The gut microbiome participates in numerous physiologic functions and communicates intimately with the host immune system. Antimicrobial peptides are critical components of intestinal innate immunity. We report a prominent role for antimicrobials secreted by pancreatic acinari in shaping the gut microbiome that is essential for intestinal innate immunity, barrier function, and survival. Deletion of the Ca2+ channel Orai1 in pancreatic acini of adult mice resulted in 60–70% mortality within three weeks. Despite robust activation of the intestinal innate immune response, mice lacking acinar Orai1 exhibited intestinal bacterial outgrowth and dysbiosis, ultimately causing systemic translocation, inflammation, and death. While digestive enzyme supplementation was ineffective, treatments constraining bacterial outgrowth (purified liquid diet, broad-spectrum antibiotics), rescued survival, feeding, and weight gain. Pancreatic levels of cathelicidin-related antimicrobial peptide (CRAMP) were reduced, and supplement of synthetic CRAMP prevented intestinal disease. These findings reveal a critical role for antimicrobial pancreatic secretion in gut innate immunity.
Chemically modified hemoglobin (Hb) solutions are promising oxygen therapeutics; however, these agents are prone to intravascular oxidation. Using a 50% exchange transfusion (ET) model with bovine polymerized hemoglobin (PolyHbBv), we examined heme oxidation, oxygenation markers, and toxicokinetics in rats, an ascorbic acid (AA)-producing species, and in guinea pigs, a non-AA-producing species. Plasma AA decreased by 50% in guinea pigs after ET, but it was unchanged in rats for the first 20 h post-ET. Both species cleared PolyHbBv from the circulation at similar rates. However, exposure to ferric PolyHbBv over time was 5-fold greater in the guinea pig. Mass spectrometry analysis of plasma revealed oxidative modifications within the tetrameric fraction of PolyHbBv in guinea pig. Oxygen equilibrium curves of PolyHbBv measured in plasma after ET were more left-shifted in guinea pigs compared with rats, consistent with increased ferric PolyHbBv formation. Renal hypoxia-inducible factor (HIF)-1␣, whose activity strictly depends on the partial pressure of oxygen increased over time, and it correlated inversely with circulating ferrous PolyHbBv in both species. Interestingly, HIF-1␣ activity was greater in guinea pigs compared with rats at 72 h post-ET. Mean arterial pressure increases were also greater in guinea pigs; however, minimal differences in cardiac and renal pathology were observed in either species. The present findings suggest the importance of plasma AA in maintaining the stability of acellular Hb susceptible to oxidation, and they may be relevant to humans, which display a similar plasma/tissue antioxidant status to guinea pig.Hemoglobin (Hb)-based oxygen carriers (HBOCs) represent a class of complex biological entities being developed as oxygen-bridging agents with volume-expanding properties. Despite their therapeutic promise, HBOCs demonstrate a significant potential for toxicity based on administration of large quantities of Hb into the plasma compartment. Normally Hb remains protected in the red blood cell, where processes exist to reduce oxidized Hb and to modulate nitric oxide (NO) binding. It has become increasingly evident that Hb oxidative toxicity can limit the safety and efficacy of current generation HBOCs (Alayash, 2004). This prompted the design of new strategies aimed at reducing or controlling Hb-oxidative side reactions. In vivo oxidation of cell-free Hb is driven spontaneously and/or chemically by variety of oxidants, including hydrogen peroxide (H 2 O 2 ) and NO. NOinduced oxidation of heme iron has the added complication of producing an immediate elevation in blood pressure as a result of removal of NO (a vasodilator) by Hb. Thus, two primary safety concerns with HBOCs in the extracellular space include hypertension and oxidative stress (Riess, 2001;Alayash, 2004). The latter effect depends on plasma and tissue reductive capacity to maintain the HBOC in a reduced and functional state.HBOCs have generally demonstrated promising safety and efficacy in animals, and, in many cases...
A new pathogenic R5-tropic simian/human immunodeficiency virus (SHIV) was generated following serial passaging in rhesus macaques. All 13 animals inoculated with SHIV AD8 passaged lineages experienced marked depletions of CD4 ؉ T cells. Ten of these infected monkeys became normal progressors (NPs) and had gradual losses of both memory and naïve CD4 ؉ T lymphocytes, generated antiviral CD4 ؉ and CD8 ؉ T cell responses, and sustained chronic immune activation while maintaining variable levels of plasma viremia (10 2 to 10 5 RNA copies/ml for up to 3 years postinfection [p.
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