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Transient receptor potential ankyrin 1 (TRPA1), a member of the TRP superfamily of cation channels, is broadly expressed in sensory neural pathways, including the trigeminal neurons innervating the nasal cavity and vagal neurons innervating the trachea and the lung. TRPA1 acts as a detector of various irritant chemicals as well as hypoxia and hyperoxia. For the past 15 years, we have characterised its role in respiratory and behavioural modulation in vivo using Trpa1 knockout (KO) mice and wild‐type (WT) littermates. Trpa1 KO mice failed to detect, wake up from sleeping, and escape from formalin vapour and a mild hypoxic (15% O2) environment. Respiratory augmentation induced by mild hypoxia was absent in either Trpa1 KO mice or WT mice treated with a TRPA1 antagonist. Irritant gas introduced into the nasal cavity inhibited respiratory responses in WT mice but not in the KO mice. The effect of TRPA1 on the olfactory system seemed minimal because olfactory bulbectomized WT mice reacted similarly to the intact mice. Immunohistological analyses using a cellar activation marker, the phosphorylated form of extracellular signal‐regulated kinase, confirmed activation of trigeminal neurons in WT mice but not in Trpa1 KO mice in response to irritant chemicals and mild hypoxia. These data collectively show that TRPA1 is necessary for multiple chemical‐induced protective responses in respiration and behaviour. We propose that TRPA1 channels in the airway may play a sentinel role for environmental threats and prevent incoming damage. [ABSTRACT FROM AUTHOR]

Background Postanesthetic shivering can be triggered by surgical stress and several aspects of anesthetic management and is frequently preceded by a decrease in peripheral blood flow due to thermoregulatory vasoconstriction. As perfusion index correlates with peripheral blood flow, we examined whether perioperative perfusion index, measured using pulse oximetry, might be correlated with post-anesthetic shivering. Methods Twenty-eight patients presenting for elective abdominal surgery were enrolled. Core (esophagus) and peripheral (finger) temperatures and perfusion index were recorded in the perioperative periods. Correlations between perfusion index and peripheral temperature and core-to-peripheral temperature gradient were then explored. Plasma levels of epinephrine and norepinephrine were also measured. The extent of shivering was graded after emergence from anesthesia. Results Perfusion index declined before emergence from anesthesia in patients who then developed post-anesthetic shivering. This coincided with the time at which the difference between core and peripheral temperature became dissociated and peripheral temperature declined. Perioperative perfusion index was correlated with peripheral temperature and peripheral-core temperature gradient. Perfusion index at closure of the peritoneum predicted postanesthetic shivering and was significantly correlated with the extent of shivering. Plasma levels of both epinephrine and norepinephrine were significantly elevated after shivering events. Conclusions Perfusion index was significantly lower in patients with postanesthetic shivering before emergence from anesthesia, indicating that measurement of perfusion index during and before the end of anesthesia might be a useful means of predicting postanesthetic shivering. Keywords Postanesthetic shivering * Perfusion index * Core-to-peripheral temperature gradient, Introduction Postanesthetic shivering occurs in approximately 40% of unwarmed patients recovering from general anesthesia and is associated with substantial adrenergic activation and discomfort [1]. Shivering can increase tissue oxygen consumption [...]

We have previously shown that some features of the defense response, such as increases in arterial blood pressure (AP), heart rate (HR), and ventilation were attenuated in prepro-orexin knockout (ORX-KO) mice. Here, we examined whether the same was true in orexin neuron-ablated [orexin/ataxin-3 transgenic mice (ORX/ATX-Tg)] mice. In addition, we examined other features of the defense response: skeletal muscular vasodilation and shift of baroreceptor reflex. In both anesthetized and conscious conditions, basal AP in ORX/ATX-Tg mice was significantly lower by ~20 mmHg than in wild-type (WT) controls, as was the case in ORX-KO mice. The difference in AP disappeared after treatment with an [alpha]-blocker but not with a [beta]-blocker, indicating lower sympathetic vasoconstrictor outflow. Stimulation of the perifornical area (PFA) in urethane-anesthetized ORX/ATX-Tg mice elicited smaller and shorter-lasting increases in AP, HR, and ventilation, and skeletal muscle vasodilation than in WT controls. In addition, air jet stress-induced elevations of AP and HR were attenuated in conscious ORX/ATX-Tg mice. After pretreatment with a [beta]-blocker, atenolol, stimulation of PFA suppressed phenylephrine (50 [micro]g/kg iv)-induced bradycardia ([DELTA]HR = -360 [+ or -] 29 beats/min without PFA stimulation vs. -166 [+ or -] 26 during stimulation) in WT. This demonstrated the resetting of the baroreflex. In ORX/ATX-Tg mice, however, no significant suppression was observed (-355 [+ or -] 16 without stimulation vs. -300 [+ or -] 30 during stimulation). The present study provided further support for our hypothesis that orexin-containing neurons in PFA play a role as a master switch to activate multiple efferent pathways of the defense response and also operate as a regulator of basal AP. hypothalamus; stress; blood pressure; respiration

The core fucosylation ([alpha]1,6-fucosylation) of glycoproteins is widely distributed in mammalian tissues, and is altered under pathological conditions. To investigate physiological functions of the core fucose, we generated [alpha]1,6-fucosyltransferase (Fut8)-null mice and found that disruption of Fut8 induces severe growth retardation and death during postnatal development. Histopathological analysis revealed that [Fut8.sup.-/-] mice showed emphysema-like changes in the lung, verified by a physiological compliance analysis. Biochemical studies indicated that lungs from [Fut.sup.8-/-] mice exhibit a marked overexpression of matrix metalloproteinases (MMPs), such as MMP-12 and MMP-13, highly associated with lung-destructive phenotypes, and a down-regulation of extracellular matrix (ECM) proteins such as elastin, as well as retarded alveolar epithelia cell differentiation. These changes should be consistent with a deficiency in TGF-[beta]1 signaling, a pleiotropic factor that controls ECM homeostasis by down-regulating MMP expression and inducing ECM protein components. In fact, [Fut8.sup.-/-] mice have a marked dysregulation of TGF-[beta]1 receptor activation and signaling, as assessed by TGF-[beta]1 binding assays and Smad2 phosphorylation analysis. We also show that these TGF-[beta]1 receptor defects found in [Fut8.sup.-/-] cells can be rescued by reintroducing Fut8 into [Fut8.sup.-l-] cells. Furthermore, exogenous TGF-[beta]1 potentially rescued emphysema-like phenotype and concomitantly reduced MMP expression in [Fut8.sup.-/-] lung. We propose that the lack of core fucosylation of TGF-[beta]1 receptors is crucial for a developmental and progressive/ destructive emphysema, suggesting that perturbation of this function could underlie certain cases of human emphysema. fucosylation | glycobiology | matrix metalloproteinase

The perifornical area of the hypothalamus has been known as the center for the defense response, or 'fight or flight' response, which is characterized by a concomitant rise in arterial blood pressure (AP), heart rate (HR), and respiratory frequency (Rf). We examined whether orexin, a recently identified hypothalamic neuropeptide, contributes to the defense response and basal cardiovascular regulation using orexin knockout mice. Microinjection of a GABA-A receptor antagonist, bicuculline methiodide (0.1-1 mM in 20 nl), to the perifornical area in urethane-anesthetized wild-type mice elicited dose-dependent increases in AP, HR, and Rf. Although similar changes were observed in orexin knockout mice, intensities were smaller and duration was shorter than those in wild-type mice. Moreover, in an awake and freely moving condition, telemeter-indwelling orexin knockout mice showed diminished cardiovascular and behavioral responses to emotional stress in the residentintruder test. We also found that basal AP in orexin knockout mice was significantly lower in both anesthetized (117 [+ or -] 8 mmHg in wild type and 92 [+ or -] 3 in knockout) and conscious (125 [+ or -] 6 mmHg in wild type and 109 [+ or -] 2 in knockout) conditions. [alpha]-Adrenergic blockade with prazosin or ganglion blockade with hexamethonium canceled the difference in basal AP. HR and cardiac contractile parameters by echocardiography did not differ between the two strains of mice. These results indicate lower sympathetic vasoconstrictor tone in knockout mice. The present study suggests that orexin-containing neurons in the perifornical area play a role as one of the efferent pathways of defense response and also operate as a regulator of AP at basal condition by activating sympathetic outflow. hypothalamus; stress; respiration; sympathetic nervous system; circadian rhythm