Mechanisms of glucocorticoid action and insensitivity in airways disease.

Glucocorticoids are the mainstay for the treatment of chronic inflammatory diseases including asthma and chronic obstructive pulmonary disease (COPD). However, it has been recognized that glucocorticoids do not work well in certain patient populations suggesting reduced sensitivity. The ultimate biologic responses to glucocorticoids are determined by not only the concentration of glucocorticoids but also the differences between individuals in glucocorticoid sensitivity, which is influenced by multiple factors. Studies are emerging to understand these mechanisms in detail, which would help in increasing glucocorticoid sensitivity in patients with chronic airways disease. This review aims to highlight both classical and emerging concepts of the anti-inflammatory mechanisms of glucocorticoids and also review some novel strategies to overcome steroid insensitivity in airways disease.

Transforming growth factor-ß impairs glucocorticoid activity in the A549 lung adenocarcinoma cell line.

BACKGROUND AND PURPOSE: The lung adenocarcinoma cell line, A549, undergoes epithelial-mesenchymal cell transition (EMT) in response to TGF-ß. Glucocorticoids do not prevent the EMT response, but TGF-ß induced resistance to the cytokine-regulatory action of glucocorticoids. We sought to characterize the impairment of glucocorticoid response in A549 cells. EXPERIMENTAL APPROACH: A549 cells were exposed to TGF-ß for up to 96 h before glucocorticoid treatment and challenge with IL-1α to assess glucocorticoid regulation of IL-6 and CXCL8 production. Nuclear localization of the glucocorticoid receptor α (GRα) was ascertained by immunofluorescence and Western blotting. Transactivation of the glucocorticoid response element (GRE) was measured with a transfected GRE-secreted human placental alkaline phosphatase reporter. KEY RESULTS: TGF-ß (40-400 pM) reduced the maximum inhibitory effect of dexamethasone on IL-1α-induced IL-6 and CXCL8 production. The impaired glucocorticoid response was detected with 4 h of TGF-ß (40 pM) exposure (and 4 h IL-1α to induce CXCL8 expression) and therefore was not secondary to EMT, a process that requires longer incubation periods and higher concentrations of TGF-ß. TGF-ß also impaired dexamethasone regulation of granulocyte-macrophage colony-stimulating factor in thrombin-stimulated BEAS-2B epithelial cells. Impaired regulation of CXCL8 was associated with markedly reduced GRE transactivation and reduced induction of mRNA for IκBα, the glucocorticoid-inducible leucine zipper and the epithelial sodium channel (SCNN1A). The expression, cellular levels and nuclear localization of GRα were reduced by TGF-ß. CONCLUSIONS AND IMPLICATIONS: We have identified mechanisms underlying the impairment of responses to glucocorticoids by TGF-ß in the A549 and BEAS-2B cell lines.

In vitro and in vivo evidence for anti-inflammatory properties of 2-methoxyestradiol.

2-Methoxyestradiol (2MEO) is an endogenous metabolite of 17ß-estradiol that interacts with estrogen receptors and microtubules. It has acute anti-inflammatory activity in animal models that is not attributable to known antiproliferative or antiangiogenic actions. Because macrophages are central to the innate inflammatory response, we examined whether suppression of macrophage activation by 2MEO could account for some of its anti-inflammatory effects. Inflammatory mediator production stimulated by lipopolysaccharide (LPS) and interferon-γ in the J774 murine macrophage cell line or human monocytes was measured after treatment with 2MEO or the anti-inflammatory agent dexamethasone. The effect of these agents on LPS-induced acute lung inflammation in mice was also examined. 2MEO suppressed J774 macrophage interleukin-6 and prostaglandin E2 production (by 30 and 47%, respectively, at 10 µM) and human monocyte tumor necrosis factor-α production (by 60% at 3 µM). Estradiol had no effect on J774 macrophage activation, nor did the estrogen receptor antagonist 7α-[9-[(4,4,5,5,5-pentafluoropentyl)sulfinyl]nonyl]estra-1,3,5(10)-triene-3,17ß-diol (ICI 182,780) prevent the effects of 2MEO. The actions of 2MEO were not mimicked by the microtubule-interfering agents colchicine or paclitaxel. In mice exposed to LPS, bronchoalveolar lavage protein content, a measure of vascular leak and epithelial injury, was reduced to a comparable extent (~54%) by treatment with 2MEO (150 mg · kg⁻¹) or dexamethasone (1 mg · kg⁻¹). In addition, 2MEO reduced LPS-induced interleukin-6 gene expression. Thus, 2MEO modulates macrophage activation in vitro and has high-dose acute anti-inflammatory activity in vivo. These findings are consistent with the acute anti-inflammatory actions of 2MEO being mediated in part by the suppression of macrophage activation.

High risk for venous thromboembolism in diabetics with hyperosmolar state: comparison with other acute medical illnesses.

BACKGROUND: Diabetes mellitus is generally not recognized as an important risk factor for venous thromboembolism (VTE). However, clinical observations and case reports have suggested that patients with diabetes and hyperosmolarity may be at increased risk for VTE. OBJECTIVES: To determine the risk of VTE in patients hospitalized for diabetes with hyperosmolar state compared to patients with other acute medical illnesses. PATIENTS/METHODS: The California Patient Discharge Data Set was used to determine the incidence of first-time VTE in all patients admitted between 1995 and 2000 for diabetes with hyperosmolarity and 11 other acute medical conditions. Proportional hazard modeling was used to adjust for age, race, gender, and prior hospitalization within 3 months. RESULTS: Among 2859 patients with diabetes and hyperosmolarity, 34 (1.2%) developed VTE during the hospitalization and 14 (0.5%) developed VTE within 91 days after discharge. In an adjusted multivariate model comparing the risk of VTE to cases with depression, patients with hyperosmolarity had a significantly higher risk of VTE [hazard ratio (HR) = 16.3; 95% confidence interval (CI): 10-25] comparable to the risk associated with sepsis (HR = 19.3; 95% CI: 13-29) or acute connective tissue disease (HR = 21; 95% CI: 15-31). Compared to uncomplicated diabetes, patients with hyperosmolarity had a significantly higher risk of VTE (HR = 3.0; 95% CI: 2.1-4.5) whereas patients with ketoacidosis were not at higher risk (HR = 1.2; 95% CI: 0.8-1.7). CONCLUSIONS: Patients hospitalized for diabetes with hyperosmolarity are at increased risk for developing VTE both during their inpatient stay and in the 3 months after discharge. Thromboprophylaxis in these patients appears warranted, and extended prophylaxis for after hospital discharge should be studied.

Cardiovascular afferent signals and drinking in response to hypotension in dogs.

Arterial hypotension stimulates increases in plasma arginine vasopressin (AVP), plasma renin activity (PRA), and water intake in conscious dogs. We have previously reported that increasing left atrial but not right atrial pressure completely blocks the increase in plasma AVP and PRA induced by hypotension. The goal of the present study was to examine the effect of increasing right or left atrial pressure on water intake induced by arterial hypotension. Dogs were prepared with occluding cuffs on the thoracic inferior vena cava, the pulmonary artery, and the ascending aorta. We reduced mean arterial pressure (MAP) 25% below control by either inferior vena cava constriction (IVCC), pulmonary artery constriction (PAC), or ascending aorta constriction (AAC) and measured water intake over a 2-h period. Cumulative water intake during IVCC (n = 6) and PAC (n = 6) was 7.8 +/- 2.0 and 6.7 +/- 2.6 ml/kg, respectively. There was no difference between either the latency or the volume consumed between the two treatments. In contrast, none of the dogs drank during hypotension induced by AAC (n = 5). Because the degree of arterial baroreceptor unloading was the same in each treatment by design, we conclude that stimulation of left atrial receptors inhibits drinking in response to arterial hypotension but that stimulation of right atrial receptors has no effect on the response in dogs.

Revascularization in coronary artery disease. A review of randomized trial data.

Since the advent of bypass surgery in the late 1960s and catheter-based intervention in the late 1970s, the treatment of coronary artery disease has been revolutionized by the concept of revascularization. Surveys have demonstrated that the practice patterns around the world and within the US are inconsistent for these important treatment options and are often driven by availability and economics rather than evidence-based data. In addition, the studies examining the use of medical therapy, balloon angioplasty, atherectomy, coronary stenting, and bypass surgery are consistently lagging behind the technological advances in this field. This article reviews the data that randomized trials and meta-analyses provide to compare these modalities. We attempt to provide a framework for reasoned clinical decision making to help guide patient care. While the breakpoints between the medicine bottle, cath lab, and operating room will continue to evolve, we offer a revascularization strategy for patient subgroups based on what clinical data supports.