Publications

1. We studied the effect of platelet activating factor (PAF) on leakage of albumin, and secretion of fucose (a marker for mucus glycoprotein) and protein into the tracheal lumen of the guinea-pig isolated in situ, and on bioelectric properties and fluxes of mannitol in vitro. We also studied the effect of PAF on mucus secretion in human bronchi in vitro. 2. In guinea-pig, intravenous PAF markedly increased the luminal concentration of protein but did not significantly increase fucose concentrations. Increased albumin leakage (274% above controls at a dose of 50 ng/kg PAF) was associated with the increased luminal content of protein (248% above controls at the same dose of PAF). 3. Leakage of albumin was maximal 10 min after PAF, was significantly reduced by 20 min and had returned to baseline by 30 min. This pattern of leakage could be repeated with successive administrations of PAF. 4. PAF induced small but significant biphasic changes in bioelectric properties in vitro. The initial response was rapid in onset and characterized by maximal increases in short-circuit current (Isc) of 6.5% above controls at 7.5 min and in conductance (G) of 7% at 20 min. Both responses were blocked by the PAF receptor antagonist WEB 2086. Amiloride blocked the increase in Isc. Permeability of the tissue to mannitol (Pmann) was unaltered. The delayed response was characterized by maximal increases in Isc and G of 10% above controls at 60-90 min which were not significantly affected by WEB 2086 or amiloride. Pmann was increased by 38% at 90 min. 5. PAF increased fucose secretion in human bronchi in vitro. 6. Lyso-PAF in vitro caused changes similar to those induced by PAF on bioelectric properties and mucus secretion, but had no significant effects in vivo. 7. Light microscopy showed no evidence of epithelial disruption in animals given intravenous PAF at a dose causing significant albumin transudation. 8. We conclude that PAF increases the protein content of guinea-pig tracheal fluid principally by inducing plasma leakage rather than mucus secretion and that the small changes in ion transport and epithelial conductance may reduce the tendency to epithelial disruption during plasma leakage.

Coronary artery bifurcation lesions comprise approximately 15-20% of all percutaneous coronary interventions (PCI) and constitute a complex lesion subgroup. Intravascular optical coherence tomography (OCT) is a promising adjunctive tool for guiding coronary bifurcation with its unrivalled high resolution. Compared to angiography, intravascular OCT has a clear advantage in that it depicts ostial lesion(s) in bifurcation without the misleading two-dimensional appearance of conventional angiography such as overlap and foreshortening. In addition, OCT has the ability to reconstruct a bifurcation in three dimensions and to assess the side branch ostium from 3D reconstruction of the main vessel pullback, which can be applied to ensure the optimal recrossing position of the wire after main vessel stenting. Recently, online co-registration of OCT and angiography became widely available, helping the operator to position a stent in precise landing zones, reducing the risk of geographic miss. Despite these technological advances, the currently available clinical data are based mainly on observational studies with a small number of patients; there is little evidence from randomised trials. The joint working group of the European Bifurcation Club and the Japanese Bifurcation Club reviewed all the available literature regarding OCT use in bifurcation lesions and here provides recommendations on OCT guiding of coronary interventions in bifurcation lesions.

This study was undertaken to characterize the muscarinic receptor subtypes present in adult pig peripheral lung and airway smooth muscle. The binding of the nonselective muscarinic antagonist [N-methyl-3H]scopolamine ([3H]NMS) to pig airways showed a single class of binding sites with a maximum density of 172 and 450 fmol/mg protein in peripheral lung and airway smooth muscle, respectively. Unlike [3H]NMS, the M1-selective antagonist, [3H]telenzepine, recognized two populations of binding sites in peripheral lung. Approximately 14% of total [3H]telenzepine binding sites displayed high affinity [dissociation constant (Kd) = 0.95 nM], whereas the remaining sites showed low affinity (Kd = 14.2 nM). The high- and the low-affinity [3H]telenzepine binding sites displayed the pharmacological profile of M1 and M2 receptors, respectively. Heterogeneity of pig airways muscarinic receptor was also revealed by competitive binding experiments against [3H]NMS with the M2-selective antagonist methoctramine. This compound recognized 70 and 90% of total receptors with high affinity in airway smooth muscle (Ki = 4.44 nM) and peripheral lung (Ki = 9.82 nM), respectively. This result suggests that the dominant muscarinic receptor in pig airways is of the M2 subtype. Northern blot analysis demonstrated the presence of m1 and m2 mRNAs transcripts in peripheral lung and m2 and m3 mRNAs in airway smooth muscle with no evidence for m4 mRNA.

Lower airway bacterial colonisation (LABC) in COPD patients is associated with increased exacerbation frequency and faster lung function decline. Defective macrophage phagocytosis in COPD drives inflammation, but how defective macrophage function contributes to exacerbations is not clear. This study investigated the association between macrophage phagocytosis and exacerbation frequency, LABC and clinical parameters.Monocyte-derived macrophages (MDM) were generated from 92 stable COPD patients, and at the onset of exacerbation in 39 patients. Macrophages were exposed to fluorescently labelled Haemophilus influenzae or Streptococcus pneumoniae for 4 h, then phagocytosis measured by fluorimetry and cytokine release by ELISA. Sputum bacterial colonisation was measured by PCR.Phagocytosis of H. influenzae was negatively correlated with exacerbation frequency (r = 0.440, p < 0.01), and was significantly reduced in frequent vs. infrequent exacerbators (1.9 × 103 RFU vs. 2.5 × 103 RFU, p < 0.01). There was no correlation for S. pneumoniae. There was no association between phagocytosis of either bacteria with age, lung function, smoking history or treatment with inhaled corticosteroids, or long-acting bronchodilators. Phagocytosis was not altered during an exacerbation, or in the 2 weeks post-exacerbation. In response to phagocytosis, MDM from exacerbating patients showed increased release of CXCL-8 (p < 0.001) and TNFα (p < 0.01) compared to stable state.Impaired COPD macrophage phagocytosis of H. influenzae, but not S. pneumoniae is associated with exacerbation frequency, resulting in pro-inflammatory macrophages that may contribute to disease progression. Targeting these frequent exacerbators with drugs that improve macrophage phagocytosis may prove beneficial.