[Effects of antenatal inflammation on the developing lung]. / Pathogenetische Effekte der prä- und postnatalen Inflammationsreaktion in den Lungen.

The developing lung and immune systems are very plastic and their developmental pathway can be influenced by various endogenous and/or exogenous factors. In the last years translational research with various animal models has been helpful to answer some basic questions about the effect of chorioamnionitis on maturation and development of the foetal lung and immune system. Chorioamnionitis can induce a cascade of lung injury, pulmonary inflammation and remodelling in the foetal lung. Chorioamnionitis-induced IL-1 production is consistently associated with lung maturation, induced by enhancing surfactant protein and lipid synthesis. IL-1 therefore seems to be the main link between lung inflammation and lung maturation, which largely prevents RDS in preterm infants. On the other hand, chorioamnionitis can also cause structural lung changes and affect the expression of growth factors, like TGF-ß, CTGF, FGF-10 or BMP-4, which are crucial for branching morphogenesis. These changes result in alveolar and microvascular simplification similar to BPD. Neonatal outcome may also be affected by chorioamnionitis by modulating the efficacy of the immune system. Chorioamnionitis can induce LPS-tolerance (endotoxin hyporesponsiveness/immunoparalysis), which may prevent further foetal lung damage but increases susceptibility to postnatal infections. The inflammatory and developmental signalling pathways affected by chorioamnionitis form delicately regulated networks, which interact with each other to control lung development. In addition to chorioamnionitis, these pathways can be affected by other prenatal (steroid) or postnatal factors (mechanical ventilation, oxygen exposure, infection, steroids). Because the postnatal response to injury appears to be highly dependent on prenatal exposures, the "secondary hit" hypothesis is very plausible, in which exposure to chorioamnionitis is a predisposition for the development of adverse neonatal outcomes.

In vivo characterization of vasodilating muscarinic-receptor subtypes in humans.

The role of muscarinic (M)-receptor subtypes in the regulation of vascular tone has not yet been defined in humans. To analyze the role of M-receptor subtypes in the forearm resistance vasculature of normotensive volunteers (n = 20), we infused acetylcholine (ACh) and methacholine (MCh) in the presence of saline and the antagonists atropine (nonselective), pirenzepine (M1 selective), and AF-DX 116 (M2 selective), using automated R-wave-triggered venous occlusion plethysmography. Schild analysis was applied by calculating plasma concentrations of the infused compounds and determining EC50 values. ACh and MCh both caused dose-dependent vasodilation, with EC50 values of 537 and 52 nmol/L, respectively. The apparent 10-fold higher potency of MCh compared with ACh may be explained by rapid degradation of ACh in plasma. The concentration-response curve of MCh was shifted to the right by atropine, pirenzepine, and AF-DX 116, with apparent pA2 values of 8.03 +/- 0.03, 6.71 +/- 0.08, and 5.32 +/- 0.05, respectively, and slopes not different from unity. The present technique enabled us to perform M-receptor characterization by Schild analysis in humans. The affinity constants and rank order of potency--atropine > pirenzepine > AF-DX 116-suggest that cholinergic vasodilation in this vascular bed is predominantly mediated by the M3-receptor subtype. The EC50 value of MCh and the pA2 values of pirenzepine and AF-DX 116 are comparable to values reported for in vitro experiments.

Carbamazepine-induced pseudolymphoma and immune dysregulation.

Pseudolymphoma is a condition that closely resembles malignant lymphoma, both clinically and on histopathological examination. Immunological cell typing is necessary for correct diagnosis. We present here the case of a patient with carbamazepine-induced generalized lymphadenopathy, hepatosplenomegaly, anaemia, abnormal differential leucocyte count, and hypergammaglobulinaemia. There was evidence of severe immune dysregulation. All abnormalities subsided spontaneously after withdrawal of carbamazepine and the patient remained in good health afterwards.