut

Sepsis and multiple organ failure are common after hemorrhagic shock. The goal of the current experiments was to determine whether hemorrhagic shock would promote the translocation of bacteria from the gut to visceral organs. Twenty-four hours after being subjected to sham shock, or 30, 60, or 90 minutes of shock (30 mm Hg), rats were sacrificed and their organs quantitatively cultured for translocating bacteria. There was a direct relationship between the duration of hemorrhagic shock and the 24-hour mortality rate (p = 0.02). Bacteria did not translocate from the gut in the sham-shock rats, but did translocate to the mesenteric lymph nodes, livers, and spleens of the rats subjected to hemorrhagic shock (p less than 0.01). Rats subjected to 90 minutes of shock shock exhibited a greater degree of bacterial translocation than rats receiving 30 or 60 minutes of shock (p less than 0.05). The most common translocating bacteria were Escherichia coli and Enterococcus. Hemorrhagic shock injured the gut mucosa and caused subepithelial edema and focal areas of necrosis. Thus hemorrhagic shock followed by reinfusion of shed blood disrupts the gut barrier and allows indigenous bacteria normally contained within the gut to cause systemic infections.     

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.     

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.     

Effect of polymyxin B on intestinal bacterial translocation in Pseudomonas aeruginosa wound-colonized burned mice.

Bacterial translocation (BT) from the gastrointestinal tract has been proposed to play a role in the pathogenesis of septic complications in severely burned patients. In a burn model the effect of a subtherapeutic dose of polymyxin B-sulfate (PB) at BT was examined in Escherichia coli-monoassociated mice with Pseudomonas aeruginosa-inoculated burn wounds. The BT incidence and number of translocating microorganisms to the spleen (p less than 0.01), liver (p less than 0.01), lung (p less than 0.05) and heart (p less than 0.05) were diminished significantly in the PB-treated versus the untreated group. Endotoxin in plasma was detectable in one of the 16 PB-treated versus 6 of the 17 control mice (p less than 0.05). The relation of Pseudomonas burn wound inoculation, BT, endotoxin and the endotoxin-neutralizing properties of PB will be discussed.     

The effect of perioperative exogenous growth hormone on wound bursting strength in normal and malnourished rats

Patients with significant malnutrition secondary to underlying disease may require major surgical intervention on an urgent basis. Nutritional restoration using enteral or intravenous alimentation requires a delay of 10 to 14 days and is frequently not practical. With the availability of human growth hormone (GH) produced by recombinant DNA technology, this study was undertaken to evaluate the effect of exogenous GH on wound tensile strength in a rat model. Fifty-four animals were divided into three groups: group I, normal nourished control; group II, malnourished; group III, malnourished, rat GH treated (1 mg GH administered 3 days preoperative and 5 days postoperative celiotomy). Wound tensile strength was measured at 6 days postoperatively. Wound strengths in malnourished rats were significantly less than in normal controls (P less than .001). With the administration of growth hormone in group III, wound strength was significantly improved when slightly improved over normally nourished controls (P less than .05). A dose response curve demonstrated progressive improvement in wound tensile strength from 0.01 mg/d to 1.0 mg/d. Thus growth hormone administration to malnourished animals significantly enhances wound strength. With the availability of recombinant produced human GH these observations may be clinically applicable.     

The effects of sepsis and endotoxemia on gut glutamine metabolism.

The effects of sepsis on gut glutamine (GLN) metabolism were studied to gain further insight into the regulation of the altered glutamine metabolism that characterizes critical illnesses. Studies were done in laboratory rats and in hospitalized patients. The human studies were done in seven healthy surgical patients (controls) and six septic patients who underwent laparotomy. Radial artery and portal vein samples were obtained during operation and were analyzed for GLN and oxygen content. Despite no reduction in arterial glutamine concentration in the septic patients, gut glutamine extraction was diminished by 75% (12.0% +/- 1.6% in controls vs. 2.8% +/- 0.8% in septic patients, p less than 0.01). Similarly gut oxygen extraction was diminished by nearly 50% in the septic patients (p less than 0.05). To further investigate these abnormalities, endotoxin (10 mg/kg intraperitoneally) or saline (controls) was administered to adult rats 12 hours before cannulation of the carotid artery and portal vein. The arterial GLN concentration was increased by 13% in the endotoxin-treated animals (p less than 0.05) but gut glutamine uptake was diminished by 46% (526 +/- 82 nmol/100 g BW/minute in controls vs. 282 +/- 45 in endotoxin, p less than 0.01). Simultaneously gut glutaminase activity was diminished by 30% (p less than 0.01) and intestinal glutamate release fell by two thirds. Blood cultures were negative in control animals (0 of 20), but were positive in 25% of endotoxemic animals (6 of 24) for gram-negative rods (p = 0.019). Sepsis and endotoxemia impair gut glutamine metabolism. This impairment may be etiologic in the breakdown of the gut mucosal barrier and in the development of bacterial translocation.     

Splenectomy influences endotoxin-induced bacterial translocation

To determine whether splenectomy affects the antibacterial defenses of the gut, experiments were performed using bacterial translocation (BT) as a marker of intestinal barrier failure. The incidence of BT was measured 8 days after splenectomy or sham-splenectomy in mice receiving or not receiving endotoxin (0.1 mg IP). Splenectomy does not appear to promote BT from the gut, since the incidence of bacterial translocation after splenectomy or sham-splenectomy (5%) were not different. A second experiment was performed to determine whether the resistance to endotoxin-induced BT was modified after splenectomy. The incidence of endotoxin-induced BT was 73% in the unoperated control group, 59% in the sham-splenectomy group, but 23% in the splenectomy group (p less than 0.002). Thus, splenectomy but not sham-splenectomy increased the resistance of otherwise healthy mice to endotoxin-induced BT.     

Bacteriuria and urinary tract infections in malnourished children

We prospectively examined the incidence of bacteriuria in malnourished patients between 6 months and 5 years of age. For each patient, a normally nourished control matched for age, sex, and presence of fever and diarrhea was included. Of 112 patients (65 boys), 55 had moderate and 57 had severe malnutrition; 43 had diarrhea and 35 had fever. Clean-catch and suprapubic urine specimens were examined microscopically and cultured. Significant bacteriuria was found in 17 (15.2%) malnourished and 2 (1.8%) control subjects ( P<0.01). The incidence of bacteriuria in malnourished and normally nourished subjects with fever was 28.6% and 5.7%, respectively ( P<0.05). The risk of bacteriuria increased significantly with the severity of malnutrition and in patients with diarrhea. Bacteriuria was associated with symptoms (70.6%) and elevated levels of acute-phase reactants (88.2%), indicating the presence of urinary tract infections (UTI) rather than asymptomatic colonization. Our observations show that malnourished children, particularly those with fever, are at risk for UTI. Urinalysis is useful for screening for UTI in these subjects. Urine culture should be performed in patients showing an abnormal urinalysis, and if the likelihood of detecting bacteriuria is high (as in patients with fever or diarrhea). Significant bacteriuria in malnourished subjects should be treated with appropriate antimicrobials.     

喹吖因对肠道缺血再灌注损伤后肠道细菌/内毒素移位的影响

目的 探讨磷脂酶A2（PLA2）抑制剂喹吖因对大鼠肠道缺血再灌注（gut ischemia reperfusion,GIR)损伤后肠源性细菌／内毒素移位的影响。方法 42只wistar大鼠随机分为正常组（6只）和GIR损伤组（36只）。GIR损伤组又分为GIR损伤对照组、再灌注后3h喹吖用药组和12h喹吖用药组,每组12只。取正常对照组、GIR损伤对照组及用药组48、72h门、腔静脉血测定内毒素含量、腔静脉血浆TNFα含量和肠系膜淋巴结、肝、肺、肾等肠道外器官组织进行细菌培养。结果 早期应用喹吖因,无论是GIR损伤后3h用药组还是12h用药组,均可明显降低GIR损伤后血浆内毒素和TNFα水平（P＜0．01）;显降低GIR损伤后肠系膜淋巴结和肺、肝、肾组织器官中的细菌移位发生率（P＜0．05－0．01）。结论 GIR损伤后早期应用喹吖因可显地降低肠源性细菌／内毒素移位,减轻促炎性介质和细菌因子的释放,减轻肠道外脏器损伤。     

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.     

Bacterial translocation to the thoracic duct in a setting of ischemia, partial resection and reperfusion of the porcine liver.

BACKGROUND/AIMS: Bacterial translocation is postulated as a risk factor in the development of a systemic inflammatory response syndrome (SIRS). Research on this topic has focused on the detection of bacteria and endotoxin in blood or mesenteric lymph nodes (MLNs). We investigated whether bacterial translocation occurs beyond the MLNs into the thoracic duct in a setting of ischemia, partial resection and reperfusion of the porcine liver. METHODS: A porcine model of severe, extra-intestinal tissue injury, consisting of prolonged hepatic ischemia and reperfusion, in combination with hemihepatectomy, was used (experimental group, n = 5 pigs). To prevent venous congestion of the gut during ischemia, a temporary portal-caval shunt was created. In 5 animals (sham group) a sham portal-caval shunt was constructed while liver ischemia, partial resection and reperfusion were not induced. Thoracic duct lymph, portal blood and systemic blood were collected, and analyzed for the presence of bacteria and endotoxin. RESULTS: In the experimental group, the incidence of bacterial translocation to the thoracic duct was significantly higher during early reperfusion compared to the sham group (5/5 animals versus 1/5 animals, p < 0.05). CONCLUSION: This study demonstrates bacterial translocation into the thoracic duct. Translocation at this level leads to direct discharge of bacteria and endotoxin into the systemic circulation and therefore, may potentially enhance the development of SIRS.     

Effect of total parenteral nutrition plus morphine on bacterial translocation in rats.

OBJECTIVE: This study tested the hypothesis that gut stasis induced by parenteral morphine sulfate (MS) leads to enhanced bacterial translocation in rats on total parenteral nutrition (TPN). SUMMARY BACKGROUND DATA: TPN and MS are common adjuncts in the care of critically ill patients. TPN is known to provoke a variable degree of translocation. MS induces gut stasis with an accompanying bacterial overgrowth. The effect of these two treatments in combination on translocation is not known. METHODS: Rats were provided with central and subcutaneous lines for the continuous infusion of nutrients and drugs, respectively. Intestinal transit was assessed by the caudal movement of a fluorescent marker intubated into the proximal duodenum. Quantitative bacteriology was carried out from various segments of the gut and from ileocecal mesenteric lymph nodes (MLN), spleen, liver, and systemic blood obtained by cardia puncture on sacrifice at 96 hours. RESULTS: Transit was unchanged by TPN alone but prolonged when given in combination with MS. Bacterial overgrowth was also enhanced by MS and increased the bacterial translocation to MLN from 50% of animals with TPN, to 100% in those receiving both TPN and MS; the colony-forming units per MLN increased from 33 +/- 14 with TPN alone to 2079 +/- 811 (STD) with TPN plus MS. Furthermore, no bacteria were found at systemic sites with TPN alone, but in 93.3% of animals receiving TPN and MS. In a subgroup of rates provided with glutamine in TPN, the TPN plus MS effects on translocation were not reversed. CONCLUSIONS: These observations demonstrate the important role that morphine plays in promoting translocation, presumably by disrupting fasting motility and enhancing bacterial overgrowth.     

Effect of malnutrition on serum creatinine and cystatin C levels

The concentration of cystatin C has been shown to be independent of age, gender and height, but the effect of malnutrition has not been studied. Levels of serum creatinine and cystatin C were estimated in 77 malnourished and 77 normally nourished boys between 2 years and 6 years of age without evidence of renal disease. The mean (95% confidence interval) serum creatinine level in the malnourished boys was significantly lower than that in the normally nourished boys [0.42 (0.38–0.45) mg/dl and 0.51 (0.48–0.55)] mg/dl, respectively, (P < 0.01)]. The mean level of serum cystatin C was 1.05 (0.94–1.17) mg/l and 1.12 (1.01–1.24) mg/l, respectively, in normally nourished and malnourished boys (P = 0.35). Mean glomerular filtration rate (GFR) estimated by the Schwartz equation in the malnourished boys was significantly higher than that in normally nourished children [141.8 (123.3–160.2) ml/min per 1.73 m² body surface area and 119.4 (109.3–129.5) ml/min per 1.73 m² body surface area], respectively (P = 0.04). However, the mean cystatin C-derived GFR was similar in the malnourished and normally nourished boys [99.70 (85.8–113.5) ml/min per 1.73 m² and 109.2 (94.4–124.0) ml/min per 1.73 m²], respectively (P = 0.35). The mean bias between GFR estimates using Bland and Altman analysis was greater in the malnourished children than in the normally nourished children (32.3% and 17.6%, respectively) (P = 0.15). Serum creatinine levels are lower in malnourished children and lead to overestimation of GFR, while cystatin C levels are unaffected.     

Distribution and survival of Escherichia coli translocating from the intestine after thermal injury.

The present investigation was performed to study the kinetics of tissue distribution and deposition of Escherichia coli and endotoxin translocating from the intestine after thermal injury. Escherichia coli was grown in the presence of 14C glucose and both labeled bacteria and endotoxin prepared from the labeled bacteria were used as translocation probes. Escherichia coli (10(8) to 10(10) bacteria) and E. coli endotoxin (100 micrograms per animal) were gavaged into the stomach immediately before a 30% burn injury was inflicted in mice. Animals were killed 1, 4 and 24 hours after burn injury. Translocation occurred extensively within 1 hour after burn injury. Expressed as amount of radioactivity per gram of tissue, translocation was greatest in the mesenteric lymph node (MLN) followed by spleen, lung, and liver. Translocation of endotoxin was similar to translocation of intact bacteria, with the exception that less radioactivity could be found in the peritoneal cavity and more in the liver. Both intact E. coli and endotoxin translocated directly through the intact bowel wall. Killing of bacteria was greatest in the MLN and spleen, approximating 95% to more than 99% of translocating bacteria. Killing efficiency was lowest in the lungs. It is concluded that estimation of translocation by viable bacterial counts in tissues grossly underestimates the extent of translocation of bacteria and ignores the extent of translocation of endotoxin. Translocation of endotoxin may have biologic significance that is independent of and in addition to translocation of intact bacteria.     

Impaired macrophage function in severe protein-energy malnutrition.

Protein-energy malnutrition induces immunosuppression that predisposes to sepsis, but the mechanisms are unclear. This study examines the role of the macrophage in host defense in the malnourished state. Swiss-Webster mice (N = 300) were randomly allocated to control (24% casein) or low-protein (2.5% casein) diets for 8 weeks. We studied the ability of two populations of macrophages, peritoneal macrophages, and Kupffer cells to produce superoxide anion after in vivo administration of endotoxin or mycobacterium (bacille Calmette-Guérin). Phorbol diester and Candida albicans were used as stimuli. In another group of mice, we evaluated the ability of interferon gamma to up-regulate superoxide anion release and Candida phagocytosis and killing. Mice under protein-energy malnutrition demonstrated decreased mean body weights, serum protein levels, and cell yields. Superoxide anion production in resident and activated (lipopolysaccharide, interferon gamma, bacille Calmette-Guérin infection) peritoneal macrophages was significantly reduced in the malnourished group. Candida phagocytosis and killing were also both depressed in malnourished mice. Kupffer cells failed to generate superoxide anion in all groups. We conclude that severe protein-energy malnutrition significantly impairs macrophage function, which could diminish response to acute and chronic septic challenges. Interferon gamma up regulated peritoneal macrophage and Kupffer cell microbicidal function, which suggests a therapeutic role for this lymphokine in the malnourished septic host.