Thomas J. Ferro

Increased endothelial albumin permeability mediated by protein kinase C activation.

We examined the effects of activation of endothelial protein kinase C (PKC) of the endothelial barrier function. Exposure of confluent bovine pulmonary artery endothelial cell monolayers to phorbol 12-myristate 13-acetate (PMA) resulted in concentration-dependent (10(-8)-10(-6) M) increases in PKC activity and in the transendothelial flux of 125I-albumin. Exposure of the endothelium to 1-oleoyl 2-acetyl glycerol (OAG) also increased the transendothelial flux of 125I-albumin in a concentration-dependent manner. Neither 4 alpha-phorbol didecanoate nor 1-mono-oleoyl glycerol, which do not activate PKC, altered permeability. The increase in 125I-albumin permeability induced by PMA was inhibited by 25 microM H7 (a PKC inhibitor), but not by the control compound HA1004 (25 microM). After 16 h of exposure to PMA, 125I-albumin permeability returned to baseline and a significant reduction in cytosolic PKC activity was noted. Further challenge with PMA at this time resulted in no significant increase in PKC activity indicating downregulation of the enzyme; moreover, this PMA challenge did not increase endothelial permeability. Exposure of endothelial monolayers to phospholipase C (PLC), which increases membrane phosphatidylinositide turnover, or to alpha-thrombin also induced concentration-dependent activation of PKC and increases in 125I-albumin endothelial permeability. The thrombin- and PLC-induced permeability increases were inhibited by H7, but not by HA1004. The activation of endothelial PKC directly by PMA or OAG and by PLC and alpha-thrombin increases the transendothelial albumin permeability, indicating that PKC activation is an important signal transduction pathway by which extracellular mediators increase endothelial macromolecular transport.

Differential Prostaglandin Production by Unfractionated and Density-Fractionated Human Monocytes and Alveolar Macrophages

Mononuclear phagocyte elaboration of E series prostaglandins (PGE) may be important in the regulation of inflammatory and fibrotic reactions. Mononuclear phagocytes are morphologically and functionally heterogeneous cells. To further understand the processes controlling inflammation and fibrosis, in particular that in the human lung, we characterized the ability of unfractionated and density‐fractionated human alveolar macrophages and blood monocytes to elaborate PGE. Alveolar macrophages and blood monocytes constitutively elaborated small amounts of PGE, and their elaboration of PGE was increased with lipopolysaccharide (LPS) stimulation. Monocytes elaborated more PGE than autologous alveolar macrophages. In addition, denser monocytes (specific gravity > 1.055) and denser alveolar macrophages (specific gravity > 1.044) elaborated more PGE than less dense monocytes and alveolar macrophages, respectively. When monocytes were incubated in vitro, their constitutive PGE elaboration decreased with time. However, in vitro incubation did not cause monocytes to lose their capacity to elaborate PGE in response to LPS. Thus, mononuclear phagocyte populations differ in their ability to elaborate PGE. These differences can be only partially attributed to differences in cell maturation.

Mechanisms of lung vascular injury and edema after pulmonary microembolism

N THIS ARTICLE, we review recent studies of the mechanisms of pulmonary vascular injury and edema induced by pulmonary embolism. Several models of embolism-induced pulmonary edema have been studied.’ The focus of this review will be the microembolism induced by the intravenous (IV) infusion of a-thrombin in sheep. The term “microembolism” describes the diffuse deposition of fibrin-platelet thrombi in the small blood vessels (~500 mm in diamater) of the lung, as opposed to the large vessel embolism which may result from deep venous thrombosis. We will discuss the roles of blood components (eg, fibrinogen), inflammatory cells (eg, macrophages and neutrophils), and pulmonary hemodynamic factors in mediating the lung vascular injury and pulmonary edema.

Exercise and Quality of Life in Chronic Obstructive Pulmonary Disease: Effects of Treatment

Chronic obstructive pulmonary disease has a dramatic effect on a patients ability to tolerate exercise and overall quality of life. Mortality risk is higher in more incapacitated patients. Short-acting bronchodilators generally do not seem to improve exercise tolerance. The long-acting anticholinergic agent tiotropium and long-acting β-agonist salmeterol, on the other hand, have been shown to reduce the work of breathing and thus increase exercise tolerance.

Hospitalist Management of Community-Acquired Pneumonia: Consensus Statement

T he management of community-acquired pneumonia (CAP) is a topic of great interest for hospitalists, who individually care for an average of 20 to 40 cases of CAP in their hospitals each year. As specialists in the on-site medical care of hospital patients, hospitalists can be instrumental in improving the outcomes and efficiency of inpatient care for CAP patients. Although the percentage of CAP patients who require admission to the hospital is relatively small, the majority of the cost associated with CAP occurs in the hospital setting. In the mid-1990s, there were 5.6 million cases of CAP per year resulting in total costs of approximately US

Getting the most from antibiotic therapy: Maximizing compliance

8.4 billion per year. Although only about 20% of these patients were admitted to the hospital, the hospitalized population accounted for more than 90% of the total cost. Hospitals are increasingly aware of the need to maintain high-quality care while reducing unnecessary expenditures. Because hospitalists are familiar with hospital systems and are comfortable managing illnesses such as complicated pneumonia, they are in a unique position to implement more efficient clinical pathways that optimize resource utilization and patient outcomes. This is borne out by the published outcomes literature, which to date has demonstrated that hospitalists are able to realize significant and consistent cost savings associated with no decrease in quality. The purpose of this report is to provide hospitalists with concise recommendations for the inpatient management of CAP, based on the suggestions of the Hospitalist Management of Community-Acquired Pneumonia (H-CAP) Consensus Panel, a panel of hospitalists, internists, and pulmonary disease specialists. The H-CAP Consensus Panel convened on September 27, 2003, to address the complex issues surrounding care of the hospitalized patient with CAP and to make recommendations that would help hospitalists evaluate and manage patients with respiratory infections. National guidelines issued by the American Thoracic Society (ATS), the Infectious Diseases Society of America, and the Centers for Disease Control and Prevention were reviewed and included in the process. The panel discussed specific issues relating to the hospitalist’s role in guideline use, admission strategies, choice of therapeutic agents, and duration of therapy. The resulting statement outlined below focuses only on the management of patients in regular hospital beds, not outpatients or intensive care unit (ICU) patients.

Overview of national treatment guidelines for common respiratory tract infections.

Physicians should consider 3 criteria when selecting antibiotics. Two of these—expected outcomes and risk of resistance—have already been discussed in some detail. The third, but just as important, is patient compliance. What influences compliance? Is there a link between compliance and outcomes and compliance and resistance? How can physicians ensure prescription compliance? Members of the BEST Clinical Consensus Panel addressed these questions in a roundtable discussion.

Chronic Necrotizing Pulmonary Aspergillosis*: Approach to Management

CAP, ABECB, and AOM are common community-acquired infections accounting for many office visits and many prescriptions for antibacterial agents. In addition, bacterial resistance to common antibacterial agents is on the rise and is related to antibacterial usage rates. Therefore, careful consideration is required before prescribing an antibacterial agent for a patient suspected of having one of these infections. Whenever possible, preventive strategies, including immunization, smoking cessation, and the correction of underlying anatomic defects, should be considered. Before prescribing an antibiotic, the provider should determine that the criteria for antibacterial usage are met in the patient. If an antibiotic must be used, then one should be selected that has a chance of curing the patient and preserving the sensitivity pattern of the community.