Malnourished Host Research Articles

Innate lung defenses and compromised Pseudomonas aeruginosa clearance in the malnourished mouse model of respiratory infections in cystic fibrosis.

Cystic fibrosis (CF) is characterized by dysfunction of the digestive and respiratory tracts resulting in generalized malnutrition and chronic respiratory infections. Chronic lung infections with Pseudomonas aeruginosa, intense neutrophil-dominated airway inflammation, and progressive lung disease are the major cause of high morbidity and mortality in CF. Here we investigated the effects of malnutrition in CF on innate lung defenses, susceptibility to P. aeruginosa colonization, and associated inflammation, using aerosol models of acute and chronic infections in normal, malnourished, and transgenic mice. CFTR(m1Unc-/-) knockout mice displayed body weight variations and showed variable pulmonary clearance of P. aeruginosa. This variability was not detected in bitransgenic CFTR(m1Unc-/-)(FABP-hCFTR) mice in which the intestinal defect had been corrected. Diet-induced protein calorie malnutrition in C57BL/6J mice resulted in impaired pulmonary clearance of P. aeruginosa. Tumor necrosis factor alpha (TNF-alpha) and nitrite levels detected upon exposure to P. aeruginosa aerosols were lower in the lungs of the malnourished C57BL/6J mice relative than in lungs of mice fed a normal diet. The role of TNF-alpha and reactive nitrogen intermediates in P. aeruginosa clearance was tested in TNF-alpha and inducible nitric oxide synthase (iNOS) knockout mice. P. aeruginosa clearance was diminished in transgenic TNF-alpha- and iNOS-deficient mice. In contrast to the effects of TNF-alpha and iNOS, gamma interferon knockout mice retained a full capacity to eliminate P. aeruginosa from the lung. Malnutrition also contributed to excessive inflammation in C57BL/6J mice upon chronic challenge with P. aeruginosa. The repeatedly infected malnourished host did not produce interleukin-10, a major anti-inflammatory cytokine absent or diminished in the bronchoalveolar fluids of CF patients. These results are consistent with a model in which defective CFTR in the intestinal tract leads to nutritional deficiency which in turn contributes to compromised innate lung defenses, bacterial colonization, and excessive inflammation in the CF respiratory tract.

The role of zinc and vitamin A in persistent diarrhea among infants and young children.

The role of zinc and vitamin A in persistent diarrhea among infants and young children.

Effects of protein calorie malnutrition on tuberculosis in mice.

Infectious diseases and malnutrition represent major burdens afflicting millions of people in developing countries. Both conditions affect individuals in industrialized nations, particularly the aged, the HIV-infected, and people with chronic diseases. While malnutrition is known to induce a state of immunodeficiency, the mechanisms responsible for compromised antimicrobial resistance in malnourished hosts remain obscure. In the present study, mice fed a 2% protein diet and developing protein calorie malnutrition, in contrast to well-nourished controls receiving a 20% protein diet, rapidly succumbed to infection with Mycobacterium tuberculosis. Malnourished mice exhibited a tissue-specific diminution in the expression of interferon gamma, tumor necrosis factor alpha, and the inducible form of nitric oxide synthase in the lungs, but not the liver. The expression of these molecules critical to the production of mycobactericidal nitrogen oxides was depressed in malnourished animals in the lungs specifically at early times (< 14 days) after infection. At later times, levels of expression became comparable to those in well-nourished controls, although the bacillary burden in the malnourished animals continued to rise. Nevertheless, urinary and serum nitrate contents, an index of total nitric oxide (NO) production in vivo, were not detectably diminished in malnourished, mycobacteria-infected mice. In contrast to the selective and early reduction of lymphokines and the inducible form of nitric oxide synthase in the lung, a marked diminution of the granulomatous reaction was observed in malnourished mice throughout the entire course of infection in all tissues examined (lungs, liver, and spleen). Remarkably, the progressively fatal course of tuberculosis observed in the malnourished mice could be reversed by restoring a full protein (20%) diet. The results indicate that protein calorie malnutrition selectively compromises several components of the cellular immune response that are important for containing and restricting tuberculous infection, and suggest that malnutrition-induced susceptibility to some infectious diseases can be reversed or ameliorated by nutritional intervention.

Antimicrobial effects of granulocyte-macrophage colony-stimulating factor in protein-energy malnutrition.

To evaluate, in a murine model of protein-energy malnutrition, whether granulocyte-macrophage colony-stimulating factor (GM-CSF) improves the host response to a septic challenge and to determine the potential mechanisms involved. Nonblinded study of GM-CSF in mice with protein-energy malnutrition. A university-based surgical laboratory and animal facility. In study 1, malnourished mice were randomized to receive either GM-CSF (120 micrograms/kg subcutaneously to receive either GM-CSF (120 micrograms/kg subcutaneously from day 4 to 7 of the protein-free diet) or saline vehicle as a control. On day 7, all mice were given Candida albicans (5 x 10(5) organisms intravenously). In study 2, malnourished mice received the same dose of GM-CSF or saline vehicle for 7 days of the protein-free diet. In study 1 mice were followed up for survival. In study 2, after 7 days of diets, splenic macrophages were harvested and were assayed for interleukin-6, superoxide anion, and nitric oxide production. Splenocytes were stimulated with concanavalin A (5 micrograms/mL) for interleukin-4, interleukin-10, and interferon-gamma production. Treatment with GM-CSF significantly enhanced survival in malnourished mice infected with C albicans. Treatment with GM-CSF was associated with increased production from splenic macrophages of interleukin-6, superoxide anion, and nitric oxide as well as decreased interleukin-4 production from splenocytes. This study suggests a beneficial role for GM-CSF in the malnourished host predisposed to infection. The antimicrobial properties of GM-CSF may function through enhanced production of nitric oxide and superoxide anion.

NUTRITION, INFECTION, AND IMMUNOCOMPETENCE

The nutritional status of an individual has a profound effect on both host susceptibility to specific infectious diseases and on their outcome. Available data suggest that specific and aggregate nutritional deficiencies can alter a host's immune response and increase susceptibility to infection. From a nutritional point of view, the process of nutrient loss and redistribution has the potential for being exploited to the benefit of the infected malnourished host. The proposal to use nutritional support to bolster the host response to infection in severely ill malnourished patients gains support from the fact that this reiterative cycle of malnutrition and infection is the main cause of morbidity and mortality in children in underdeveloped countries.

The role of nematode parasites in Soay sheep (Ovis aries L.) mortality during a population crash.

In early 1989, two-thirds of the Soay sheep population on St Kilda died over 12 weeks. Post-mortem examinations revealed emaciated carcasses and considerable nematode burdens, with protein-energy malnutrition as the probable cause of death. Haematological and blood biochemical changes in the sheep, as well as fecundity of gastrointestinal nematodes, suggested the hosts were immunosuppressed. In parallel, laboratory experiments in which Soay sheep on a high plane of nutrition were artificially infected with Ostertagia circumcincta, showed no clinical signs or mortality when supporting worm burdens similar to those recorded in dead sheep on St Kilda. Anthelmintic treatment of a group of animals increased daily survival rates in ewes and male lambs, although treated animals became re-infected as the 'crash' progressed. It is suggested that parasites contribute to mortality in malnourished hosts, exacerbating the effects of food shortage.

Postoperative Infections in Spinal Implants Classification and Analysis—A Multicenter Study

A multicenter study was undertaken to analyze postoperative wound infections after posterior spinal instrumentation and fusion. The infection rate of these procedures has been documented in multiple reports. From these results, a classification scheme was developed that can guide therapy and determine the populations at risk. The patients were categorized according to two parameters, the first being the severity or type of infection, and the second being the host response or physiologic classification of the patient. This classification scheme is based on the clinical staging system for adult osteomyelitis developed by Cierny. The severity of infection is divided into three groups. Group 1 is a single-organism infection, either superficial or deep. Group 2 is a multiple-organism, deep infection. Group 3 is multiple organisms with myonecrosis. The host response, likewise, is divided into three classes. Class A is a host with normal systemic defenses, metabolic capabilities, and vascularity. Class B patients demonstrate local or multiple systemic diseases, including cigarette smoking. Class C requires an immunocompromised or severely malnourished host. Our data have demonstrated that single organisms, Group 1, generally can be dealt with by single irrigation and debridement, and closure over suction drainage tubes without the use of an inflow-irrigation system. The Group 2 patients, with multiple organisms and deep infection, required an average of three irrigation debridements. They have a higher percentage of successful closures with closed inflow-outflow suction irrigation systems when compared to simple suction drainage systems without constant inflow irrigation. Multiple-organism infections with myonecrosis, Group 3, are exceedingly difficult to manage, and portend a poor outcome. Patients without normal host defenses, Classes B and C, are at high risk for developing postoperative wound infection. Specifically, this study demonstrated that cigarette smoking may be a significant risk factor.

Protein-calorie malnutrition impairs host defense against Candida albicans

Protein-calorie malnutrition (PCM) impairs immune responsiveness predisposing to Candida albicans sepsis, but mechanisms are unclear. This study examined the effect of PCM on enteric-derived C. albicans intestinal translocation and the ability of in vivo interferon-γ (IFN-γ) to upregulate macrophage (MØ) candidacidal mechanisms in PCM mice. Control (24% casein) and low protein (2.5%) diets were given for 4 weeks. Mice ( n = 160) were fed C. albicans in their drinking water for 3 days and C. albicans translocation (mean colony-forming units (CFU)/g tissue ± SEM) to the GI tract, liver, spleen, and kidney was assessed at 1 and 5 days following endotoxin challenge of 1, 5, and 10 mg/kg body wt. In a separate study ( n = 100 mice), IFN-γ (1000–10,000 U/day ip) vs saline was given for 3 days prior to harvesting peritoneal macrophages for assay of superoxide anion (O 2 −, percentage macrophage phagocytosis of C. albicans, and percentage killing of C. albicans. On Day 1, fungal translocation to the intestinal wall and systemic organs in the PCM group was significantly higher. On Day 5, mean CFU were significantly higher in the PCM group, indicating impaired organ clearance. Mean O 2, phagocytosis, and killing were significantly impaired in the PCM group ( P < 0.05), but IFN-γ improved all functions. PCM significantly depressed host responses to C. albicans. IFN-γ treatment enhanced candidacidal mechanisms, suggesting a therapeutic role in the malnourished host predisposed to C. albicans sepsis.

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.

A Study on the B Cell Activity in Protein Deficient Rats Exposed to Methyl Isocyanate Vapour

The effect of MIC on the humoral immunity of the malnourished (protein deficient) subjects has been investigated. A single exposure of MIC (1.60 mg/l) on protein deficient rats showed no significant change in the body weight and mortality rate compared with the normal but the serum protein levels were found significantly low (P less than 0.01) in the protein deficient diet fed control (PDC) ones. Both PDC and protein deficient MIC exposed (PDMIC) rat showed diminished B-cell proliferation with the optimal dose of LPS, compared to the NDC and normal diet fed MIC exposed (NDMIC) group. Furthermore significant suppression (P less than 0.01) in the B-cell activation by LPS was observed in the PDMIC compared to PDC. The total IgM level in PDMIC was 43% less while 26% higher in NDMIC compared to NDC. The total IgG level in PDMIC and NDMIC was higher (20%) compared to NDC, while 25% less in PDC. The antigen specific B-cell immunity was affected in PDMIC, PDC and NDMIC. As the terminal differentiation process of B-cells were found equally affected in both PDC and NDMIC, it appears that MIC has no synergistic effect on the humoral immunity of the protein malnourished host.

Immunity to internal parasites

This review of internal parasitic diseases discusses methods of immune diagnosis, immune mechanisms of the host, and immunoprophylaxis against both protozoan and metazoan parasites of livestock. The limiting factors for immunodiagnosis are specificity and whether the host animals respond sufficiently to produce detectable serological responses. Because the array of antigens is so complex, the method of choice for helminths is to use excretory/secretory products of the parasite as antigens for microplate ELISA. Similarly, for protozoa, immunodiagnosis is facilitated by using a few, selected, immunodominant antigens rather than extracts of whole parasite. However, serodiagnosis does not always identify parasitised animals especially in the young, malnourished or sick host. Similarly, parasites may themselves modulate the response of the host and remain serologically undetectable. The production of recombinant, pure, parasite proteins is already facilitating diagnostic serology for several parasite species and, using recombinant DNA probes, it is now possible to distinguish inter- and intra-species differences. The central role of inflammatory cytokines, the regulatory proteins produced by activated T helper cells, in modulating both protective and potentially damaging inflammatory responses is discussed. Finally, the genetic control of the immune response and its relevance to immunoprophylaxis is considered. Several interesting developments in the production of sub-unit vaccines and the potential methods of delivery are appraised.

Cell-mediated Immune Responses in Malnourished Host

One hundred children in the age group 6 months to 5 years were investigated for cell-mediated immune response in relation to their nutrition. The nutritional status was assessed by the Wellcome classification. The majority (54 per cent) of children had marasmus. Absolute lymphocyte count was found to be significantly low (P less than 0.01) in all malnourished groups except in mild forms of undernutrition. Small lymphocytes were also found to be significantly decreased (P less than 0.001) in malnourished children. A significant depression (P less than 0.001) was observed in the percentage and absolute T cells in all the malnourished children with kwashiorkor who showed the maximum depression of counts. All the control children showed DNCB skin reactions above grade 2+ while only 39 per cent of malnourished children showed reaction of this grade. After 4-6 weeks of dietary therapy, T cell counts were comparable with control values and DNCB skin test returned to normal in more than 75 per cent of cases.

Monokine Secretion in Aging and Protein Malnutrition

Aged and protein-malnourished hosts have diminished febrile responses and increased morbidity and mortality from infection that could be due to deficiencies in the production of certain monokines. In this study, the ability of peritoneal macrophages from aged and protein-malnourished rats to produce IL-1 and TNF was explored. Aged rats fed a standard diet produced less IL-1 and TNF, as measured by the thymocyte proliferation and L929 cytotoxicity assays, than young and middle-aged rats. Monokine production was not diminished by protein malnutrition in any age group. No synergistic decline in IL-1 or TNF production was seen with increasing age in malnourished rats. Diminished IL-1 and TNF production may partially explain the severity of infection seen in the elderly patient, but not the malnourished host. The role of other cytokines such as IL-6 and cytokine inhibitors in aging and malnutrition should be explored.

Polyamine-directed preferential nutritional repletion of normal tissues in tumor-bearing hosts.

Our previous study demonstrated that total parenteral nutrition (TPN) increases erythrocyte (RBC) polyamines selectively in cancer patients but not in non-cancer patients, suggesting that these changes may relate to tumor presence. We therefore studied the possible relationship between RBC polyamine levels and potential tumor growth induced by TPN. In addition, we attempted to control tumor growth during TPN with alpha-difluoromethylornithine (DFMO), a suicide inhibitor of ornithine decarboxylase (ODC), in a fibrosarcoma-bearing rat model. Rats in a control group received chow ad libitum for 3 weeks and their tumors grew exponentially. A restricted intake (RI) tumor-bearing group received 8 g chow per day per rat; this produced malnourished rats in which tumor growth significantly slowed. The third group (RI----TPN) received the RI diet for 2 weeks and TPN for 1 week, which resulted in an increase in tumor growth. The last group (RI----TPN + DFMO) received a 2-week RI regimen and 1-week TPN plus DFMO regimen, which inhibited tumor growth to the level of the RI group due to the addition of DFMO (1 g/kg/day). Although the addition of TPN to the RI regimen markedly increased tumor ODC activity, as well as tumor putrescine and RBC putrescine levels, the addition of DFMO to the RI----TPN regimen entirely abolished these increases. Despite DFMO treatment, liver ODC activity in RI----TPN + DFMO group was unaffected. The plasma albumin level, an indicator of host nutrition, of the RI----TPN + DFMO group was significantly higher than that of the RI group. Liver, spleen, kidney and total body weights of the RI----TPN or RI----TPN + DFMO group were significantly higher than those of the RI group. These results indicate that TPN can enhance tumor growth in malnourished hosts and that the addition of DFMO to TPN can effectively control this TPN-enhanced tumor growth, leading to preferential nutritional repletion of the host.

Effect of Strongyloides ratti on small bowel function in normal and immunosuppressed host rats.

Although Strongyloides stercoralis is a common parasite, little is known about its effect on intestinal function. Published clinical studies are difficult to evaluate and compare because of the inability to differentiate the effects of the parasite load from that of various other coexisting features such as bacterial overgrowth, multiparasitism, malnutrition, or tropical sprue. Using a rat model where these problems do not occur, we found that Strongyloides ratti did not inhibit intestinal function in the healthy rat. In fact, in normal rats S. ratti appeared to increase ileal sucrase activity. In contrast, in the methylprednisolone-treated rat, S. ratti produced a decrease in lactase and sucrase activity and an increase in alkaline phosphatase activity. S. ratti had no effect on 3-O-methylglucose uptake or D-xylose absorption in either group. These results suggest that S. ratti has little effect on small bowel function in a healthy rat but can cause minor alterations in intestinal function in an immunosuppressed, methylprednisolone-treated, malnourished host. These results are also consistent with clinical observations seen with S. stercoralis in humans and with another nematode, Ascaris suus, in the pig model.

EFFECT OF MALNUTRITION ON ILEAL RESPONSE TO YERSINIA ENTEROCOLITICA (Y. E.) ENTERITIS

The course of Y.E. enteritis was examined in the ileum of control (C) and undernourished (M) 27-28 d old rabbits. Malnutrition was induced by litter expansion 7 d post partum (M, 13-16 pups/litter; C, 6-8). Animals were infected at 17 or 22 d with 109 organisms of Y.E. Weight of M animals at the time of infection was significantly (p<0.01) less than C. Undernutrition alone (M) significantly (Table, p<0.05) reduced mucosal weight, protein, DNA, lactase and villus height but increased (p<0.02) short-circuited glucose-stimulated Na+ transport (Δglu JNa) compared to C. Infected animals from both dietary groups evaluated at 6 d demonstrated comparable findings. Infected animals with a normal dietary intake at 10 d (110) showed complete recovery of mucosal weight, protein, DNA, and lactase, morphology and Δglu JNa compared to C (Table). In contrast, M animals 10 d post infection (MI10) demonstrated persistant mucosal inflammation, increased mucosal weight, protein and DNA and depressed Δglu JNa compared to noninfected M (Table, p<0.01). We conclude that ileal recovery after a bacteria enteritis in a malnourished host is prolonged as evidenced by persistant inflammation and depressed glucose stimulated Na+ transport.

Nutrition and immunity

SummaryIt is well recognised that dietary factors play an important role in maintaining immune defences. Malnourished populations are known to have increased incidence and duration of infectious diseases, and data from numerous clinical and experimental studies have demonstrated impaired immunocompetence in the malnourished host. Restoring the food supply to an affected individual restores cell‐mediated immunity, except when malnutrition has occurred during foetal development. The developing immune system is particularly susceptible to nutritional deprivation. The problem of malnourishment is not restricted to developing countries. Malnutrition has been reported among hospitalized patients, generally as a result of illness but also as a consequence of surgery and sometimes from inappropriate feeding regimes. Alterations of the immune response can be demonstrated in obesity as well as in the malnourished state, and excess intake of polyunsaturated fatty acids (PUFA) has been shown to suppress immunity. Vitamins and trace minerals are also important in maintaining immunocompetence. Selenium and vitamin E have enhancing effects, probably due to their ability to prevent peroxidation of PUFA, and deficiency of pyridoxine (B6), zinc and vitamin A has been associated with impairment of immune functions. Knowledge gained of the interactions between nutritional factors and immunity offer the possibility of altering dietary regimes in order to modulate immune function and thus improve resistance to infectious disease and other diseases associated with impaired immunity.

International symposium on toxicity of chemicals in malnourished hosts

International symposium on toxicity of chemicals in malnourished hosts

Nonspecific stimulation of host defenses against a bacterial challenge in malnourished hosts

Nonspecific stimulation of host defenses against a bacterial challenge in malnourished hosts

Nonspecific stimulation of host defenses against bacterial challenge in immunosuppressed mice.

Muramyl dipeptide (MDP) has been shown to be a safe and effective host defense stimulant in both normal and malnourished hosts exposed to a bacterial challenge. We investigated its effect in mice compromised by pretreatment with either cyclophosphamide or steroids. The bacterial challenge, designed to simulate a surgical wound infection, consisted of a Klebsiella pneumoniae-laden suture. The MDP treatment resulted in lower local and systemic bacterial spread and increased survival in mice immunosuppressed by cyclophosphamide than in untreated controls. No such effect was demonstrated in animals compromised by steroids. These results suggest that MDP exerts its effect primarily on the macrophage.