A selective antagonist of histamine H₄ receptors prevents antigen-induced airway inflammation and bronchoconstriction in guinea pigs:involvement of lipocortin-1

BACKGROUND AND PURPOSE: Among the pathogenic mechanisms of asthma, a role for oxidative/nitrosative stress has been well documented. Recent evidence suggests that histamine H₄ receptors play a modulatory role in allergic inflammation. Here we report the effects of compound JNJ 7777120 (JNJ), a selective H4 receptor antagonist, on antigen-induced airway inflammation, paying special attention to its effects on lipocortin-1 (LC-1/annexin-A1), a 37 kDA anti-inflammatory protein that plays a key role in the production of inflammatory mediators.

EXPERIMENTAL APPROACH: Ovalbumin (OA)-sensitized guinea pigs placed in a respiratory chamber were challenged with antigen. JNJ (5, 7.5 and 10 mg.kg⁻¹) was given i.p. for 4 days before antigen challenge. Respiratory parameters were recorded. Bronchoalveolar lavage (BAL) fluid was collected and lung specimens taken for further analyses 1 h after antigen challenge. In BAL fluid, levels of LC-1, PGD2 , LTB4 and TNF-α were measured. In lung tissue samples, myeloperoxidase, caspase-3 and Mn-superoxide dismutase activities and 8-hydroxy-2-deoxyguanosine levels were measured.

KEY RESULTS: OA challenge decreased LC-1 levels in BAL fluid, induced cough, dyspnoea and bronchoconstriction and increased PGD2 , LTB4 and TNF-α levels in lung tissue. Treatment with JNJ dose-dependently increased levels of LC-1, reduced respiratory abnormalities and lowered levels of PGD2 , LTB4 and TNF-α in BAL fluid.

CONCLUSIONS AND IMPLICATIONS: Antigen-induced asthma-like reactions in guinea pigs decreased levels of LC-1 and increased TNF-α and eicosanoid production. JNJ pretreatment reduced allergic asthmatic responses and airway inflammation, an effect associated with LC-1 up-regulation.

Electron impact excitation of A1 XIII: A relativistic approach

Energy levels, radiative rates, collision strengths, and effective collision strengths for all transitions up to and including the n = 5 levels of AlXIII have been computed in the j j coupling scheme including relativistic effects. All partial waves with angular momentum J less than or equal to 60 have been included, and resonances have been resolved in a fine energy grid in the threshold region. Collision strengths are tabulated at energies above thresholds in the range 170.0 less than or equal to E less than or equal to 300.0 Ryd, and results for effective collision strengths, obtained after integrating the collision strengths over a Maxwellian distribution of electron velocities, are tabulated over a wide temperature range of 4.4 less than or equal to log T-e less than or equal to 6.8 K. The importance of including relativistic effects in a calculation is discussed in comparison with the earlier available non-relativistic results.

Synthesis of (+)-piclavines A1 and A2

Piclavines AI and A2 have been synthesised for the first time. The route is short with the key step being the reaction of a bicyclic N-acyl iminium ion with 3-trimethysilyl-1-decene. This convergent strategy gave exclusively compounds in which the pendant decenyl group was axial, as a 6:1 mixture of E:Z-alkene diastereoisomers. Reduction of the lactam carbonyl group gave a 6:1 mixture of piclavines Al and A2, (C) 2000 Published by Elsevier Science Ltd.