Caveolin1 interacts with the glucocorticoid receptor in the lung but is dispensable for its anti-inflammatory actions in lung inflammation and Trichuris Muris infection.

Glucocorticoids (Gcs) are widely prescribed anti-inflammatory compounds, which act through the glucocorticoid receptor (GR). Using an unbiased proteomics screen in lung tissue, we identified the membrane protein caveolin -1 (Cav1) as a direct interaction partner of the GR. In Cav1 knockout mice GR transactivates anti-inflammatory genes, including Dusp1, more than in controls. We therefore determined the role of Cav1 in modulating Gc action in two models of pulmonary inflammation. We first tested innate responses in lung. Loss of Cav1 impaired the inflammatory response to nebulized LPS, increasing cytokine/chemokine secretion from lung, but impairing neutrophil infiltration. Despite these changes to the inflammatory response, there was no Cav1 effect on anti-inflammatory capacity of Gcs. We also tested GR/Cav1 crosstalk in a model of allergic airway inflammation. Cav1 had a very mild effect on the inflammatory response, but no effect on the Gc response - with comparable immune cell infiltrate (macrophage, eosinophils, neutrophils), pathological score and PAS positive cells observed between both genotypes. Pursuing the Th2 adaptive immune response further we demonstrate that Cav1 knockout mice retained their ability to expel the intestinal nematode parasite T.muris, which requires adaptive Th2 immune response for elimination. Therefore, Cav1 regulates innate immune responses in the lung, but does not have an effect on Th2-mediated adaptive immunity in lung or gut. Although we demonstrate that Cav1 regulates GR transactivation of anti-inflammatory genes, this does not translate to an effect on suppression of inflammation in vivo.

What we know and what we would like to know about genetics and pulmonary arterial hypertension.

Research on the molecular basis of PAH caused by BMPR-II mutations is beginning to yield novel approaches to therapy, for example, small molecule inhibitors of ALK-5. Enhancement of BMP signalling may be possible with BMP-derived ligands or rescue of BMPR-II cell surface expression for some mutations. For mutations leading to nonsense mediated mRNA decay, approaches aimed at transcript stabilisation provide another possible intervention. To further our genetic understanding of this rare disease, large international collaborative studies are needed to generate the numbers of patients necessary to undertake meaningful genome wide association studies for novel susceptibility genes or disease modifying genes. In addition, to provide accurate information to families, longitudinal cohort studies, coupled with biomarker studies, are required of affected and unaffected individuals in families segregating BMPR-II mutations.

Initial oxygen management in patients with an exacerbation of chronic obstructive pulmonary disease.

BACKGROUND: The Norfolk and Norwich University Hospital (NNUH) is situated in rural Norfolk, and ambulance journey times are often >30 min. Longer ambulance journeys could lead to a greater risk of hypercapnia, if inappropriately high concentrations of oxygen are given during an exacerbation of COPD. AIM: To investigate the effect of high concentration oxygen (HCO, FiO(2) > 0.28) on COPD patients, and the outcome of instituting a simple protocol to reduce such exposure. DESIGN: Retrospective audit. METHOD: An audit was conducted of all patients admitted with an exacerbation of COPD to the NNUH during the 2 months from 1 December 2001 to 31 January 2002 (n = 108). Results were shared with paramedics, and guidelines agreed for the initial provision of lower concentrations of oxygen (LCO, FiO(2) < or = 0.28). A second audit was conducted a year later between 1 December 2002 and 31 January 2003 (n = 103). RESULTS: HCO caused significant (p < 0.01) acidosis and inappropriately high PaO(2) and PaCO(2), compared to initial LCO therapy. There was a significantly increased complication rate during admission (p < 0.01) in those COPD patients receiving HCO compared to LCO, particularly when ambulance journeys exceeded 30 min. The second audit demonstrated a significant (p < 0.001) reduction in the number of patients initially receiving HCO, but the complication rate was unaltered. DISCUSSION: A simple intervention, such as providing paramedics with 28% Venturi masks, can reduce the number of COPD patients exposed to HCO. A randomized controlled trial is long overdue to establish whether HCO or LCO as initial management is associated with the most favourable prognosis in different hospital settings.

Importance of basolateral K+ conductance in maintaining Cl- secretion in murine nasal and colonic epithelia.

1. Epithelia lining the nasal passages and descending colon of wild-type and cystic fibrosis (CF) mice were examined by the short-circuit current technique. Additionally, intracellular Ca2+ ion determinations were made in nasal epithelial cells. Forskolin produced anion secretory currents in wild-type and CF nasal epithelia. It produced similar effects in wild-type colonic epithelia, but not in colonic epithelia from CF mice. 2. After electrogenic Na+ transport was blocked with amiloride and electrogenic Cl- secretion was stimulated with forskolin, the ability of K+ channel blockers to inhibit the forskolin-induced Cl- current was determined. The order of efficiency for nasal epithelium was: Ba2+ > clofilium >>> TEA = azimilide >>> trans-6-cyano-4-(N-ethylsulphonyl-N-methylamino)-3-hydroxy-2, 2-dimethyl-chromane (293B) = charybdotoxin, whereas for the colonic epithelium the order was: Ba2+ = 293B >>> azimilide = TEA >>> clofilium = charybdotoxin. 3. 1-Ethyl-2-benzimdazolinone (1-EBIO) was able to generate large Cl--secretory currents in colonic epithelia which were partially sensitive to charybdotoxin, with the remaining current being inhibited by 293B. In nasal epithelia 1-EBIO produced only a small transient effect on current. 4. Forskolin released intracellular Ca2+ in nasal epithelial cells; this activity was attenuated when more powerful Ca2+-releasing agents were applied first. 5. It is concluded that an action on basolateral cAMP-sensitive K+ channels is an important determinant of the maintained responses to forskolin in nasal and colonic epithelia, in addition to the effects on the cystic fibrosis transmembrane conductance regulator (CFTR) in the apical membrane. In CF nasal epithelia the activation of calcium-activated chloride channels (CACs) substitutes for the effect on CFTR. On the basis of the different orders of potency of the blocking agents and the differential response to 1-EBIO it is concluded that the cAMP-sensitive K+ channels are different in the airways and the gut.