Search

Objective: To focus on the intersection of perception, diagnosis, stigma, and weight bias in the management of obesity and obtain consensus on actionable steps to improve care provided for persons with obesity., Methods: The American Association of Clinical Endocrinology (AACE) convened a consensus conference of interdisciplinary health care professionals to discuss the interplay between the diagnosis of obesity using adiposity-based chronic disease (ABCD) nomenclature and staging, weight stigma, and internalized weight bias (IWB) with development of actionable guidance to aid clinicians in mitigating IWB and stigma in that context., Results: The following affirmed and emergent concepts were proposed: (1) obesity is ABCD, and these terms can be used in differing ways to communicate; (2) classification categories of obesity should have improved nomenclature across the spectrum of body mass index (BMI) using ethnic-specific BMI ranges and waist circumference (WC); (3) staging the clinical severity of obesity based on the presence and severity of ABCD complications may reduce weight-centric contribution to weight stigma and IWB; (4) weight stigma and internalized bias are both drivers and complications of ABCD and can impair quality of life, predispose to psychological disorders, and compromise the effectiveness of therapeutic interventions; (5) the presence and of stigmatization and IWB should be assessed in all patients and be incorporated into the staging of ABCD severity; and (6) optimal care will necessitate increased awareness and the development of educational and interventional tools for health care professionals that address IWB and stigma., Conclusions: The consensus panel has proposed an approach for integrating bias and stigmatization, psychological health, and social determinants of health in a staging system for ABCD severity as an aid to patient management. To effectively address stigma and IWB within a chronic care model for patients with obesity, there is a need for health care systems that are prepared to provide evidence-based, person-centered treatments; patients who understand that obesity is a chronic disease and are empowered to seek care and participate in behavioral therapy; and societies that promote policies and infrastructure for bias-free compassionate care, access to evidence-based interventions, and disease prevention., Competing Interests: Disclosures The Task Force was empaneled in accordance with AACE Conflict of Interest (COI) Policy and approved by the AACE COI Subcommittee. All members of the expert Task Force completed AACE’s disclosure form regarding any multiplicities of interests related to commercial and direct financial relationships within the preceding 12 months with companies that develop products connected with endocrine disorders. Categories for disclosure include employment, stock or other ownership, direct financial relationships (eg, speaker or consultant), research funding, authorship or panel involvement on a guidance document related to an overlapping topic, or other situations related to a perceived COI. The AACE COI Subcommittee reviewed these disclosures against an AACE-approved list of ineligible companies for this consensus statement and reached consensus regarding members who could serve on the Task Force in the nonconflicted majority, those who could serve in the conflicted minority with management strategy, and those who were disqualified from serving on the Task Force. The AACE CPG Oversight Committee reviewed and approved the AACE COI Subcommittee’s decisions regarding manageable COI and empanelment. Members of this Task Force were reminded to update potential disclosures if new potential conflicts arose during their appointments and to verify currency of disclosures. AACE made every effort to minimize the potential for conflicts of interest that could influence the recommendations of this CPG. Disclosures related to obesity are provided below; however, none were deemed as conflicts of interest as there were no discussions of treatment or management options in the development of the consensus statement. B.A. serves on speakers’ bureaus for Astra Zeneca, Corcept, Eli Lilly, and Novo Nordisk. J.A. serves on advisory boards for Eli Lilly and Novo Nordisk. W.G. serves as a volunteer consultant on advisory boards for Jazz Pharmaceuticals, Boehringer Ingelheim, Eli Lilly, Novo Nordisk, and Pfizer without financial compensation, serves on advisory boards for Alnylam Pharmaceuticals, Boehringer Ingelheim, Eli Lilly, Fractyl Health, and Novo Nordisk with financial compensation, and receives research support as a site principal investigator for clinical trials sponsored by his institution and funded by Eli Lilly, Novo Nordisk, Epitomee, and Pfizer. T.K. is the owner of Ted Kyle Consulting, LLC and a consultant for Gelesis, Johnson & Johnson, Novo Nordisk, and Nutrisystem. K.N., M.A., M.B., and M.C. have nothing to disclose., (Copyright © 2023 AACE. Published by Elsevier Inc. All rights reserved.)

Objective: This 2023 updated protocol summarizes the American Association of Clinical Endocrinology's (AACE's) new framework for the development of clinical practice guidelines and other guidance documents that includes changes to methodology, processes, and policies., Methods: AACE has critically reviewed its development processes for guidance documents over the last several years against the National Academy of Medicine Standards for Developing Trustworthy Clinical Practice Guidelines and the Council of Medical Specialty Societies Principles for Development of Specialty Society Clinical Guidelines to determine areas for improvement., Results: The new AACE framework for development of guidance documents incorporates many changes, including a revised conflicts of interest (COI) policy; strengthened commitment to collection of disclosures and management of relevant COI during development; open calls to membership for authors; new requirements for authors; new diversity, equity, and inclusion (DEI) policy; new empanelment process that incorporates consideration of DEI; and adoption of the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology to increase the quality of evidence assessment and standardize recommendation grades and statements, among other improvements., Conclusions: AACE has revised its policies and adopted a completely new methodology for guideline development in support of the mission to elevate the practice of clinical endocrinology to improve patient care. With the use of an evidence-based medicine framework and by continually assessing and improving its processes for development of guidance, AACE strives to deliver trustworthy, unbiased, and up-to-date information that ensures clinician and patient confidence in AACE content. Further, AACE hopes that these enhancements foster a more collaborative approach to development and increase engagement with the worldwide medical community to improve global health., Competing Interests: Disclosures R.C. is the current chair of the AACE CPG Oversight Committee, a member of the AACE Board of Directors, and in leadership positions at the American Medical Association, Western Endocrine Alliance, American Federation of Medical Research, Association of Program Directors in Endocrinology, Diabetes and Metabolism, and Endocrine Society. J.M. is the current vice-chair of the AACE CPG Oversight Committee and in a leadership position at the Georgia Society of Endocrinology. T.H. is on the advisory board (no financial compensation) for Horizon therapeutics and a consultant for Acella (no financial compensation). S.J. is editor-in-chief of AACE Clinical Case Reports. D.C.L. is in leadership positions at the American Diabetes Association, Association of Program Directors in Endocrinology, Diabetes and Metabolism, and Endocrine Society. S.L.W. is a past president of AACE and former chair of the AACE CPG Oversight Committee, and receives research support and is a national or overall principal investigator for Novo Nordisk. M.B., D.C., and C.S. have nothing to disclose., (Copyright © 2023 AACE. Published by Elsevier Inc. All rights reserved.)

Across Canada's boreal forest, linear disturbances, including cutlines such as seismic lines and roads, crisscross the landscape to facilitate resource exploration and extraction; many of these linear disturbances cross peatland ecosystems. Changes in tree canopy cover and the compression of the peat by heavy equipment alter local thermal, hydrological, and ecological conditions, likely changing carbon exchange on the disturbance, and possibly in the adjacent peatland. We measured bulk density, water table, soil temperature, plant cover, and CO 2 and CH 4 flux along triplicate transects crossing a winter road through a wooded fen near Peace River, Alberta, Canada. Sample plots were located 1, 5, and 10 m from the road on both sides with an additional three plots on the road. Productivity of the overstory trees, when present, was also determined. The winter road had higher bulk density, shallower water table, higher graminoid cover, and thawed earlier than the adjacent peatland. Tree productivity and CO 2 flux varied between the plots, and there was no clear pattern in relation to distance from the road. The plots on the winter road acted as a greater CO 2 sink and greater CH 4 source compared to the adjacent peatland with plots on the winter road emitting on average (standard error) 479 (138) compared to 41 (10) mg CH 4  m -2  day -1 in the adjacent peatland. Considering both gases, global warming potential increased from 70 to 250 g CO 2 e m -2  year -1 in the undisturbed area to 2100 g CO 2 e m -2  year -1 on the winter road. Although carbon fluxes on any given cutline through peatland will vary depending on level of compaction, line width and vegetation community shifts, the large number of linear disturbances in Canada's boreal forest and slow recovery on peatland ecosites suggest they could represent an important anthropogenic greenhouse gas source., (© 2017 John Wiley & Sons Ltd.)

Background: Ethanol (EtOH) exposure prior to traumatic injury, such as a burn, elevates systemic and local inflammatory responses and increases morbidity and mortality. Adipose is a large tissue mass that is often inflamed during obesity or other stresses, which disturbs metabolic homeostasis. To date, there has been little investigation into the inflammatory response of adipose tissue after combined EtOH exposure and burn injury., Methods: Two EtOH exposure regimens were utilized to examine the role of inflammation in adipose tissue after EtOH and burn injury. Mice were either given a single or episodic binge exposure to EtOH or saline followed by scald (burn) or sham injury 30 minutes later. Twenty-four hours post injury, serum and adipose tissue were collected for assessment of inflammatory mediators., Results: Single binge EtOH alone induced no inflammation in adipose when compared with sham vehicle-treated mice. However, single binge EtOH followed by burn injury induced significant elevations in mRNA and protein concentrations of pro-inflammatory mediators interleukin-6 (IL-6), KC, and monocyte chemoattractant protein 1 compared with either insult alone or sham vehicle group. Additionally, EtOH exposure and burn injury significantly blunted inducible nitric oxide synthase (iNOS), indicating a complex inflammatory response. Episodic binge EtOH exposure followed by burn injury exacerbated the postburn adipose inflammatory response. The magnitude of the episodic binge-induced inflammatory parameters postburn were 2- to 5-fold greater than the response detected after a single exposure of EtOH, indicating EtOH-induced potentiation of burn-induced inflammatory response. Finally, inflammatory loci and crown-like structures in adipose were significantly increased by episodic binge EtOH and burn injury., Conclusions: This is the first report of binge and burn-induced crown-like structure formation. Evidence presented herein suggests an important role for alcohol and burn as an additional mediator of adipose inflammation in postburn injury, a common complication in burn patients., (Copyright © 2013 by the Research Society on Alcoholism.)

Events such as a nuclear meltdown accident or nuclear attack have potential for severe radiation injuries. Radiation injury frequently occurs in combination with other forms of trauma, most often burns. Thus far, combined injury studies have focused mainly on skin wound healing and damage to the gut. Since both radiation exposure and remote burn have pulmonary consequences, we examined the early effects of combined injury on the lung. C57BL/6 male mice were irradiated with 5 Gy of total body irradiation followed by a 15% total body surface area scald burn. Lungs from surviving animals were examined for evidence of inflammation and pneumonitis. At 48 h post-injury, pathology of the lungs from combined injury mice showed greater inflammation compared to all other treatment groups, with marked red blood cell and leukocyte congestion of the pulmonary vasculature. There was excessive leukocyte accumulation, primarily neutrophils, in the vasculature and interstitium, with occasional cells in the alveolar space. At 24 and 48 h post-injury, myeloperoxidase levels in lungs of combined injury mice were elevated compared to all other treatment groups (P < 0.01), confirming histological evidence of neutrophil accumulation. Pulmonary levels of the neutrophil chemoattractant KC (CXCL1) were 3 times above that of either injury alone (P < 0.05). Further, monocyte chemotactic protein-1 (MCP-1, CCL2) was increased two- and threefold compared to burn injury or radiation injury, respectively (P < 0.05). Together, these data suggest that combined radiation and burn injury augments early pulmonary congestion and inflammation. Currently, countermeasures for this unique type of injury are extremely limited. Further research is needed to elucidate the mechanisms behind the synergistic effects of combined injury in order to develop appropriate treatments.

Alcohol consumption leads to an exaggerated inflammatory response after burn injury. Elevated levels of interleukin-6 (IL-6) in patients are associated with increased morbidity and mortality after injury, and high systemic and pulmonary levels of IL-6 have been observed after the combined insult of ethanol exposure and burn injury. To further investigate the role of IL-6 in the pulmonary inflammatory response, we examined leukocyte infiltration and cytokine and chemokine production in the lungs of wild-type and IL-6 knockout mice given vehicle or ethanol (1.11 g/kg) and subjected to a sham or 15% total body surface area burn injury. Levels of neutrophil infiltration and neutrophil chemoattractants were increased to a similar extent in wild-type and IL-6 knockout mice 24 h after burn injury. When ethanol exposure preceded the burn injury, however, a further increase of these inflammatory markers was seen only in the wild-type mice. Additionally, signal transducer and activator of transcription-3 (STAT3) phosphorylation did not increase in response to ethanol exposure in the IL-6 knockout mice, in contrast to their wild-type counterparts. Visual and imaging analysis of alveolar wall thickness supported these findings and similar results were obtained by blocking IL-6 with antibody. Taken together, our data suggest a causal relationship between IL-6 and the excessive pulmonary inflammation observed after the combined insult of ethanol and burn injury., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Interleukin 6 (IL-6) is an inflammatory cytokine known to be elevated in chronic diseases and after insults such as trauma and infection. Although necessary for the development of B cells and Th17 cells, IL-6, at elevated levels, can also cause tissue damage and lead to a rise in inflammation. Previous work in our laboratory has shown that IL-6 is increased both systemically and in multiple organ systems including the ileum after ethanol exposure and burn injury. As this combined insult causes elevated intestinal morphological damage, tight junction protein localization alterations, and phosphorylated myosin light chain levels, we sought to determine the role of IL-6 in these intestinal responses using a model of binge ethanol exposure and burn injury. Interleukin 6 antibody treatment after the combined insult reduced morphological changes in the ileum, bacterial translocation, and phosphorylated myosin light chain levels relative to either injury alone. Zonula occludens protein 1 and occludin localization was also reestablished in wild-type mice given IL-6 antibody after ethanol and burn. Interleukin 6-knockout mice given ethanol and burn injury also had reduced intestinal damage; however, no changes in bacterial translocation or tight junction protein localization were observed as compared with similarly treated wild-type mice. These data suggest that IL-6 may have a role in intestinal tissue damage observed after the combined insult of binge ethanol exposure and burn injury, although complete loss of IL-6 does not seem to be beneficial in this model. Modulation of IL-6 may present a new option for preventing intestinal damage and associated inflammation after a combined insult of ethanol exposure and burn injury.

Laboratory evidence suggests that intestinal permeability is elevated following either binge ethanol exposure or burn injury alone, and this barrier dysfunction is further perturbed when these insults are combined. We and others have previously reported a rise in both systemic and local proinflammatory cytokine production in mice after the combined insult. Knowing that long myosin light-chain kinase (MLCK) is important for epithelial barrier maintenance and can be activated by proinflammatory cytokines, we examined whether inhibition of MLCK alleviated detrimental intestinal responses seen after ethanol exposure and burn injury. To accomplish this, mice were given vehicle or a single binge ethanol exposure followed by a sham or dorsal scald burn injury. Following injury, one group of mice received membrane permeant inhibitor of MLCK (PIK). At 6 and 24 h postinjury, bacterial translocation and intestinal levels of proinflammatory cytokines were measured, and changes in tight junction protein localization and total intestinal morphology were analyzed. Elevated morphological damage, ileal IL-1β and IL-6 levels, and bacterial translocation were seen in mice exposed to ethanol and burn injury relative to either insult alone. This increase was not seen in mice receiving PIK after injury. Ethanol-exposed and burn-injured mice had reduced zonula occludens protein-1 and occludin localization to the tight junction relative to sham-injured mice. However, the observed changes in junctional complexes were not seen in our PIK-treated mice following the combined insult. These data suggest that MLCK activity may promote morphological and inflammatory responses in the ileum following ethanol exposure and burn injury.

Objectives: To determine whether the graded severity of smoke inhalation is reflected by the acute pulmonary inflammatory response to injury., Design: In a prospective observational study, we assessed the bronchoalveolar lavage fluid for both leukocyte differential and concentration of 28 cytokines, chemokines, and growth factors. Results were then compared to the graded severity of inhalation injury as determined by Abbreviated Injury Score criteria (0, none; 1, mild; 2, moderate; 3, severe; 4, massive)., Setting: All patients were enrolled at a single tertiary burn center., Patients: The bronchoalveolar lavage fluid was obtained from 60 patients within 14 hrs of burn injury who underwent bronchoscopy for suspected smoke inhalation., Interventions: None., Measurements and Main Results: Those who presented with worse grades of inhalation injury had higher plasma levels of carboxyhemoglobin and enhanced airway neutrophilia. Patients with the most severe inhalation injuries also had a greater requirement for tracheostomy, longer time on the ventilator, and a prolonged stay in the intensive care unit. Of the 28 inflammatory mediators assessed in the bronchoalveolar lavage fluid, 21 were at their highest in those with the worst inhalation injury scores (grades 3 and 4), the greatest of which was interleukin-8 (92,940 pg/mL, grade 4). When compared in terms of low inhalation injury (grades 1-2) vs. high inhalation injury (grades 3-4), we found significant differences between groups for interleukin-4, interleukin-6, interleukin-9, interleukin-15, interferon-γ, granulocyte-macrophage colony-stimulating factor, and monocyte chemotactic protein-1 (p < .05 for all)., Conclusions: These data reveal that the degree of inhalation injury has basic and profound effects on burn patient morbidity, evokes complex changes of multiple alveolar inflammatory proteins, and is a determinant of the pulmonary inflammatory response to smoke inhalation. Accordingly, future investigations should consider inhalation injury to be a graded phenomenon.

The 15th annual meeting of the Alcohol and Immunology Research Interest Group was held on November 19, 2010, at Loyola University Medical Center in Maywood, IL. This year, the focus of the meeting was on alcohol's effect on the immune system in both clinical and experimental systems. The event consisted of three sessions, which featured plenary talks from invited speakers along with oral presentations from selected abstracts, in addition to a poster session. Participants presented a variety of information on ethanol-induced effects on infection susceptibility and resolution, oxidative stress, and organ inflammation. Specifically, speakers presented new insights on the mechanism of alcohol-mediated deleterious effects in the lung, liver, skin, and neuroendocrine system, as well as on immune cells in both in vivo and in vitro systems. Additional oral presentations suggested possible mechanisms of how alcohol-induced reactive oxygen species promote immune dysregulation both locally and systemically., (Copyright © 2012 Elsevier Inc. All rights reserved.)

CD8(+) T cells are important for resolution of HSV-2 lesions from the female genital epithelium. It is uncertain whether optimal clearance of viruses such as HSV-2 that cause a limited, non-systemic infection solely requires expression of effector functions by infiltrating CD8(+) T lymphocytes, or if the clearance rate is reflective of the expression level of critical effector functions. To address this, CD8(+) T cells from normal OT-I mice or OT-I mice deficient in IFNγ (IFNγ(-/-)) or the IFNγ receptor (IFNγR(-/-)) were activated in vitro in the presence of IFNγ or IL-4 to generate a series of effector populations (Tc1 and Tc2-like respectively) that secreted different levels of IFNγ and expressed different levels of HSV-specific cytolytic function. Compared with Tc1 cells, Tc2-like cells produced the type 2 cytokines IL-4 and IL-5, exhibited decreased IFNγ secretion, diminished proliferation in vitro, and decreased antigen-specific cytolysis in vivo. Clearance of an ovalbumin-expressing HSV-2 strain (HSV-2 tk(-) OVA) by adoptively transferred Tc2-like cells was delayed relative to Tc1 cell recipients. Because donor Tc2-like cells proliferated in vivo and infiltrated the infected genital epithelium similar to Tc1 cells, the diminished virus clearance by Tc2-like effector cells correlated with reduced expression of critical effector functions. Together, these results suggest that high level expression of protective T cell functions by effector T cells is necessary for optimal clearance of HSV-2 from the genital epithelium. These results have important implications for vaccines designed to elicit CD8(+) T cells against viruses such as HSV-2 that infect the genital tract., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

Combined radiation and burn injuries are likely to occur after nuclear events, such as a meltdown accident at a nuclear energy plant or a nuclear attack. Little is known about the mechanisms by which combined injuries result in higher mortality than by either insult alone, and few animal models exist for combined radiation and burn injury. Herein, the authors developed a murine model of radiation and scald burn injury. Mice were given a single dose of 0, 2, 4, 5, 6, or 9 Gray (Gy) alone, followed by a 15% TBSA scald burn. All mice receiving ≤4 Gy of radiation with burn survived combined injury. Higher doses of radiation (5, 6, and 9 Gy) followed by scald injury had a dose-dependent increase in mortality (34, 67, and 100%, respectively). Five Gy was determined to be the ideal dose to use in conjunction with burn injury for this model. There was a decrease in circulating white blood cells in burn, irradiated, and combined injury (5 Gy and burn) mice by 48 hours postinjury compared with sham (49.7, 11.6, and 57.3%, respectively). Circulating interleukin-6 and tumor necrosis factor-α were increased in combined injury at 48 hours postinjury compared with all other treatment groups. Prolonged overproduction of proinflammatory cytokines could contribute to subsequent organ damage. Decreased leukocytes might exacerbate immune impairment and susceptibility to infections. Future studies will determine whether there are long lasting consequences of this early proinflammatory response and extended decrease in leukocytes.

Background: Clinical and laboratory evidence suggests that alcohol consumption prior to burn injury leads to dysregulated immune function and subsequent higher rates of morbidity and mortality. Our laboratory previously observed higher levels of pro-inflammatory cytokines and leukocyte infiltration in the lungs of mice following ethanol and burn injury. To understand the mechanism of the increased inflammatory response, we looked at different signaling initiators of inflammation including toll-like receptors 2 and 4 (TLR2 and 4) pathways., Methods: Wild-type, TLR2, and TLR4 knockout mice were treated with vehicle or a single binge dose of ethanol (1.11 g/kg) and subsequently given a sham or burn injury. Twenty-four hours postinjury, systemic and pulmonary levels of pro-inflammatory cytokines were quantified, and differences in neutrophil infiltration were determined by histological examination., Results: Higher numbers of neutrophils were observed in the lungs of wild-type mice following the combined insult of ethanol and burn injury relative to either injury alone. This increase in leukocyte accumulation was absent in the TLR4 knockout mice. Circulating levels of IL-6 and tumor necrosis factor-α were also elevated in wild-type mice but not in TLR4 knockout mice. Consistent with these findings, pulmonary levels of KC and IL-6 were increased in wild-type mice following burn and ethanol compared to burn injury alone as well as to their TLR4 knockout counterparts. In contrast, TLR2 knockout mice displayed similar levels, to wild-type mice, of neutrophil infiltration as well as IL-6 and KC in the lung., Conclusions: These data suggest that TLR4 signaling is a crucial contributory component in the exuberant inflammation after ethanol and burn injury. However, TLR2 does not appear to play a vital role in the aberrant pulmonary inflammation., (Copyright © 2010 by the Research Society on Alcoholism.)

Clinical and laboratory evidence suggests that alcohol consumption dysregulates immune function. Burn patients who consume alcohol before their injuries demonstrate higher rates of morbidity and mortality, including acute respiratory distress syndrome, than patients without alcohol at the time of injury. Our laboratory observed higher levels of proinflammatory cytokines and leukocyte infiltration in the lungs of mice after ethanol exposure and burn injury than with either insult alone. To understand the mechanism of the increased pulmonary inflammatory response in mice treated with ethanol and burn injury, we investigated the role of intercellular adhesion molecule (ICAM)-1. Wild-type and ICAM-1 knockout (KO) mice were treated with vehicle or ethanol and subsequently given a sham or burn injury. Twenty-four hours postinjury, lungs were harvested and analyzed for indices of inflammation. Higher numbers of neutrophils were observed in the lungs of wild-type mice after burn and burn with ethanol treatment. This increase in pulmonary inflammatory cell accumulation was significantly lower in the KO mice. In addition, levels of KC, interleukin-1beta, and interleukin-6 in the lung were decreased in the ICAM-1 KO mice after ethanol exposure and burn injury. Interestingly, no differences were observed in serum or lung tissue content of soluble ICAM-1 24 hours postinjury. These data suggest that upregulation of adhesion molecules such as ICAM-1 on the vascular endothelium may play a critical role in the excessive inflammation seen after ethanol exposure and burn injury.

Interferon gamma (IFNgamma) is important for immune resistance to herpes simplex virus (HSV) infection. To examine the influence of IFNgamma on the development of HSV-specific immune responses and test for IFNgamma-independent adaptive immune mechanisms of protection, IFNgamma-deficient mice (IFNgamma(-/-)) were immunized with thymidine kinase-deficient HSV-2 (HSV-2 333tk(-)). HSV-specific cellular and humoral responses were elicited in immunized IFNgamma(-/-) mice resulting in increased resistance relative to non-immune C57BL/6J (B6) mice following challenge with fully virulent HSV-2. CD8(+) T cells from IFNgamma(-/-) mice displayed cytotoxic activity and secreted TNFalpha. HSV-specific CD4(+) T cells from immunized IFNgamma(-/-) mice secreted IL-4, TNFalpha, and IL-17, but unlike T cells from HSV-immune B6 mice, could not clear virus from genital tissue following adoptive transfer. HSV-immune IFNgamma(-/-) mice produced predominantly IgG(1) HSV-specific antibodies while immune B6 mice produced predominantly IgG(2c) antibodies. Transfer of equivalent amounts of HSV-specific antibodies from either strain to naïve mice imparted equivalent early resistance against infection of the genital epithelia. However, protection against neurological symptoms mediated by immune B6 antibodies was superior late in infection. Taken together, these results demonstrate that the limited resistance of HSV-immune IFNgamma(-/-) mice to HSV-2 infection resulted from the action of HSV-specific Ab rather than IFNgamma-independent effector functions of T cells. Further, protection against neurological manifestations of HSV-2 infection was superior in mice receiving Ab from immune B6 mice suggesting that Ab-mediated protective mechanisms involving IFNgamma-induced IgG subclasses were more effective once virus had spread to neural tissues., (2009 Elsevier Ireland Ltd. All rights reserved.)

The purpose of this study was to determine whether 26S proteasome is detectable in human bronchoalveolar lavage fluid (BALF) and whether burn and inhalation injury is accompanied by changes in BALF proteasome content or activity. BALF was obtained on hospital admission from 28 patients with burn and inhalation injury (controls: 10 healthy volunteers). Proteasome concentrations were quantified by enzyme-linked immunosorbent assay, and their native molecular mass was assessed by gel filtration. Proteasome peptidase activity was measured using a chymotryptic-like peptide substrate in combination with epoxomicin (specific proteasome inhibitor). BALF protein was increased in patients (P<.001) and correlated positively with the degree of inhalation injury. The 20S/26S proteasomes were detectable in all BALF by enzyme-linked immunosorbent assay. Gel filtration confirmed the presence of intact 20S and 26S proteasome that was stable without soluble ATP/Mg. In all BALF chymotryptic-like activity was detectable and could be inhibited with epoxomicin by 60 to 70% (P<.01). Absolute amounts of 20S/26S proteasomes and proteasome activity were increased in patients (P<.001 for all). The relative BALF composition after injury was characterized by increased concentrations of 20S proteasome/mg protein (P=.0034 vs volunteers), decreased concentrations of 26S proteasome/mg protein (P=.041 vs volunteers), and reduced specific proteasome activity (P=.044 vs volunteers). The 26S proteasome per milligram and specific proteasome activity were even further reduced in patients who developed ventilator-associated pneumonia (P=.045 and P=.03 vs patients without ventilator-associated pneumonia). This study supports the novel concept that extracellular proteasomes could play a pathophysiological role in the injured lung and suggests that insufficient proteasome function may increase susceptibility for pulmonary complications.

Clinical and experimental evidence demonstrates that ethanol exposure prior to injury alters local and systemic inflammatory responses, increasing morbidity and mortality. Moreover, the aberrant inflammatory responses can directly and indirectly lead to the poor prognosis after injury by altering leukocyte infiltration into the wound site and remote organs and by suppressing immunity leading to increased susceptibility to opportunistic infections. Recent studies from our laboratory have focused on inflammatory responses at the wound site and in other distal organs after exposure to acute ethanol and burn injury. This combined insult leads to increased mortality after dermal or intratracheal pseudomonas infection, relative to infected mice given ethanol or burn injury alone. The increased mortality in mice given ethanol and burn injury parallels elevated serum levels of proinflammatory cytokines, IL-6 and TNF-alpha, marked infiltration of leukocytes into the lung and gut, as well as immunosuppression at the sites of infection. Bacterial translocation from the gut is likely to be responsible, in part, for the aberrant accumulation of leukocytes in the lungs of ethanol-exposed, burn-injured mice. Additionally, other factors, such as expression of adhesion molecules, increased chemokine production, and leakiness of the vascular endothelium, may also be involved.

Cell-mediated immunity is extremely important for resolution of infection and for proper healing from injury. However, the cellular immune response is dysregulated following injuries such as burn and hemorrhage. Sex hormones are known to regulate immunity, and a well-documented dichotomy exists in the immune response to injury between the sexes. This disparity is caused by differences in immune cell activation, infiltration, and cytokine production during and after injury. Estrogen and testosterone can positively or negatively regulate the cellular immune response either by aiding in resolution or by compounding the morbidity and mortality. It is apparent that the hormonal dysregulation is dependent not only on the type of injury sustained but also the amount of circulating hormones. Therefore, it may be possible to design sex-specific therapies to improve immunological function and patient outcome.

Early clearance of a thymidine kinase-deficient strain of herpes simplex virus type 2 from the female genital tract required T-cell-produced gamma interferon (IFN-gamma). Transfer of activated CD8+ T cells to irradiated C57BL/6 mice resulted in rapid virus clearance, but clearance was greatly delayed in recipients deficient in the IFN-gamma receptor (IFN-gammaR). Early virus clearance was demonstrated in radiation chimeras in which IFN-gammaR expression was limited to parenchymal cells, but resolution was significantly delayed in chimeras deficient in IFN-gammaR expression and chimeras expressing IFN-gammaR only on hematopoietic cells. Together, these results suggest that early IFN-gamma-mediated protection was manifested mainly by stimulation of genital parenchymal cells.