Targeting remodeling in respiratory inflammation

Chronic asthma causes considerable morbidity, mortality and utilization of healthcare resources. The fact that asthma still causes such problems despite the widespread use of anti-inflammatory treatment suggests that new approaches are needed. Airways in chronic asthma are characterized by considerable remodeling which affects a number of structures, particularly airway smooth muscle and changes in airway smooth muscle thickness may be one of the most important determinants of bronchial hyperresponsiveness. Here we suggest new approaches that might be used to target smooth muscle remodeling in asthma.     

Radiation induces upregulation of cyclooxygenase-2 (COX-2) protein in PC-3 cells

PURPOSE: To investigate the impact of gamma-irradiation on cyclooxygenase-2 (COX-2) expression and its enzymatic activity in PC-3 cells. Cell cycle redistribution, viability, and apoptosis were quantitated in control and irradiated cells with or without the COX-2 inhibitor NS-398. METHODS AND MATERIALS: Western blot analysis was used to assess COX-2 protein expression. Prostaglandin (PGE(2)) was measured after addition of arachidonic acid (AA) using a Monoclonal Immunoassay Kit. Cell cycle and apoptosis were assessed using flow cytometry. RESULTS: We observed a dose-dependent increase in COX-2 of 37.0%, 79.7%, and 97.5% following irradiation with 5, 10, and 15 Gy, respectively. The PGE(2) level of irradiated cells was higher than in controls (1512 +/- 157.5 vs. 973.7 +/- 54.2 rhog PGE(2)/mL; p < 0.005, n = 4) while cells irradiated in the presence of NS-398 had reduced PGE(2) levels (218.8 +/- 80.1 rhog PGE(2)/mL; p < 0.005; n = 4). We found no differences in cell cycle distribution or apoptosis between cells irradiated in the presence or absence of NS-398. CONCLUSIONS: COX-2 protein is upregulated and enzymatically active after irradiation, resulting in elevated levels of PGE(2). This effect can be suppressed by NS-398, which has clinical implications for therapies combining COX-2 inhibitors with radiation therapy.     

Factor VIII-von Willebrand factor requires calcium for facilitation of platelet adherence

The role of divalent cations in platelet adherence to deendothelialized human arteries in flowing blood was investigated in an annular perfusion chamber. Spreading of platelets on the subendothelium was impaired below 30 microM of free Ca2+ ions (Ca2+). When Ca2+ was replaced by Mg2+, adherence was unchanged in perfusates without exogenous factor VIII-von Willebrand factor (FVIII-vWF), but the ability of FVIII-vWF to support platelet adherence was lost. Binding of FVIII-vWF to the vessel wall was independent of divalent cations, but bound FVIII-vWF was only able to mediate adherence after exposure to Ca2+. Pretreatment of FVIII-vWF with the calcium chelator EGTA (10 mM) resulted in loss of the ability to facilitate platelet adherence, while the ristocetin cofactor activity remained intact. Full restoration of the ability to mediate platelet adherence could only be obtained by prolonged dialysis against Ca2+ in the millimolar range. These data indicate that divalent cations have at least two separate roles to play in supporting platelet adherence: (1) platelet spreading on the subendothelium requires Ca2+ or Mg2+; (2) FVIII-vWF should be exposed to Ca2+ to obtain its optimal biologic activity in supporting platelet adherence.     

SOCIAL ISOLATION AND CARDIOVASCULAR DISEASE: AN ATHEROSCLEROTIC PATHWAY?

This paper outlines two pathways through which social support can influence the prevention or progression of cardiovascular disease: health behaviors and neuroendocrine mechanisms. Its primary focus is on neuroendocrine pathways, reviewing data which suggest that lack of social support is etiologically related to coronary artery lesion development through two mechanisms: sympathetic-adrenomedullary influences on platelet function, heart rate and blood pressure in the initial endothelial injury; and pituitary-adrenal cortical factors involved in smooth muscle cell proliferation during progression of the lesion after injury has taken place. It hypothesizes that the buffering effect of social support on the cardiovascular system is mediated primarily through mechanisms associated with the release of oxytocin. © 1998 Elsevier Science Ltd. All rights reserved.