Phillip Factor

Inflammation, Oxidative Stress, and Repair Capacity of the Vascular Endothelium in Obstructive Sleep Apnea

Background— Indirect evidence implicates endothelial dysfunction in the pathogenesis of vascular diseases associated with obstructive sleep apnea (OSA). We investigated directly whether dysfunction and inflammation occur in vivo in the vascular endothelium of patients with OSA. The effects of continuous positive airway pressure (CPAP) therapy on endothelial function and repair capacity were assessed. Methods and Results— Thirty-two patients with newly diagnosed OSA and 15 control subjects were studied. Proteins that regulate basal endothelial nitric oxide (NO) production (endothelial NO synthase [eNOS] and phosphorylated eNOS) and inflammation (cyclooxygenase-2 and inducible NOS) and markers of oxidative stress (nitrotyrosine) were quantified by immunofluorescence in freshly harvested venous endothelial cells before and after 4 weeks of CPAP therapy. Vascular reactivity was measured by flow-mediated dilation. Circulating endothelial progenitor cell levels were quantified to assess endothelial repair capacity. Baseline endothelial expression of eNOS and phosphorylated eNOS was reduced by 59% and 94%, respectively, in patients with OSA compared with control subjects. Expression of both nitrotyrosine and cyclooxygenase-2 was 5-fold greater in patients with OSA than in control subjects, whereas inducible NOS expression was 56% greater. Expression of eNOS and phosphorylated eNOS significantly increased, whereas expression of nitrotyrosine, cyclooxygenase-2, and inducible NOS significantly decreased in patients who adhered to CPAP ≥4 hours daily. Baseline flow-mediated dilation and endothelial progenitor cell levels were lower in patients than in control subjects, and both significantly increased in patients who adhered to CPAP ≥4 hours daily. Conclusions— OSA directly affects the vascular endothelium by promoting inflammation and oxidative stress while decreasing NO availability and repair capacity. Effective CPAP therapy is associated with the reversal of these alterations.

Upregulation of Alveolar Epithelial Active Na+ Transport Is Dependent on β2-Adrenergic Receptor Signaling

Abstract— Alveolar epithelial β-adrenergic receptor (βAR) activation accelerates active Na+ transport in lung epithelial cells in vitro and speeds alveolar edema resolution in human lung tissue and normal and injured animal lungs. Whether these receptors are essential for alveolar fluid clearance (AFC) or if other mechanisms are sufficient to regulate active transport is unknown. In this study, we report that mice with no β1- or β2-adrenergic receptors (β1AR−/−/β2AR−/−) have reduced distal lung Na,K-ATPase function and diminished basal and amiloride-sensitive AFC. Total lung water content in these animals was not different from wild-type controls, suggesting that βAR signaling may not be required for alveolar fluid homeostasis in uninjured lungs. Comparison of isoproterenol-sensitive AFC in mice with β1- but not β2-adrenergic receptors to β1AR−/−/β2AR−/− mice indicates that the β2AR mediates the bulk of β-adrenergic–sensitive alveolar active Na+ transport. To test the necessity of βAR signaling in acute lung injury, β1AR−/−/β2AR−/−, β1AR+/+/β2AR−/−, and β1AR+/+/β2AR+/+ mice were exposed to 100% oxygen for up to 204 hours. β1AR−/−/β2AR−/− and β1AR+/+/β2AR−/− mice had more lung water and worse survival from this form of acute lung injury than wild-type controls. Adenoviral-mediated rescue of β2-adrenergic receptor (β2AR) function into the alveolar epithelium of β1AR−/−/β2AR−/− and β1AR+/+/β2AR−/− mice normalized distal lung β2AR function, alveolar epithelial active Na+ transport, and survival from hyperoxia. These findings indicate that βAR signaling may not be necessary for basal AFC, and that β2AR is essential for the adaptive physiological response needed to clear excess fluid from the alveolar airspace of normal and injured lungs.

Adenovirus-mediated transfer of an Na+/K+ -ATPase β1 subunit gene improves alveolar fluid clearance and survival in hyperoxic rats

Pulmonary edema is cleared via active Na(+) transport by alveolar epithelial Na(+)/K(+)-ATPases and Na(+) channels. Rats exposed to acute hyperoxia have a high mortality rate, decreased Na(+)/K(+)-ATPase function, and decreased alveolar fluid clearance (AFC). We hypothesized that Na(+)/K(+)-ATPase subunit gene overexpression could improve AFC in rats exposed to hyperoxia. We delivered 4 x 10(9) PFU of recombinant adenoviruses containing rat alpha(1) and beta(1) Na(+)/K(+)-ATPase subunit cDNAs (adalpha(1) and adbeta(1), respectively) to rat lungs 7 days prior to exposure to 100% O(2) for 64 hr. As compared with controls and ad alpha(1), AFC in the adbeta(1) rats was increased by >300%. Permeability for large solutes was less in the ad beta(1) than in the other hyperoxia groups. Glutathione oxidation, but not superoxide dismutase activity, was increased only in the adbeta(1) group. Survival through 14 days of hyperoxia was 100% in the adbeta(1) group but was not different from hyperoxic controls in animals given adalpha(1). Our data show that overexpression of a beta(1) Na(+)/K(+)-ATPase subunit augments AFC and improves survival in this model of acute lung injury via antioxidant-independent mechanisms. Conceivably, restoration of AFC via gene transfer of Na(+)/K(+)-ATPase subunit genes may prove useful for the treatment of acute lung injury and pulmonary edema.

Adenosine regulation of alveolar fluid clearance

Adenosine is a purine nucleoside that regulates cell function through G protein-coupled receptors that activate or inhibit adenylyl cyclase. Based on the understanding that cAMP regulates alveolar epithelial active Na+ transport, we hypothesized that adenosine and its receptors have the potential to regulate alveolar ion transport and airspace fluid content. Herein, we report that type 1 (A1R), 2a (A2aR), 2b (A2bR), and 3 (A3R) adenosine receptors are present in rat and mouse lungs and alveolar type 1 and 2 epithelial cells (AT1 and AT2). Rat AT2 cells generated and produced cAMP in response to adenosine, and micromolar concentrations of adenosine were measured in bronchoalveolar lavage fluid from mice. Ussing chamber studies of rat AT2 cells indicated that adenosine affects ion transport through engagement of A1R, A2aR, and/or A3R through a mechanism that increases CFTR and amiloride-sensitive channel function. Intratracheal instillation of low concentrations of adenosine (≤10−8M) or either A2aR- or A3R-specific agonists increased alveolar fluid clearance (AFC), whereas physiologic concentrations of adenosine (≥10−6M) reduced AFC in mice and rats via an A1R-dependent pathway. Instillation of a CFTR inhibitor (CFTRinh-172) attenuated adenosine-mediated down-regulation of AFC, suggesting that adenosine causes Cl− efflux by means of CFTR. These studies report a role for adenosine in regulation of alveolar ion transport and fluid clearance. These findings suggest that physiologic concentrations of adenosine allow the alveolar epithelium to counterbalance active Na+ absorption with Cl− efflux through engagement of the A1R and raise the possibility that adenosine receptor ligands can be used to treat pulmonary edema.

Interdependency of β-Adrenergic Receptors and CFTR in Regulation of Alveolar Active Na+ Transport

&bgr;-Adrenergic receptors (&bgr;AR) regulate active Na+ transport in the alveolar epithelium and accelerate clearance of excess airspace fluid. Accumulating data indicates that the cystic fibrosis transmembrane conductance regulator (CFTR) is important for upregulation of the active ion transport that is needed to maintain alveolar fluid homeostasis during pulmonary edema. We hypothesized that &bgr;AR regulation of alveolar active transport may be mediated via a CFTR dependent pathway. To test this hypothesis we used a recombinant adenovirus that expresses a human CFTR cDNA (adCFTR) to increase CFTR function in the alveolar epithelium of normal rats and mice. Alveolar fluid clearance (AFC), an index of alveolar active Na+ transport, was 92% greater in CFTR overexpressing lungs than controls. Addition of the Cl− channel blockers NPPB, glibenclamide, or bumetanide and experiments using Cl− free alveolar instillate solutions indicate that the accelerated AFC in this model is due to increased Cl− channel function. Conversely, CFTR overexpression in mice with no &bgr;1- or &bgr;2-adrenergic receptors had no effect on AFC. Overexpression of a human &bgr;2AR in the alveolar epithelium significantly increased AFC in normal mice but had no effect in mice with a non-functional human CFTR gene (&Dgr;&phgr;508 mutation). These studies indicate that upregulation of alveolar CFTR function speeds clearance of excess fluid from the airspace and that CFTRs effect on active Na+ transport requires the &bgr;AR. These studies reveal a previously undetected interdependency between CFTR and &bgr;AR that is essential for upregulation of active Na+ transport and fluid clearance in the alveolus.

Severe status asthmaticus: Management with permissive hypercapnia and inhalation anesthesia

ObjectiveTo describe the difficulties that can be encountered during mechanical ventilation of severe status asthmaticus and to discuss the safety of permissive hypercapnia as a ventilatory strategy and the role and limitations of inhalation anesthesia in the treatment of refractory cases. DesignCase series and review of literature. SettingIntensive care unit of a tertiary care hospital. PatientsTwo patients with severe status asthmaticus. InterventionsAdministration of inhalational anesthetics. Measurements and Main ResultsBoth patients had respiratory failure secondary to status asthmaticus requiring mechanical ventilation and permissive hypercapnia. They also received inhalational anesthetics because of refractory bronchoconstriction. Levels of Paco2 in each case were among the highest and most prolonged elevations (>150 mm Hg for several hours) reported to date. In one case, life-threatening difficulties with ventilation were encountered related to the use of an anesthesia ventilator. Although they had complications related to the severity of their illnesses, both were treated to recovery. ConclusionsMechanical ventilation in severe status asthmaticus can be challenging. Permissive hypercapnia is a relatively safe strategy in the ventilatory management of asthma. High levels of hypercapnia and associated severe acidosis are well tolerated in the absence of contraindications (i.e., preexisting intracranial hypertension). Inhalation anesthesia may be useful in the treatment of refractory cases of asthma but should be used carefully because it may be hazardous owing to poor flow capabilities of most anesthesia ventilators.

Endothelial repair capacity and apoptosis are inversely related in obstructive sleep apnea

Purpose: To investigate the impact of obstructive sleep apnea (OSA) on endothelial repair capacity and apoptosis in the absence of potentially confounding factors including obesity. Patients and methods: Sixteen patients with a body mass index <30 and newly diagnosed OSA and 16 controls were studied. Circulating levels of endothelial progenitor cells, a marker of endothelial repair capacity, and endothelial microparticles, a marker of endothelial apoptosis, were quantified before and after four-week therapy with continuous positive airway pressure (CPAP). Endothelial cell apoptotic rate was also quantified in freshly harvested venous endothelial cells. Vascular reactivity was measured by flow-mediated dilation. Results: Before treatment, endothelial microparticle levels were greater and endothelial progenitor cell levels were lower in patients with OSA than in controls (P < 0.001 for both). Levels of endothelial microparticles and progenitors cells were inversely related (r = −0.67, P < 0.001). Endothelial progenitor cell levels increased after effective treatment (P = 0.036). Conclusions: In the absence of any co-morbid conditions including obesity, OSA alone impairs endothelial repair capacity and promotes endothelial apoptosis. These early endothelial alterations may underlie accelerated atherosclerosis and increased cardiovascular risk in OSA.

Gene therapy for asthma

The accessibility of the airway epithelium and the limitations of current treatments for asthma make the disease a logical target for gene therapy. Study of the immunopathology of chronic airway inflammation has recently identified several pathways that lead to the maladaptive, antigen-induced polarization of CD4+ T cells to a type-2 phenotype. This polarization is thought to lead to IgE production and eosinophil recruitment and activation that is associated with epithelial cell injury and airway hyper-reactivity. Gene transfer to the bronchial epithelium has been used in experimental models to redirect these pathways toward a less injurious, type-1 phenotype. This mini-review highlights recent mechanism-based immunomodulatory and supportive gene transfer approaches to treat animal models of asthma. Although substantial hurdles to airway gene transfer remain, gene transfer offers the possibility of interrupting the pathophysiology of airway inflammation. Doing so can be expected to yield long-lasting protection from bronchospastic challenge and reduced dependence on inhaled and oral medications.

Clinical review: Airway hygiene in the intensive care unit

Maintenance of airway secretion clearance, or airway hygiene, is important for the preservation of airway patency and the prevention of respiratory tract infection. Impaired airway clearance often prompts admission to the intensive care unit (ICU) and can be a cause and/or contributor to acute respiratory failure. Physical methods to augment airway clearance are often used in the ICU but few are substantiated by clinical data. This review focuses on the impact of oral hygiene, tracheal suctioning, bronchoscopy, mucus-controlling agents, and kinetic therapy on the incidence of hospital-acquired respiratory infections, length of stay in the hospital and the ICU, and mortality in critically ill patients. Available data are distilled into recommendations for the maintenance of airway hygiene in ICU patients.

Prevention and Treatment of Gastrointestinal Complications in Patients on Mechanical Ventilation

There exists a complex, dynamic interaction between mechanical ventilation and the splanchnic vasculature that contributes to a myriad of gastrointestinal tract complications that arise during critical illness. Positive pressure-induced splanchnic hypoperfusion appears to play a pivotal role in the pathogenesis of these complications, the most prevalent of which are stress-related mucosal damage, gastrointestinal hypomotility and diarrhea. Furthermore, characteristics of the splanchnic vasculature make the gastrointestinal tract vulnerable to adverse effects related to positive pressure ventilation. While most of these complications seen in mechanically ventilated patients are reflections of altered gastrointestinal physiology, some may be attributed to medical interventions instituted to treat critical illness.Since maintenance of normal hemodynamics cannot always be achieved, pharmacologic prophylactic therapy has become a mainstay in the prevention of gastrointestinal complications in the intensive care unit. Improved understanding of the systemic effects of mechanical ventilation and greater application of lung-protective ventilatory strategies may potentially minimize positive pressure-induced reductions in splanchnic perfusion, systemic cytokine release and, consequently, reduce the incidence of gastrointestinal complications associated with mechanical ventilation. Herein, we discuss the pathophysiology of gastrointestinal complications associated with mechanical ventilation, summarize the most prevalent complications and focus on preventive strategies and available treatment options for these complications.The most common causes of gastrointestinal hemorrhage in mechanically ventilated patients are bleeding from stress-related mucosal damage and erosive esophagitis. In general, histamine H2 receptor antagonists and proton pump inhibitors prevent stress-related mucosal disease by raising the gastric fluid pH. Proton pump inhibitors tend to provide more consistent pH control than histamine H2 receptor antagonists. There is no consensus on the drug of choice for stress ulcer prophylaxis with several meta-analyses providing conflicting results on the superiority of any medication. Prevention of erosive esophagitis include careful use of nasogastric tubes and institution of strategies that improve gastric emptying. Many mechanically ventilated patients have gastrointestinal hypomotility and diarrhea. Treatment options for gastrointestinal motility are limited, thus, preventive measures such as correction of electrolyte abnormalities and avoidance of medications that impair gastrointestinal motility are crucial. Treatment of diarrhea depends on the underlying cause. When associated with Clostridium difficile infection antibacterial therapy should be discontinued, if possible, and treatment with oral metronidazole should be initiated.More studies are warranted to better understand the systemic effects of mechanical ventilation on the gastrointestinal tract and to investigate the impact of lung protective ventilatory strategies on gastrointestinal complications.