Kathryn B. Renegar

Loss of upper respiratory tract immunity with parenteral feeding.

OBJECTIVE The authors examine the effect of route and type of nutrition on an established upper respiratory tract immunity and investigate potential mechanisms for increased pneumonia rates in critically injured patients fed parenterally. SUMMARY BACKGROUND DATA The primary immunologic defense against many mucosal infections is IgA. Prior work shows that mice fed total parenteral nutrition (TPN) solutions either intravenously or intragastrically had small intestinal gut-associated lymphoid tissue (GALT) atrophy along with decreased intestinal IgA compared with animals fed complex enteral diets. The small intestine is postulated to be the origin of most mucosal immunity, both intraintestinal and extraintestinal. The impact of diets affecting GALT, small intestine IgA, and upper respiratory tract immunity is studied. METHODS Male Institute of Cancer Research mice underwent intranasal inoculation with a mouse-specific influenza virus to establish immunity. Three weeks later, the mice were randomized to chow, intragastric Nutren (Clintec, Chicago, IL), intravenous TPN, or intragastric TPN. After 5 days of feeding, mice were challenged with intranasal virus and killed at 40 hours to determine viral shedding from the upper respiratory tract. RESULTS Despite similar body weights, there was significant atrophy in the Peyers patch cells from animals fed the TPN solution intravenously or intragastrically. There was no viral shedding in any animal fed via the gastrointestinal tract, whereas 5 of 10 animals fed intravenous TPN had continued viral shedding. CONCLUSIONS The IgA-dependent upper respiratory tract immunity was preserved with enteral feeding but not with intravenous feeding. Upper respiratory tract immunity is not dependent on intestinal GALT mass but is influenced by route of nutrition. The underlying mechanisms may explain the higher pneumonia rate in critically injured patients fed parenterally.

Route and type of nutrition influence mucosal immunity to bacterial pneumonia.

OBJECTIVE To develop a model of established respiratory immunity against Pseudomonas aeruginosa pneumonia and to investigate the effects of route and type of nutrition on this immunity. SUMMARY BACKGROUND DATA Diet influences the ability of gut-associated lymphoid tissue (GALT) to maintain mucosal immunity. Complex enteral diets and chow maintain normal GALT populations against established IgA-mediated antiviral respiratory immunity. Both intravenous and intragastric total parenteral nutrition (TPN) produce GALT atrophy, but only intragastric TPN preserves established antiviral immunity. The authors hypothesized that both GALT-depleting diets (intragastric and intravenous TPN) would impair immunity against bacterial pneumonia. METHODS P. aeruginosa was administered intratracheally to determine the mortality rate at increasing doses, and liposomes containing P. aeruginosa antigens were used to generate effective respiratory immunization. In the final experiment, mice received liposomes containing P. aeruginosa antigens to establish immunity and then were randomized to chow, complex enteral diets, intragastric TPN, or intravenous TPN. After 5 days of diet, mice received live intratracheal P. aeruginosa, and the death rate was recorded at 24 and 48 hours. RESULTS The LD50 and LD100 were 9 x 10(7) and 12 x 10(7), respectively. Immunization reduced the mortality rate from 66% to 12%. This immunization was maintained in mice fed chow or a complex enteral diet and was lost in animals receiving intravenous TPN. Intragastric TPN partially preserved this respiratory immunity. CONCLUSIONS Protection against bacterial pneumonia can be induced by prior antigenic immunization. This protection is lost with intravenous TPN, partially preserved with a chemically defined enteral diet, and completely preserved with chow or complex enteral diets. Both route and type of nutrition influence antibacterial respiratory tract immunity.

Cytokines in sleep regulation

The central thesis of this essay is that the cytokine network in brain is a key element in the humoral regulation of sleep responses to infection and in the physiological regulation of sleep. We hypothesize that many cytokines, their cellular receptors, soluble receptors, and endogenous antagonists are involved in physiological sleep regulation. The expressions of some cytokines are greatly amplified by microbial challenge. This excess cytokine production during infection induces sleep responses. The excessive sleep and wakefulness that occur at different times during the course of the infectious process results from dynamic changes in various cytokines that occur during the hosts response to infectious challenge. Removal of any one somnogenic cytokine inhibits normal sleep, alters the cytokine network by changing the cytokine mix, but does not completely disrupt sleep due to the redundant nature of the cytokine network. The cytokine network operates in a paracrine/autocrine fashion and is responsive to neuronal use. Finally, cytokines elicit their somnogenic actions via endocrine and neurotransmitter systems as well as having direct effects neurons and glia. Evidence in support of these postulates is reviewed in this essay.

Effect of glutamine-enriched total parenteral nutrition on small intestinal gut-associated lymphoid tissue and upper respiratory tract immunity.

BACKGROUND Our prior work shows that total parenteral nutrition (TPN) causes small intestinal gut-associated lymphoid tissue (GALT) atrophy, lowers small intestinal immunoglobulin A (IgA) levels, and impairs secretory IgA-mediated mucosal immunity of the upper respiratory tract. These experiments examine whether an isonitrogenous 2% glutamine-enriched TPN solution prevents these changes. METHODS Institute of Cancer Research mice were randomized to chow (chow), intravenous feeding of a TPN solution (TPN), or glutamine-enriched TPN (glutamine) groups. After mice were fed for 5 days, lymphocytes were isolated from Peyers patches, the intraepithelial layer, and lamina propria to determine cell yields and phenotypes. Total small intestinal IgA levels were analyzed by means of enzyme-linked immunosorbent assay. In a second series of experiments, mice underwent intranasal inoculation with H1N1 virus to establish immunity. After 3 weeks mice were randomized to chow, TPN, or glutamine groups. After feeding for 5 days, mice were rechallenged with intranasal virus and killed at 40 hours to determine viral shedding from the upper respiratory tract. RESULTS Total lymphocyte yield in the Peyers patches, the intraepithelial layer, and lamina propria, small intestinal IgA levels, and the CD4+/CD8+ ratio in the lamina propria decreased with TPN but remained normal with glutamine. On rechallenge, 87% of the mice in the TPN group shed virus in nasal secretions, whereas only 38% of the glutamine-treated group (p < 0.05 versus TPN) and 7.1% of the chow group (p < 0.002 versus TPN) were virus positive. CONCLUSIONS Isonitrogenous supplementation of TPN with 2% glutamine improves IgA-mediated protection in the upper respiratory tract and normalizes GALT populations.

Bombesin Recovers Gut-Associated Lymphoid Tissue and Preserves Immunity to Bacterial Pneumonia in Mice Receiving Total Parenteral Nutrition

OBJECTIVE To study the ability of bombesin (BBS) to recover gut-associated lymphoid tissue (GALT) and preserve immunity in a lethal model of Pseudomonas aeruginosa (Ps) pneumonia in mice receiving total parenteral nutrition (TPN). SUMMARY BACKGROUND DATA TPN causes depression of mucosal immunity compared with enterally fed animals, which may explain the increased incidence of pneumonia in parenterally fed trauma patients. BBS prevents this TPN-induced GALT atrophy, depressed gastrointestinal and respiratory tract IgA levels, and impaired antiviral IgA-mediated mucosal immunity. The authors examined whether some supplement could be added to TPN to avoid this GALT atrophy and lower the incidence of infectious complications in the parenterally fed animal. METHODS Male mice were randomized to chow or intravenous (IV) TPN. After 5 days of IV TPN, mice received 0, 1, 2, or 3 days of BBS IV three times a day and then were killed to harvest Peyers patch, intraepithelium, and lamina propria for cell yields. Gastrointestinal and respiratory tract IgA levels were analyzed by enzyme-linked immunosorbent assay. Next, mice underwent intranasal inoculation with liposomes alone (nonimmune) or liposome-containing Ps polysaccharide. Ps immune mice were catheterized and randomized to chow, IV TPN, or IV TPN + BBS. The liposome group received chow but no IV catheter. These mice were given an LD90 dose of intratracheal Ps, and death rates were recorded. RESULTS GALT and gastrointestinal and respiratory tract IgA levels improved to those in chow-fed mice after 3 days of BBS. Immunization reduced the death rate from 92% in chow-fed liposome-only animals to 20% in immunized animals. TPN-fed animals lost their mucosal immunity, with a death rate of 86% compared with 21% in the TPN + BBS group. CONCLUSION The results demonstrate that BBS reverses TPN-induced changes in GALT and preserves mucosal immunity. Ps immunization reduces the death rate in a gram-negative pneumonia model and maintains gastrointestinal and respiratory immunity in Ps immune mice receiving IV TPN.

Glycyl-L-glutamine-enriched total parenteral nutrition maintains small intestine gut-associated lymphoid tissue and upper respiratory tract immunity.

BACKGROUND i.v. administration of a total parenteral nutrition (TPN) solution results in small intestinal gut-associated lymphoid tissue (GALT) atrophy, lowers small intestinal immunoglobulin A (IgA) levels, and impairs upper respiratory tract secretory IgA-mediated mucosal immunity; isonitrogenous supplementation of TPN with 2% glutamine attenuates these changes. This experiment examines whether a 2% glycyl-L-glutamine-enriched TPN solution reverses i.v. TPN-induced changes as effectively as L-glutamine. METHODS Male Institute of Cancer Research (ICR) mice underwent intranasal inoculation with H1N1 influenza virus to establish immunity. After 3 weeks, mice were randomized to chow, i.v. feeding of a TPN solution, glutamine-enriched TPN, or glycyl-L-glutamine-enriched TPN. After 4 days of feeding, mice were challenged intranasally with influenza virus and killed at 40 hours to determine viral shedding from the respiratory tract; normal convalescent mice do not shed virus because they possess intact IgA-mediated mechanisms Lymphocytes were isolated from Peyers patches, the intraepithelial layer, and lamina propria to determine cell yields. RESULTS Total lymphocyte yield in the Peyers patches, the intraepithelial layer, and lamina propria decreased with TPN but remained normal with glutamine and glycyl-L-glutamine. Upon challenge, 70% of the mice in the TPN group shed virus in nasal secretions, whereas only 20% of the glutamine-treated group, 18% of glycyl-L-glutamine group and none of the Chow group were virus positive. CONCLUSIONS L-Glutamine and glycyl-L-glutamine have similar effects on i.v. administered TPN-associated (GALT) atrophy and decreased upper respiratory tract immunity.

Influenza Viral Infections Enhance Sleep in Mice

Abstract Sleepiness is a common perception during viral infection. Nevertheless, very little is known about the effects of viral infection on sleep. The aim of the present study was to test whether sleep was altered by influenza viral infection in mice. After 2-3 days of baseline sleep recordings, Swiss-Webster mice were infected intranasally with a lethal (H1N1) or a nonlethal (H3N2) strain of influenza virus. Sleep was recorded again for an additional 3 days. Non–rapid eye movement sleep (NREMS) was dramatically increased after inoculation of the H1N1 virus with a latency about 16 hr. Rapid eye movement sleep (REMS) was significantly suppressed after a longer latency. Both changes lasted until the end of the recording and occurred in both young (35-day-old) and adult (90- to 100-day-old) animals. Control animals did not show changes in sleep after sham infection with allantoic fluid. The H1N1 virus also caused dramatic decreases in body temperature and locomotor activities with a latency about 4-5 hr after viral inoculation. The H3N2 virus induced very similar changes in sleep, although the effects were much smaller in magnitude than those induced by the H1N1 virus, even though a much higher dose (10-fold) of the H3N2 virus was used. The present study shows that influenza viral infection induces profound and long-lasting increase of NREMS and suppression of REMS. These viral-induced changes in sleep likely represent a host-defense response. [P.S.E.B.M. 1995, Vol 210]

Impairment of Mucosal Immunity by Total Parenteral Nutrition: Requirement for IgA in Murine Nasotracheal Anti-Influenza Immunity

Secretory IgA (SIgA) is the primary mucosal Ig and has been shown to mediate nasotracheal (NT) mucosal immunity in normal immune BALB/c mice. This finding has been challenged by a report of NT immunity without IgA in knockout mice, suggesting that IgA may not be necessary for the protection of mucosal surfaces. Although other protective mechanisms may become active in the congenital absence of SIgA, these mechanisms are not the primary means of protection in normal mice. In this paper we show that feeding chemically defined total parenteral nutrition (TPN) to genetically normal, immune ICR mice by the i.v. route results in loss of nasal anti-influenza immunity and a significant drop in influenza-specific SIgA in the upper respiratory tract compared with chow-fed mice (p < 0.005), while the serum influenza-specific IgG titer is unaffected. Loss of upper respiratory tract mucosal immunity is not related to serum Ab, because 10 of 13 TPN-fed mice shed virus into their nasal secretions despite adequate serum anti-influenza IgG titers. The number of IgG Ab-secreting cells in the nasal passages and spleens of TPN-fed mice was unaffected, while both the number and the percentage of splenic IgA-secreting cells were decreased relative to those in chow-fed animals. The loss of immunity is due to the route of nutrition, not the composition of the diet, because TPN solution fed orally via gastrostomy instead of i.v. maintains NT anti-influenza mucosal immunity. We hypothesize that delivery of nutrition via the gut triggers the release of gastrointestinal neuropeptides necessary for maintenance of the mucosal immune system.

Route of Nutrition Influences Generation of Antibody-Forming Cells and Initial Defense to an Active Viral Infection in the Upper Respiratory Tract

ObjectiveTo assess whether lack of enteral feeding significantly impairs generation of specific immune responses to an acute viral infection. Summary Background DataParenteral feeding provides adequate nutrients to meet metabolic needs, but lack of enteral stimulation creates a defect in mucosal immunity characterized by loss of IgA-mediated defenses in the respiratory tract. MethodsThe enzyme-linked Immunospot (ELISPOT) assay was used to determine accumulation of immunologic cells in the nasal passages after diet manipulation. Viral shedding and nasal IgA levels were measured in additional groups of mice. ResultsAfter determining the time course of antibody-forming cells (AFCs) via ELISPOT to an active infection with the A/PR8 influenza virus, a significant reduction was found in total AFCs, IgA-producing AFCs, and IgG-producing AFCs over the course of a 13-day experiment with significant depression in viral-specific respiratory IgA levels. Eight days following an active infection, seven of nine total parenteral nutrition-fed animals continued to have viral shedding in the nasal passages compared to one of nine chow-fed mice and one of six animals fed a complex enteral diet. ConclusionsLack of enteral stimulation significantly impairs the generation of IgA-mediated mucosal immunity.

Individual neuropeptides regulate gut-associated lymphoid tissue integrity, intestinal immunoglobulin A levels, and respiratory antibacterial immunity

BACKGROUND Total parenteral nutrition (TPN) leads to atrophy of the gut-associated lymphoid tissue (GALT) and a significant decrease in intestinal immunoglobulin A (IgA) levels, a major constituent of mucosal immunity. Bombesin (BBS) prevents TPN-induced GALT atrophy and maintains intestinal IgA levels. BBS, a neuropeptide analogous to gastrin-releasing peptide in humans, stimulates the release of other gut neuropeptides including cholecystokinin (CCK), gastrin, and neurotensin (NT). This study investigates the ability of CCK, gastrin, or NT to individually prevent TPN-induced GALT atrophy and preserve respiratory immunity. METHODS Experiment 1: Male mice were randomly assigned to receive chow, TPN, TPN plus CCK, TPN plus gastrin, or TPN plus NT. After 5 days of feeding, Peyers patches (PP) from the proximal and distal small bowel were harvested and analyzed for cell yields. PP cells were also analyzed for GALT cell type. Small bowel IgA levels were measured by enzyme-linked immunosorbent assay (ELISA). Experiment 2: Mice were randomly assigned to receive either liposomes containing Pseudomonas antigen or liposomes without antigen. After 10 days, mice were randomly assigned to the same five treatment groups, fed for 5 days, and then given intratracheal Pseudomonas. Mortality was assessed after 48 hours. RESULTS Experiment 1: GALT cell reductions due to IV-TPN were greater in the distal than proximal small bowel. All three neuropeptides prevented most TPN-induced GALT atrophy due mainly to the maintenance of the B-cell and T-cell populations in the PP of the distal bowel. Intestinal IgA levels were significantly higher in the animals treated with neuropeptides than animals treated with TPN only; however, these IgA levels were not maintained at levels observed in chow-fed animals. Experiment 2: Immunization resulted in significantly lower mortality in animals fed chow, TPN plus CCK, and TPN plus gastrin. TPN alone and TPN plus NT resulted in loss of immunity and mortality rate at comparable levels to unimmunized animals. CONCLUSIONS Supplementation of IV-TPN with CCK, gastrin, and NT prevents GALT atrophy, primarily in the distal bowel. Intestinal IgA levels improve but not to normal levels. CCK and gastrin reversed IV-TPN-induced effects on antibacterial pneumonia in immunized animals while NT did not.