Pharmacological considerations in human immunodeficiency virus-infected adults in the intensive care unit.

According to estimates, 1.2 million Americans are infected with human immuno deficiency virus (HIV). Because of antiretroviral therapy, persons who have HIV infection or have progressed to AIDS are living longer. As a result, the likelihood that they will need critical care nursing is increasing. Unlike in years past, when these patients were often admitted because of the consequences of immunosuppression, today they are also being cared for in critical care units for other conditions associated with aging, other chronic health conditions, and trauma. When persons who have HIV disease or AIDS are admitted to the intensive care unit, nurses must be prepared to provide care, especially management of complexities associated with antiretroviral therapy. Therefore, this article examines critical care nurses' role in initiating and administering antiretroviral therapy in the intensive care unit and reducing the risk of drug interactions associated with the therapy.

Sustained generation of nitric oxide and control of mycobacterial infection requires argininosuccinate synthase 1.

Nitric oxide (NO) defends against intracellular pathogens, but its synthesis must be regulated due to cell and tissue toxicity. During infection, macrophages import extracellular arginine to synthesize NO, generating the byproduct citrulline. Accumulated intracellular citrulline is thought to fuel arginine synthesis catalyzed by argininosuccinate synthase (Ass1) and argininosuccinate lyase (Asl), which would lead to abundant NO production. Instead, we find that citrulline is exported from macrophages during early stages of NO production with <2% retained for recycling via the Ass1-Asl pathway. Later, extracellular arginine is depleted, and Ass1 expression allows macrophages to synthesize arginine from imported citrulline to sustain NO output. Ass1-deficient macrophages fail to salvage citrulline in arginine-scarce conditions, leading to their inability to control mycobacteria infection. Thus, extracellular arginine fuels rapid NO production in activated macrophages, and citrulline recycling via Ass1 and Asl is a fail-safe system that sustains optimum NO production.

Arginine usage in mycobacteria-infected macrophages depends on autocrine-paracrine cytokine signaling.

Nitric oxide (NO) produced by macrophages is toxic to host tissues and invading pathogens, and its regulation is essential to suppress host cytotoxicity. Macrophage arginase 1 (Arg1) competes with NO synthases for arginine, a substrate common to both types of enzymes, to inhibit NO production. Two signal transduction pathways control the production of Arg1 in macrophages: One pathway dependent on the Toll-like receptor adaptor protein myeloid differentiation marker 88 (MyD88) induces the expression of Arg1 during intracellular infections, whereas another pathway, which depends on signal transducer and activator of transcription 6 (STAT6), is required for Arg1 expression in alternatively activated macrophages. We found that mycobacteria-infected macrophages produced soluble factors, including interleukin-6 (IL-6), IL-10, and granulocyte colony-stimulating factor (G-CSF), that induced expression of Arg1 in an autocrine-paracrine manner. Arg1 expression was controlled by the MyD88-dependent production of these cytokines rather than by cell-intrinsic MyD88 signaling to Arg1. Our study revealed that the MyD88-dependent pathway that induced the expression of Arg1 after infection by mycobacteria required STAT3 activation and that this pathway may cause the development of an immunosuppressive niche in granulomas because of the induced production of Arg1 in surrounding uninfected macrophages.

Modulation of adaptive immunity by different adjuvant-antigen combinations in mice lacking Nod2.

The mechanisms underlying adjuvant effects are under renewed scrutiny because of the enormous implications for vaccine development. Additionally, new low-toxicity adjuvants are sought to enhance vaccine formulations. Muramyl dipeptide (MDP) is a component of the peptidoglycan polymer and was shown to be an active but low-toxicity component of complete Freund's adjuvant, a powerful adjuvant composed of mycobacteria lysates in an oil emulsion. MDP activates cells primarily via the cytosolic NLR family member Nod2 and is therefore linked to the ability of adjuvants to enhance antibody production. Accordingly, we tested the adjuvant properties of the MDP-Nod2 pathway. We found that MDP, compared to the TLR agonist lipopolysaccharide, has minimal adjuvant properties for antibody production under a variety of immunization conditions. We also observed that the oil emulsion incomplete Freund's adjuvant (IFA) supplanted the requirements for the TLR pathway independent of the antigen. Surprisingly, we observed that Nod2 was required for an optimal IgG1 and IgG2c response in the absence of exogenous TLR or NLR agonists. Collectively, our results argue that oil emulsions deserve greater attention for their immunostimulatory properties.