Masahiko Izumizaki

Intervention of Thymus and Activation-Regulated Chemokine Attenuates the Development of Allergic Airway Inflammation and Hyperresponsiveness in Mice

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.

The illusion of changed position and movement from vibrating one arm is altered by vision or movement of the other arm

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.

Aftereffects of mechanical vibration and muscle contraction on limb position-sense

Mechanical vibration (MV) of a muscle causes position‐sense errors during and after application. Isometric muscle contraction at a shorter (hold‐short conditioning) or longer (hold‐long conditioning) length causes limb position‐sense errors after the muscle returns to its intermediate length by means of intrafusal muscle thixotropy. However, it is unclear whether MV enhances these thixotropic position‐sense errors. We studied the after‐effects of MV on position‐sense errors induced by hold‐short and hold‐long conditioning in the biceps of 12 healthy men. After hold‐short conditioning, subjects perceived that the conditioned forearm was placed in a more extended position than occurred in reality; after hold‐long conditioning, a more flexed position was perceived. Use of MV with hold‐short or hold‐long conditioning enhanced both errors, which were most obvious at 100 HZ. These results suggest that MV and muscle conditioning work together efficiently to develop intrafusal muscle thixotropy. MV combined with hold‐long conditioning may alleviate thixotropically increased muscle stiffness, such as in spastic hypertonia. Muscle Nerve 30: 486–492, 2004

Impaired ventilation and metabolism response to hypoxia in histamine H1 receptor-knockout mice.

The role of central histamine in the hypoxic ventilatory response was examined in conscious wild-type (WT) and histamine type1 receptor-knockout (H1RKO) mice. Hypoxic gas (7% O(2) and 3% CO(2) in N(2)) exposure initially increased and then decreased ventilation, referred to as hypoxic ventilatory decline (HVD). The initial increase in ventilation did not differ between genotypes. However, H1RKO mice showed a blunted HVD, in which mean inspiratory flow was greater than that in WT mice. O(2) consumption (V(O2)) and CO(2) excretion were reduced 10min after hypoxic gas exposure in both genotypes, but (V(O2)) was greater in H1RKO mice than in WT mice. The ratio of minute ventilation to (V(O2)) during HVD did not differ between genotypes, indicating that ventilation is adequately controlled according to metabolic demand in both mice. Peripheral chemoreceptor sensitivity did not differ between genotypes. We conclude that central histamine contributes via the H1 receptor to changes in metabolic rate during hypoxia to increase HVD in conscious mice.

Effect of cooling on thixotropic position-sense error in human biceps muscle.

Muscle temperature affects muscle thixotropy. However, it is unclear whether changes in muscle temperature affect thixotropic position‐sense errors. We studied the effect of cooling on thixotropic position‐sense errors induced by short‐length muscle contraction (hold‐short conditioning) in the biceps of 12 healthy men. After hold‐short conditioning of the right biceps muscle in a cooled (5.0°C) or control (36.5°C) environment, subjects perceived greater extension of the conditioned forearm at 5.0°C. The angle differences between the two forearms following hold‐short conditioning of the right biceps muscle in normal or cooled conditions were significantly different (–3.335 ± 1.680° at 36.5°C vs. –5.317 ± 1.096° at 5.0°C; P = 0.043). Induction of a tonic vibration reflex in the biceps muscle elicited involuntary forearm elevation, and the angular velocities of the elevation differed significantly between arms conditioned in normal and cooled environments (1.583 ± 0.326°/s at 36.5°C vs. 3.100 ± 0.555°/s at 5.0°C, P = 0.0039). Thus, a cooled environment impairs a muscles ability to provide positional information, potentially leading to poor muscle performance. Muscle Nerve, 2007

Effect of quadriceps contraction on upper limb position sense errors in humans

Short-length muscle contraction (hold-short conditioning) causes limb position sense errors after the muscle returns to its intermediate length; this is due to intrafusal muscle thixotropy, which raises the muscle spindle sensitivity. In humans, contraction of muscles in the upper body (referred to as the Jendrassik manoeuvre) reinforces tendon reflexes in the lower limbs. However, it is unclear whether such a reinforcement manoeuvre enhances thixotropic position sense errors. We studied the effect of quadriceps contraction on upper limb position sense errors induced by hold-short conditioning of the biceps in 12 healthy men. Quadriceps contraction increased the tonic vibration reflex of the biceps, suggesting that quadriceps contraction has a reinforcing effect similar to that of the Jendrassik manoeuvre. After hold-short conditioning of the right biceps, subjects perceived that the conditioned forearm was placed in a more extended position than it actually was. Such position sense errors were enhanced during quadriceps contraction and the degree of error was increased with the intensity of the quadriceps contraction. These results suggest that limb position sense is affected by remote muscle contraction.

Lack of temperature-induced polypnea in histamine H1 receptor-deficient mice

Breathing patterns are influenced by body temperature. However, the central mechanism for changes of breathing patterns is unknown. We previously showed that central histamine contributed to temperature-induced polypnea in mice (Izumizaki, M., Iwase, M., Homma, I., Yanai, K., Watanabe, T. and Watanabe, T., Central histamine contributed to the temperature-induced polypnea in mice, Neurosci. Res., 23 (1999) S282). In this study we examined the role of central histamine H1 receptors in temperature-induced polypnea using wild and mutant mice lacking histamine H1 receptors. Breathing patterns were characterized at two different body temperatures during hypercapnia under conscious conditions. In wild mice a raised body temperature increased respiratory frequency mainly due to a reduction in expiratory time, whereas in mutant mice respiratory frequency did not increase even though the body temperature was elevated. These results indicate that central histamine contributes to an increase in respiratory frequency due to a reduction in expiratory time through histamine H1 receptors when body temperature is raised.

Factors contributing to thixotropy of inspiratory muscles

Thixotropy is a passive property of the skeletal muscle dependent on the muscles immediate history of contraction and length change. Thixotropic properties of inspiratory muscles, introduced by forceful muscle contraction at an inflated lung volume, cause an increased end-expiratory position (EEP) of the rib cage. We searched for factors contributing to the development of inspiratory muscle thixotropy in nine healthy subjects. Using induction plethysmography, we examined aftereffects on EEP of the duration of inspiratory muscle contraction and subsequent muscle relaxation. We also studied effects of inspiratory effort intensity measured by mouth pressure at different lung volumes. EEP elevation was noted subsequent to 5-s contraction followed by 2-s relaxation and was enhanced when conditioned at higher lung volumes with a strong inspiratory effort. Our results suggest four factors that influence inspiratory muscle thixotropy: (1) intensity of muscle contraction, (2) lung volume when contraction occurs, (3) duration of contraction, and (4) muscle relaxation.

Where is the Rhythm Generator for Emotional Breathing

As a result of recent progress in brain imaging techniques, a number of studies have been able to identify anatomical correlates of various emotions (Pujol et al., 2013; Tettamanti et al., 2012; van der Zwaag et al., 2012). However, emotions are not solely a phenomenon within the brain-they are also composed of body responses. These include autonomic and behavioral responses, such as changes in heart rate, blood pressure, skin conductance, and respiration. Among these physiological responses, respiration has a unique relationship to emotion. While the primary role of respiration concerns metabolism and homeostasis, emotions such as disgust, anger, and happiness also influence respiratory activities (Boiten et al., 1994). While respiratory change that accompanies emotions can occur unconsciously, respiration can also be voluntarily altered associating with an activation of the motor cortex. There may be no physiological expression for the association between the three areas of the brain that regulate respiration: the brainstem, the limbic system, and the cerebral cortex. The brainstem works to maintain homeostasis, the limbic system is responsible for emotional processing, and the cerebral cortex controls intention. Investigating the interaction between these brain regions may lead to an explanation about why they are so widely dispersed in the brain, despite their common role in the regulation of respiration. In this chapter, we review our findings on breathing behavior and discuss the mechanisms underlying the relationship between emotion and respiration.

Dopaminergic modulation of exercise hyperpnoea via D2 receptors in mice

Dopamine is related to behaviour (including arousal, motivation and motor control of locomotion), and its turnover in the brain is increased during exercise. We examined the hypothesis that dopamine D2 receptors contribute to exercise hyperpnoea via central neural pathways using the D2‐like receptor antagonist, raclopride. We simultaneously measured ventilation and pulmonary gas exchange for the first time in mice. Mice injected with saline and raclopride (2 mg (kg body weight)−1; i.p.) were compared for respiratory responses to constant‐load exercise at 6 m min−1. Each mouse was set in an airtight treadmill chamber. In the resting state, raclopride‐treated mice had reduced respiratory frequency (fR) and minute ventilation ( ) compared with saline‐treated mice, but arterial and pulmonary gas exchange were not affected, showing that alveolar ventilation was maintained. Inhalation of hyperoxic gas maintained in saline‐treated mice, and hypercapnic ventilatory responses between the two groups were similar. Treadmill exercise produced an abrupt increase in to a maximal level within 1 min and declined to a steady‐state level in both groups. Raclopride‐treated mice had reduced fR and compared with saline‐treated mice during steady states, but showed a similar increase in fR and at exercise onset. Minute ventilation in the steady state was controlled, along with the increase in pulmonary O2 uptake in both groups, but was lowered in raclopride‐treated mice. Thus, D2 receptors participate in resting breathing patterns to raise fR and exercise hyperpnoea in the steady state, probably through behavioural control and not central motor command, at exercise onset.