Thymus- and activation-regulated chemokine (TARC; CCL17) is a lymphocyte-directed CC chemokine that specifically chemoattracts CC chemokine receptor 4-positive (CCR4+) Th2 cells. To establish the pathophysiological roles of TARC in vivo, we investigated here whether an mAb against TARC could inhibit the induction of asthmatic reaction in mice elicited by OVA. TARC was constitutively expressed in the lung and was up-regulated in allergic inflammation. The specific Ab against TARC attenuated OVA-induced airway eosinophilia and diminished the degree of airway hyperresponsiveness with a concomitant decrease in Th2 cytokine levels. Our results for the first time indicate that TARC is a pivotal chemokine for the development of Th2-dominated experimental allergen-induced asthma with eosinophilia and AHR. This study also represents the first success in controlling Th2 cytokine production in vivo by targeting a chemokine.

Asthma is one of the most common diseases and is characterized by airway obstruction, airway inflammation, and increased airway responsiveness. Glucocorticoids are very effective in treatment, but their long-term use is associated with several side effects, so that new antiinflammatory drugs are in development.

The oxygen affinity of hemoglobin is critical for gas exchange in the lung and O 2 delivery in peripheral tissues. In the present study, we generated model mice that carry low affinity hemoglobin with the Titusville mutation in the ␣-globin gene or Presbyterian mutation in the ␤-globin gene. The mutant mice showed increased O 2 consumption and CO 2 production in tissue metabolism, suggesting enhanced O 2 delivery by mutant Hbs. The histology of muscle showed a phenotypical conversion from a fast glycolytic to fast oxidative type. Surprisingly, mutant mice spontaneously ran twice as far as controls despite mild anemia. The oxygen affinity of hemoglobin may control the basal level of erythropoiesis, tissue O 2 consumption, physical activity, and behavior in mice.

Experiments were carried out on blindfolded human subjects to study the contribution of proprioceptive inputs from both arms in a forearm position matching task. Blindfolded matching accuracy was compared with accuracy when the subject could see their indicator (matching) arm, when they used a dummy arm for matching, and when they looked at a mirror image of the matching arm. The position of the mirror had been arranged so that the image of the indicator arm coincided with the position of the reference arm. None of these conditions significantly altered the matching errors. When reference elbow flexors were vibrated at 70-80 Hz, the illusion of extension of the vibrated arm reported by blindfolded subjects was significantly reduced by vision of the mirror image of the indicator arm or when using the dummy arm. It was concluded that visual information about the position of the indicator arm, or the apparent position of the reference arm, could reduce the size of the kinaesthetic illusion from vibration, but not abolish it. In a second experiment, subjects indicated, by tracking with their vibrated arm, the illusion of forearm extension evoked by elbow flexor vibration. It was found that the perceived speed of extension could be reduced by moving the indicator into extension and increased by moving it into flexion. These experiments demonstrate the importance for the matching process of the input provided by the indicator arm. Such a conclusion may help to explain some apparent discrepancies between observations made on position sense using one-arm and two-arm tasks. More broadly, this paper provides support for the idea that aspects of proprioceptive inputs from both arms are processed conjointly, as part of a strategy for use of the two hands as a single instrument in certain skilled tasks.

The natural anticoagulant-activated protein C may inhibit inflammation and fibrosis in the lung. Platelet-derived growth factor is involved in the pathogenesis of lung fibrosis. This study assessed the effect of activated protein C on platelet-derived growth factor expression in human cell lines and in an in vivo model of lung fibrosis. Activated protein C significantly inhibited the secretion and expression of platelet-derived growth factor in human lung cell lines, primary bronchial epithelial cells, and macrophages. In vitro studies also showed that the endothelial activated protein C receptor is expressed by lung epithelial cells and macrophages, and that this receptor and the proteolytic activity of activated protein are implicated in the inhibition of platelet-derived growth factor expression. In the in vivo model of lung fibrosis, intratracheal administration of activated protein C decreased the expression of platelet-derived growth factor and suppressed the development of lung fibrosis. Concomitant intratracheal administration of activated protein C and anti-endothelial activated protein C receptor or anti-platelet-derived growth factor suppressed the inhibitory activity of activated protein C in vivo. In brief, this study describes a novel biological function of activated protein C that may further explain its inhibitory activity on lung inflammation and fibrosis.