Endogenous LXR signaling controls pulmonary surfactant homeostasis and prevents lung inflammation.

Lung type 2 pneumocytes (T2Ps) and alveolar macrophages (AMs) play crucial roles in the synthesis, recycling and catabolism of surfactant material, a lipid/protein fluid essential for respiratory function. The liver X receptors (LXR), LXRα and LXRß, are transcription factors important for lipid metabolism and inflammation. While LXR activation exerts anti-inflammatory actions in lung injury caused by lipopolysaccharide (LPS) and other inflammatory stimuli, the full extent of the endogenous LXR transcriptional activity in pulmonary homeostasis is incompletely understood. Here, using mice lacking LXRα and LXRß as experimental models, we describe how the loss of LXRs causes pulmonary lipidosis, pulmonary congestion, fibrosis and chronic inflammation due to defective de novo synthesis and recycling of surfactant material by T2Ps and defective phagocytosis and degradation of excess surfactant by AMs. LXR-deficient T2Ps display aberrant lamellar bodies and decreased expression of genes encoding for surfactant proteins and enzymes involved in cholesterol, fatty acids, and phospholipid metabolism. Moreover, LXR-deficient lungs accumulate foamy AMs with aberrant expression of cholesterol and phospholipid metabolism genes. Using a house dust mite aeroallergen-induced mouse model of asthma, we show that LXR-deficient mice exhibit a more pronounced airway reactivity to a methacholine challenge and greater pulmonary infiltration, indicating an altered physiology of LXR-deficient lungs. Moreover, pretreatment with LXR agonists ameliorated the airway reactivity in WT mice sensitized to house dust mite extracts, confirming that LXR plays an important role in lung physiology and suggesting that agonist pharmacology could be used to treat inflammatory lung diseases.

Astrocytes: Role in pathogenesis and effect of commonly misused drugs in the HIV infected brain.

The roles of astrocytes as reservoirs and producers of a subset of viral proteins in the HIV infected brain have been studied extensively as a key to understanding HIV-associated neurocognitive disorders (HAND). However, their comprehensive role in the context of intersecting substance use and neurocircuitry of the reward pathway and HAND has yet to be fully explained. Use of methamphetamines, cocaine, or opioids in the context of HIV infection have been shown to lead to a faster progression of HAND. Glutamatergic, dopaminergic, and GABAergic systems are implicated in the development of HAND-induced cognitive impairments. A thorough review of scientific literature exploring the variety of mechanisms in which these drugs exert their effects on the HIV brain and astrocytes has revealed marked areas of convergence in overexcitation leading to increased drug-seeking behavior, inflammation, apoptosis, and irreversible neurotoxicity. The present review investigates astrocytes, the neural pathways, and mechanisms of drug disruption that ultimately play a larger holistic role in terms of HIV progression and drug use. There are opportunities for future research, therapeutic intervention, and preventive strategies to diminish HAND in the subset population of patients with HIV and substance use disorder.

Complement Factor H and Apolipoprotein E Participate in Regulation of Inflammation in THP-1 Macrophages.

The alternative pathway (AP) of complement is constantly active in plasma and can easily be activated on self surfaces and trigger local inflammation. Host cells are protected from AP attack by Factor H (FH), the main AP regulator in plasma. Although complement is known to play a role in atherosclerosis, the mechanisms of its contribution are not fully understood. Since FH via its domains 5-7 binds apoliporotein E (apoE) and macrophages produce apoE we examined how FH could be involved in the antiatherogenic effects of apoE. We used blood peripheral monocytes and THP-1 monocyte/macrophage cells which were also loaded with acetylated low-density lipoprotein (LDL) to form foam cells. Binding of FH and apoE on these cells was analyzed by flow cytometry. High-density lipoprotein (HDL)-mediated cholesterol efflux of activated THP-1 cells was measured and transcriptomes of THP-1 cells using mRNA sequencing were determined. We found that binding of FH to human blood monocytes and cholesterol-loaded THP-1 macrophages increased apoE binding to these cells. Preincubation of fluorescent cholesterol labeled THP-1 macrophages in the presence of FH increased cholesterol efflux and cholesterol-loaded macrophages displayed reduced transcription of proinflammatory/proatherogenic factors and increased transcription of anti-inflammatory/anti-atherogenic factors. Further incubation of THP-1 cells with serum reduced C3b/iC3b deposition. Overall, our data indicate that apoE and FH interact with monocytic cells in a concerted action and this interaction reduces complement activation and inflammation in the atherosclerotic lesions. By this way FH may participate in mediating the beneficial effects of apoE in suppressing atherosclerotic lesion progression.

Presión inspiratoria nasal: ¿una alternativa para la evaluación de la fuerza muscular inspiratoria? / Nasal inspiratory pressure: an alternative for the assessment of inspiratory muscle strength?

Introducción: La fuerza de los músculos inspiratorios se evalúa habitualmente en la clínica a través de ladeterminación de la presión estática máxima en boca (PIM). Sin embargo, esta maniobra presenta algunosproblemas, por lo que en los últimos años se han desarrollado diferentes alternativas como la mediciónde la presión inhalatoria nasal máxima (SNIP).Objetivo: Evaluar la determinación de SNIP como alternativa para la evaluación de la fuerza muscularinspiratoria.Método: Sujetos incluidos consecutivamente en tres grupos: control (8), EPOC (23) y neuromuscular(21). Se determinaron diferentes presiones inspiratorias máximas: (a) dinámica en esófago (sniffPesmáx,variable de referencia), (b) PIM, y (c) SNIP.Resultados: SNIP y PIM mostraron una buena correlación con sniffPesmáx (r = 0,835 y 0,752, respectivamente,en los controles, p < 0,05 ambas). La correlación intraclase SNIP/sniffPesmáx fue de 0,585 (IC95%: -0,097 a 0,901) en los controles, 0,569 (IC 95%: -0,048 a 0,836) en EPOC, y 0,840 (IC 95%: 0,459 a0,943) en enfermos neuromusculares. Estos valores fueron respectivamente de 0,602 (IC 95%: -0,108 a0,933), 0,418 (IC 95%: -0,108 a 0,761), y 0,712 (IC 95%: 0,378 a 0,882) para PIM/sniffPesmáx. La SNIP yla PIM mostraron una sensibilidad del 100% en los 3 grupos mencionados, aunque la especificidad erarespectivamente del 100, 69 y 75% para la SNIP, y 83, 54 y 75%, para la PIM.Conclusiones: La SNIP constituye un buen reflejo de la fuerza muscular inspiratoria. Probablemente supapel en la clínica sea complementario al de la PIM(AU)

Introduction: The strength of inspiratory muscles is assessed thorough the determination of the staticmouth pressure (MIP). However, since this manoeuvre has some problems, alternative techniques havebeen developed in the last few years. One of the most promising is determination of sniff nasal inspiratorypressure (SNIP).Aim: To evaluate SNIP assessment as an alternative for the evaluation of the maximal inspiratory musclestrength.Methods: Subjects were consecutively included and assigned to one of three different groups: control(8), COPD patients (23) and patients with neuromuscular disorders (21). Different maximal inspiratorypressures were determined: (a) dynamic at the esophagus (sniffPesmáx, reference variable), (b) MIP, and(c) SNIP.Results: Both SNIP and MIP showed an excellent correlation with the reference variable, sniffPesmáx(r=0.835 and 0.752, respectively, P<0.05 for both). SNIP/sniffPesmáx intra-class correlation coefficientswere 0.585 (CI 95%: -0.097 to 0.901) in controls, 0.569 (CI 95%: -0.048 to 0.836) inCOPDpatients, and 0.840 (CI 95%: 0.459 to 0.943) in neuromuscular disorders, respectively. For MIP/sniffPesmáx these values were0.602 CI 95%: -0.108 to 0.933), 0.418 (CI 95%: -0.108 to 0.761), and 0.712 (CI 95%:, 0.378 a 0.882). Moreover,both SNIP and MIP showed 100% sensitivity in the three groups of subjects, although specificities were100%, 69% and 75% for SNIP, and 83%, 54% and 75% for MIP, respectively.Conclusions: SNIP is a good physiological marker of inspiratory muscle strength. Its role is likely tocomplement that of MIP(AU)

Nasal inspiratory pressure: an alternative for the assessment of inspiratory muscle strength?

INTRODUCTION: Inspiratory muscle strength is usually assessed thorough the determination of static mouth pressure (PImax). However, since this manoeuvre presents certain problems, alternative techniques have been developed over the last few years. One of the most promising is determination of sniff nasal inspiratory pressure (SNIP). AIM: To evaluate SNIP assessment as an alternative for the evaluation of the inspiratory muscle strength. METHODS: Subjects were consecutively included and assigned to one of three different groups: control (8), COPD patients (23) and patients with neuromuscular disorders (21). Different maximal inspiratory pressures were determined: (a) dynamic in the esophagus (maximal sniff Pes, reference variable), (b) PImax, and (c) SNIP. RESULTS: Both SNIP and MIP showed an excellent correlation with Pes (r=0.835 and 0.752, respectively, P<0.05 for both). SNIP/Pes intra-class correlation coefficients were 0.585 (CI 95%: −0.097 to 0.901) in controls, 0.569 (CI 95%: −0.048 to 0.836) in COPD patients, and 0.840 (CI 95%: 0.459 to 0.943) in neuromuscular disorders, respectively. For PImax/Pes, these values were 0.602 CI 95%: −0.108 to 0.933), 0.418 (CI 95%: −0.108 to 0.761), and 0.712 (CI 95%: 0.378 a 0.882). Moreover, both SNIP and PImax showed 100% sensitivity in the three groups of subjects, although specificities were 100%, 69% and 75% for SNIP, and 83%, 54% and 75% for PImax, respectively. CONCLUSIONS: SNIP is a good physiological marker of inspiratory muscle strength. Its role is likely to complement that of PImax.