G. J. Bagby

Ventilation-induced lung injury is associated with an increase in gut permeability.

Mechanical ventilation is associated with several harmful effects mainly related to high tidal volumes (Vt). Ventilator-induced lung injury can be responsible for an increased production of inflammatory mediators. We evaluated remote consequences on the gut of lung triggered inflammatory response, neutralizing anti-tumor necrosis factor (TNF) antibody was administered to assess the role of TNF in lung and gut permeability changes. Rats were anesthetized and ventilated for 2 h. A control group (Con: Vt = 10 mL/kg) was compared with a high Vt group (HV: Vt = 30 mL/kg). One &mgr;Ci of I125-labeled human serum albumin was injected to measure extravascular albumin space. Gut permeability was evaluated by plasma-to-lumen ratio leakage of I125 human serum albumin. Extravascular albumin space increased in the HV group from 446 ± 50 &mgr;L to 2783 ± 887 &mgr;L. Gut index of permeability increased from 5.1 ± 1.2 to 14.2 ± 4.9. Anti-TNF antibody prevented both lung and gut increase in permeability. High tidal volume ventilation resulted in an increase in lung edema and gut permeability, antagonism of TNF with neutralizing antibodies abrogated the increase in gut permeability as well as lung edema.

Intestinal Lymphocyte Subsets and Turnover Are Affected by Chronic Alcohol Consumption: Implications for Siv/hiv Infection

Summary: We recently demonstrated that simian immunodeficiency virus (SIV) viral loads were significantly higher in the plasma of rhesus macaques consuming alcohol compared with controls following intrarectal SIV infection. To understand the possible reasons behind increased viral replication, here we assessed the effects of chronic alcohol consumption on distribution and cycling of various lymphocyte subsets in the intestine. Macaques were administered alcohol (n = 11) or sucrose (n = 12), and percentages of memory and naive and activated lymphocyte subsets were compared in the blood, lymph nodes, and intestines. Although minimal differences were detected in blood or lymph nodes, there were significantly higher percentages of central memory (CD95+CD28+) CD4+ lymphocytes in the intestines from alcohol-receiving animals before infection compared with controls. In addition, higher percentages of naive (CD45RA+CD95−) as well as CXCR4+CD4 cells were detected in intestines of alcohol-treated macaques. Moreover, alcohol consumption resulted in significantly lower percentages of effector memory (CD95+CD28−) CD8 lymphocytes as well as activated Ki67+CD8 cells in the intestines. A subset (7 receiving alcohol and 8 receiving sucrose) were then intrarectally inoculated with SIVmac251. Viral RNA was compared in different tissues using real-time PCR and in situ hybridization. Higher levels of SIV replication were observed in tissues from alcohol-consuming macaques compared with controls. Central memory CD4 lymphocytes were significantly depleted in intestines and mesenteric lymph nodes from all alcohol animals at 8 weeks postinfection. Thus, changes in the mucosal immune compartment (intestines) in response to alcohol are likely the major reasons behind higher replication of SIV observed in these animals.

Contrasting effects of misoprostol on systemic and intrapulmonary lipopolysaccharide-induced tumor necrosis factor-alpha

Tumor necrosis factor-alpha (TNF), a cytokine produced by mononuclear phagocytes in response to lipopolysaccharide stimulation, is a potent mediator of the inflammatory cascade. However, the immunomodulatory signals regulating TNF expression in the host are poorly defined. Recently, metabolites of the prostaglandin E series have been shown to inhibit TNF production in vitro. In order to determine if PGE1 alters TNF activity in vivo, rats were given misoprostol, a synthetic PGE1 analogue, or saline by gavage and subsequently challenged with either intravenous or intratracheal Escherichia coli lipopolysaccharide. These in vivo data show that PGE1 is a potent inhibitor of TNF production by systemic mononuclear phagocytes. In contrast, alveolar macrophages appear to be refractory to misoprostols suppressive effects on LPS-induced TNF. This study supports in vitro observations that mononuclear phagocytes within different compartments exhibit differential responsiveness to immunomodulators.

Differential contribution of chronic binge alcohol and antiretroviral therapy to metabolic dysregulation in SIV-infected male macaques.

The incidence of alcohol use disorder (AUD) is higher among people living with HIV (PLWH). The advent and continued development of antiretroviral therapy (ART) has significantly reduced mortality, shifting the course of HIV infection to a chronic illness. However, this is associated with an increased incidence of comorbid conditions, including type 2 diabetes mellitus, insulin resistance, and cardiovascular complications. Using a nonhuman primate model of simian immunodeficiency virus (SIV) infection, previous studies have demonstrated that chronic binge alcohol (CBA) administration decreases whole body insulin responsiveness, irrespective of ART administration. The objective of the current study was to determine the effects of CBA and ART on insulin-sensitive peripheral tissues before the development of overt clinical symptoms of SIV disease. Our results show that CBA reduced omental adipocyte cell size, increased collagen expression, and decreased the in vitro differentiation potential of adipose-derived stem cells. In contrast, it did not alter skeletal muscle or omental or hepatic expression of insulin signaling proteins. However, ART significantly decreased skeletal muscle expression of phosphatase and tensin homolog, total mechanistic target of rapamycin, and ribosomal protein S6. In addition, ART increased hepatic phosphorylation of AMP-activated protein kinase α and increased gene expression of key enzymes required for gluconeogenesis and fatty acid synthesis. These findings suggest that CBA and ART differentially promote adverse metabolic effects in an organ-specific manner that may underlie insulin resistance associated with alcohol, SIV, and ART. Whether this is translated in PLWH with AUD remains to be determined.