In adult rats, 50,000 units of recombinant interleukin-1 beta (IL-1 beta) injected into the brain parenchyma produced an intense meningitis and disruption of the blood-CSF barrier by 4 h. No increase in vascular permeability to horseradish peroxidase or leukocyte recruitment was observed at the site of injection. By contrast, in juvenile rats, 100 units of IL-1 beta injected into the striatum gave rise to a large increase in blood-brain barrier permeability and recruitment of polymorphonuclear neutrophils into the tissue around the injection site by 4 h. This effect was also accompanied by a marked meningitis. The injection of 100 units of IL-1 beta into neonatal (2-h-old) rats gave rise to an increase in permeability of vessels to serum proteins in the meninges, but no increase in vascular permeability was observed at the injection site. The IL-1 beta-induced increases in vessel permeability in the meninges, parenchyma, and choroid plexus were polymorphonuclear neutrophil dependent, since leukocyte depletion by irradiation or polymorphonuclear neutrophil anti-serum pre-treatment eliminated the response in the juvenile animals and in the adults. Seventy-five thousand units of murine tumour necrosis factor-alpha injected into the parenchyma of both adults and juvenile animals failed to induce an increase in blood-brain barrier permeability or polymorphonuclear neutrophil recruitment, but did give rise to a mild meningitis. These findings demonstrate clear differences in the responsiveness of different CNS compartments to IL-1 beta. Furthermore, while tumour necrosis factor-alpha and IL-1 beta might have been expected to exhibit similar proinflammatory effects in the CNS, this is not the case. We also show, for the first time, that age has a significant effect on the response to a cytokine. The "window of susceptibility' to an inflammatory stimulus in juvenile rats, if paralleled in humans, may be a major factor in the increased susceptibility of children to trauma or to infectious insults to the CNS.

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We conclude that an MPO inhibitor is able to stop progression of emphysema and small airway remodeling and to partially protect against pulmonary hypertension, even when treatment starts relatively late in the course of long-term smoke exposure, suggesting that inhibition of MPO may be a novel and useful therapeutic treatment for COPD. Protection appears to relate to inhibition of oxidative damage and down-regulation of the smoke-induced inflammatory response.