Don Hayes

Azithromycin alters macrophage phenotype

OBJECTIVES To investigate the in vitro effects of azithromycin on macrophage phenotype. Utilizing a mouse macrophage cell line (J774), we examined the effect of azithromycin on the properties that define classical macrophage activation (M1) and alternative macrophage activation (M2). METHODS J774 cells were cultured in the presence of azithromycin and stimulated with classical activation [interferon-gamma (IFNgamma)] and alternative activation [interleukin (IL)-4 and IL-13] cytokines along with lipopolysaccharide (LPS). Macrophages were analysed for inflammatory cytokine production, surface receptor expression, inducible nitric oxide synthase (iNOS) protein expression and arginase activity. RESULTS Azithromycin altered the overall macrophage phenotype. Azithromycin-treated J774 macrophages demonstrated a significantly reduced production of the pro-inflammatory cytokines IL-12 and IL-6, increased production of the anti-inflammatory cytokine IL-10 and decreased the ratio of IL-12 to IL-10 by 60%. Receptor expression indicative of the M2 phenotype (mannose receptor and CD23) was increased, and receptor expression typically up-regulated in M1 cells (CCR7) was inhibited. The presence of azithromycin increased arginase (M2 effector molecule) activity 10-fold in cells stimulated with IFNgamma and LPS, and iNOS protein (M1 effector molecule) concentrations were attenuated by the drug. CONCLUSIONS These data provide evidence that azithromycin affects the inflammatory process at the level of the macrophage and shifts macrophage polarization towards the alternatively activated phenotype. This recently defined M2 phenotype has been described in conditions in which pulmonary inflammation and fibrosis are major determinants of clinical outcome, but the concept of antibiotics altering macrophage phenotype has not yet been critically evaluated.

Therapeutic Liposomal Dry Powder Inhalation Aerosols for Targeted Lung Delivery

Therapeutic liposomal powders (i.e., lipospheres and proliposomes) for dry powder inhalation aerosol delivery, formulated with phospholipids similar to endogenous lung surfactant, offer unique opportunities in pulmonary nanomedicine while offering controlled release and enhanced stability. Many pulmonary diseases such as lung cancer, tuberculosis (TB), cystic fibrosis (CF), bacterial and fungal lung infections, asthma, and chronic obstructive pulmonary disease (COPD) could greatly benefit from this type of pulmonary nanomedicine approach that can be delivered in a targeted manner by dry powder inhalers (DPIs). These delivery systems may require smaller doses for efficacy, exhibit reduced toxicity, fewer side effects, controlled drug release over a prolonged time period, and increased formulation stability as inhaled powders. This state-of-the-art review presents these novel aspects in depth.

Ambulatory venovenous extracorporeal respiratory support as a bridge for cystic fibrosis patients to emergent lung transplantation

Venovenous extracorporeal membrane oxygenation (VV ECMO) is a therapeutic option to bridge patients with advanced lung disease to lung transplantation. The use of VV ECMO avoids the use of mechanical ventilation while allowing patients to participate in physical therapy and to eat normally while receiving respiratory support. We describe the successful use of ambulatory single-venous VV ECMO as a bridge to bilateral lung transplantation in 4 patients with end-stage lung disease due to cystic fibrosis who developed acute hypercapnic respiratory failure. The use of ambulatory single-venous VV ECMO was safe and effective in this small cohort of CF patients. Based on our experiences, our belief is that a key step in the treatment course was early application of VV ECMO soon after development of acute respiratory failure requiring mechanical ventilation.

Impaired Vascular Regulation in Patients with Obstructive Sleep Apnea: Effects of Continuous Positive Airway Pressure Treatment

RATIONALE Impaired endothelium-dependent vasodilation has been documented in patients with sleep apnea. This impairment may result in blood flow dysregulation during apnea-induced fluctuations in arterial blood gases. OBJECTIVES To test the hypothesis that hypoxic and hypercapnic vasodilation in the forearm and cerebral circulation are impaired in patients with sleep apnea. METHODS We exposed 20 patients with moderate to severe sleep apnea and 20 control subjects, to isocapnic hypoxia and hyperoxic hypercapnia. A subset of 14 patients was restudied after treatment with continuous positive airway pressure. MEASUREMENTS AND MAIN RESULTS Cerebral flow velocity (transcranial Doppler), forearm blood flow (venous occlusion plethysmography), arterial pressure (automated sphygmomanometry), oxygen saturation (pulse oximetry), ventilation (pneumotachograph), and end-tidal oxygen and carbon dioxide tensions (expired gas analysis) were measured during three levels of hypoxia and two levels of hypercapnia. Cerebral vasodilator responses to hypoxia (-0.65 +/- 0.44 vs. -1.02 +/- 0.72 [mean +/- SD] units/% saturation; P = 0.03) and hypercapnia (2.01 +/- 0.88 vs. 2.57 +/- 0.89 units/mm Hg; P = 0.03) were smaller in patients versus control subjects. Hypoxic vasodilation in the forearm was also attenuated (-0.05 +/- 0.09 vs. -0.10 +/- 0.09 unit/% saturation; P = 0.04). Hypercapnia did not elicit forearm vasodilation in either group. Twelve weeks of continuous positive airway pressure treatment enhanced hypoxic vasodilation in the cerebral circulation (-0.83 +/- 0.32 vs. -0.46 +/- 0.29 units/% saturation; P = 0.01) and forearm (-0.19 +/- 0.15 vs. -0.02 +/- 0.08 units/% saturation; P = 0.003), and hypercapnic vasodilation in the brain showed a trend toward improvement (2.24 +/- 0.78 vs. 1.76 +/- 0.64 units/mm Hg; P = 0.06). CONCLUSIONS Vasodilator responses to chemical stimuli in the cerebral circulation and the forearm are impaired in many patients with obstructive sleep apnea. Some of these impairments can be improved with continuous positive airway pressure.

Antibody-mediated rejection of the lung: A consensus report of the International Society for Heart and Lung Transplantation

Antibody-mediated rejection (AMR) is a recognized cause of allograft dysfunction in lung transplant recipients. Unlike AMR in other solid-organ transplant recipients, there are no standardized diagnostic criteria or an agreed-upon definition. Hence, a working group was created by the International Society for Heart and Lung Transplantation with the aim of determining criteria for pulmonary AMR and establishing a definition. Diagnostic criteria and a working consensus definition were established. Key diagnostic criteria include the presence of antibodies directed toward donor human leukocyte antigens and characteristic lung histology with or without evidence of complement 4d within the graft. Exclusion of other causes of allograft dysfunction increases confidence in the diagnosis but is not essential. Pulmonary AMR may be clinical (allograft dysfunction which can be asymptomatic) or sub-clinical (normal allograft function). This consensus definition will have clinical, therapeutic and research implications.

Noninvasive optical evaluation of spontaneous low frequency oscillations in cerebral hemodynamics

Spontaneous low frequency oscillations (LFOs) around 0.1 Hz have been observed in mean arterial pressure (MAP) and cerebral blood flow velocity (CBFV). Previous studies have shown that cerebral autoregulation in major arteries can be assessed by quantification of the phase shift between LFOs of MAP and CBFV. However, many cerebral diseases are associated with abnormal microvasculature and tissue dysfunction in brain, and quantification of these abnormalities requires direct measurement of cerebral tissue hemodynamics. This pilot study used a novel hybrid near-infrared diffuse optical instrument to noninvasively and simultaneously detect LFOs of cerebral blood flow (CBF) and cerebral oxygenation (i.e., oxygenated/deoxygenated/total hemoglobin concentration: [HbO(2)]/[Hb]/THC) in human prefrontal cortex. Using the hybrid instrument and a finger plethysmograph, the dynamic changes of CBF, [HbO(2)], [Hb], THC and MAP were concurrently measured in 15 healthy subjects at rest, during 70° head-up-tilting (HUT) and during enforced breathing at 0.1 Hz. The LFOs were extracted from the measured variables using power spectral analysis, and the phase shifts and coherences of LFOs between MAP and each of the measured hemodynamic variables were calculated from the corresponding transfer functions. Levels of coherence (>0.4) were used to judge the success of LFO measurements. We found that CBF, [HbO(2)] and THC were reliable hemodynamic parameters in detecting LFOs and HUT was the most robust and stable protocol for quantifying phase shifts of hemodynamic LFOs. Comparing with other relevant studies, similar success rates for detecting cerebral LFOs have been achieved in our study. The phase shifts of LFOs in CBF were also close to those in CBFV reported by other groups, although the results in cerebral oxygenation measurements during enforced breathing varied across studies. Future study will investigate cerebral LFOs in patients with cerebral impairment and evaluate their cerebral autoregulation capabilities and neurocognitive functions via the quantification of LFO phase shifts.

Respiratory syncytial virus: current and emerging treatment options

Respiratory syncytial virus (RSV) is an important respiratory pathogen in infants and children worldwide. Although RSV typically causes mild upper respiratory infections, it frequently causes severe morbidity and mortality, especially in premature infants and children with other chronic diseases. Treatment of RSV is limited by a lack of effective antiviral treatments; however, ribavirin has been used in complicated cases, along with the addition of intravenous immune globulin in specific patients. Vaccination strategies for RSV prevention are heavily studied, but only palivizumab (Synagis®) has been approved for use in the United States in very select patient populations. Research is ongoing in developing additional vaccines, along with alternative therapies that may help prevent or decrease the severity of RSV infections in infants and children. To date, we have not seen a decrement in RSV morbidity and mortality with our current options; therefore, there is a clear need for novel RSV preventative and therapeutic strategies. In this review, we discuss the current and evolving trends in RSV treatment for infants and children.

Obstructive sleep apnea: the new cardiovascular disease. Part I: obstructive sleep apnea and the pathogenesis of vascular disease

Obstructive sleep apnea (OSA) is increasingly recognized as a novel cardiovascular risk factor. OSA is implicated in the pathogenesis of hypertension, left ventricular dysfunction, coronary artery disease and stroke. OSA exerts its negative cardiovascular consequences through its unique pattern of intermittent hypoxia. Endothelial dysfunction, oxidative stress, and inflammation are all consequences of OSA directly linked to intermittent hypoxia and critical pathways in the pathogenesis of cardiovascular disease in patients with OSA. This review will discuss the known mechanisms of vascular dysfunction in patients with OSA and their implications for cardiovascular disease.

Use of azithromycin for the prevention of bronchopulmonary dysplasia in preterm infants: a randomized, double‐blind, placebo controlled trial

Since preventive therapies for bronchopulmonary dysplasia (BPD) are limited we treated preterm infants with azithromycin to decrease the incidence of BPD.

Azithromycin Alters Macrophage Phenotype and Pulmonary Compartmentalization during Lung Infection with Pseudomonas

ABSTRACT Infection with mucoid strains of Pseudomonas aeruginosa in chronic inflammatory diseases of the airway is difficult to eradicate and can cause excessive inflammation. The roles of alternatively activated and regulatory subsets of macrophages in this pathophysiological process are not well characterized. We previously demonstrated that azithromycin induces an alternatively activated macrophage-like phenotype in vitro. In the present study, we tested whether azithromycin affects the macrophage activation status and migration in the lungs of P. aeruginosa-infected mice. C57BL/6 mice received daily doses of oral azithromycin and were infected intratracheally with a mucoid strain of P. aeruginosa. The properties of macrophage activation, immune cell infiltration, and markers of pulmonary inflammation in the lung interstitial and alveolar compartments were evaluated postinfection. Markers of alternative macrophage activation were induced by azithromycin treatment, including the surface expression of the mannose receptor, the upregulation of arginase 1, and a decrease in the production of proinflammatory cytokines. Additionally, azithromycin increased the number of CD11b+ monocytes and CD4+ T cells that infiltrated the alveolar compartment. A predominant subset of CD11b+ cells was Gr-1 positive (Gr-1+), indicative of a subset of cells that has been shown to be immunoregulatory. These differences corresponded to decreases in neutrophil influx into the lung parenchyma and alteration of the characteristics of peribronchiolar inflammation without any change in the clearance of the organism. These results suggest that the immunomodulatory effects of azithromycin are associated with the induction of alternative and regulatory macrophage activation characteristics and alteration of cellular compartmentalization during infection.