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A study was conducted with a Guinea Pig (GP) cough model to demonstrate that post-inhalation (PI) cough can be correlated and predicted with the acidity constant of the chemical stimulant. The test animals were exposed to nebulized solutions of citric acid and maleic acid. Cough responses were measured by audio, video, and respiratory flow signals via whole-body plethysmography. Nonparametric one-way ANOVA (Kruskal-Wallis) of cough counts showed statistically significant dose dependence for both citric acid (p 0.05). Similar results were obtained for maleic acid exposures, with cough response at the higher concentrations significantly different compared to SL (p=0.0039 for 50 mM, p

Background Asthma is characterized by chronic airway inflammation, airway hyperresponsiveness (AHR), and airway remodeling. While exposure of house dust mites (HDM) is a common cause of asthma, the pathogenesis of the HDM-induced asthma is not fully understood. Bronchopulmonary C-fibers (PCFs) contribute to the neurogenic inflammation, viral infection induced-persistent AHR, and ovalbumin induced collagen deposition largely via releasing neuropeptides, such as substance P (SP). However, PCF roles in the pathogenesis of the HDM-induced asthma remain unexplored. The goal of this study was to determine what role PCFs played in generating these characteristics. Methods We compared the following variables among the PCF-intact and -degenerated BALB/c mice with and without chronic HDM exposure (four groups): 1) AHR and pulmonary SP; 2) airway smooth muscle (ASM) mass; 3) pulmonary inflammatory cells; and 4) epithelium thickening and mucus secretion. Results We found that HDM evoked AHR associated with upregulation of pulmonary SP and inflammation, ASM mass increase, epithelium thickenings, and mucus hypersecretion. PCF degeneration decreased the HDM-induced changes in AHR, pulmonary SP and inflammation, and ASM mass, but failed to significantly affect the epithelium thickening and mucus hypersecretion. Conclusion Our data suggest an involvement of PCFs in the mechanisms by which HDM induces allergic asthma via airway inflammation, AHR, and airway remodeling.

Rat pups prenatally exposed to nicotine (PNE) present apneic (lethal ventilatory arrest) responses during severe hypoxia. To clarify whether these responses are of central origin, we tested PNE effects on ventilation and diaphragm electromyography (EMGdi) during hypoxia in conscious rat pups. PNE produced apnea (lethal ventilatory arrest) identical to EMGdi silencing during hypoxia, indicating a central origin of this apneic response. We further asked whether PNE would sensitize bronchopulmonary C-fibers (PCFs), a key player in generating central apnea, with increase of the density and transient receptor potential cation channel subfamily V member 1 (TRPV1) expression of C-fibers/neurons in the nodose/jugular (N/J) ganglia and neurotrophic factors in the airways and lungs. We compared 1) ventilatory and pulmonary C-neural responses to right atrial bolus injection of capsaicin (CAP, 0.5 μg/kg), 2) bronchial substance P-immunoreactive (SP-IR) fiber density, 3) gene and protein expressions of TRPV1 in the ganglia, and 4) nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) protein in bronchoalveolar lavage fluid (BALF) and TrkA and TrkB genes in the ganglia between control and PNE pups. PNE markedly strengthened the PCF-mediated apneic response to CAP via increasing pulmonary C-neural sensitivity. PNE also enhanced bronchial SP-IR fiber density and N/J ganglia neural TRPV1 expression associated with increased gene expression of TrkA in the N/G ganglia and decreased NGF and BDNF in BALF. Our results suggest that PNE enhances PCF sensitivity likely through increasing PCF density and TRPV1 expression via upregulation of neural TrkA and downregulation of pulmonary BDNF, which may contribute to the PNE-promoted central apnea (lethal ventilatory arrest) during hypoxia.

Lethal influenza A (H5N1) induces respiratory failure in humans. Although it also causes death at 7 days postinfection (dpi) in mice, the development of the respiratory failure and the viral impact on pre-Botzinger complex (PBC) neurons expressing neurokinin 1 receptor (NK1R), which is the respiratory rhythm generator, have not been explored. Body temperature, weight, ventilation, and arterial blood pH and gases were measured at 0, 2, 4, and 6 dpi in control, lethal HK483, and nonlethal HK486 viral-infected mice. Immunoreactivities (IR) of PBC NK1R, H5N1 viral nucleoprotein (NP), and active caspase-3 (CASP3; a marker for apoptosis) were detected at 6 dpi. HK483, but not HK486, mice showed the following abnormalities: 1) gradual body weight loss and hypothermia; 2) tachypnea at 2–4 dpi and ataxic breathing with long-lasting apneas and hypercapnic hypoxemia at 6 dpi; and 3) viral replication in PBC NK1R neurons with NK1R-IR reduced by 75% and CASP3-IR colabeled at 6 dpi. Lethal H5N1 viral infection causes tachypnea at the early stage and ataxic breathing and apneas (hypercapnic hypoxemia) leading to death at the late stage. Its replication in the PBC induces apoptosis of local NK1R neurons, contributing to ataxic breathing and respiratory failure.

Sarin is an organophosphate nerve agent that is among the most lethal chemical toxins known to mankind. Because of its vaporization properties and ease and low cost of production, sarin is the nerve agent with a strong potential for use by terrorists and rouge nations. The primary route of sarin exposure is through inhalation and, depending on the dose, sarin leads to acute respiratory failure and death. The mechanism(s) of sarin-induced respiratory failure is poorly understood. Sarin irreversibly inhibits acetylcholine esterase, leading to excessive synaptic levels of acetylcholine and, we have previously shown that sarin causes marked ventilatory changes including weakened response to hypoxia. We now show that LD50 sarin inhalation causes severe bronchoconstriction in rats, leading to airway resistance, increased hypoxia-induced factor-1α, and severe lung epithelium injury. Transferring animals into 60% oxygen chambers after sarin exposure improved the survival from about 50% to 75% at 24h; however, many animals died within hours after removal from the oxygen chambers. On the other hand, if LD50 sarin-exposed animals were administered the bronchodilator epinephrine, >90% of the animals survived. Moreover, while both epinephrine and oxygen treatments moderated cardiorespiratory parameters, the proinflammatory cytokine surge, and elevated expression of hypoxia-induced factor-1α, only epinephrine consistently reduced the sarin-induced bronchoconstriction. These data suggest that severe bronchoconstriction is a critical factor in the mortality induced by LD50 sarin inhalation, and epinephrine may limit the ventilatory, inflammatory, and lethal effects of sarin.

Background: Extracellular adenosine 5′-triphosphate (ATP) plays important mechanistic roles in pulmonary disorders in general and chronic obstructive pulmonary disease (COPD) and cough in particular. The effects of ATP in the lungs are mediated to a large extent by P2X2/3 receptors (P2X2/3R) localized on vagal sensory nerve terminals (both C and Aδ fibers). The activation of these receptors by ATP triggers a pulmonary-pulmonary central reflex, which results in bronchoconstriction and cough, and is also proinflammatory due to the release of neuropeptides from these nerve terminals via the axon reflex. These actions of ATP in the lungs constitute a strong rationale for the development of a new class of drugs targeting P2X2/3R. DT-0111 is a novel, small, water-soluble molecule that acts as an antagonist at P2X2/3R sites. Methods: Experiments using receptor-binding functional assays, rat nodose ganglionic cells, perfused innervated guinea pig lung preparation ex vivo, and anesthetized and conscious guinea pigs in vivo were performed. Results: DT-0111 acted as a selective and effective antagonist at P2X2/3R, that is, it did not activate or block P2YR; markedly inhibited the activation by ATP of nodose pulmonary vagal afferents in vitro; and, given as an aerosol, inhibited aerosolized ATP-induced bronchoconstriction and cough in vivo. Conclusions: These results indicate that DT-0111 is an attractive drug-candidate for the treatment of COPD and chronic cough, both of which still constitute major unmet clinical needs. The reviews of this paper are available via the supplementary material section.

Maternal cigarette smoke is the major risk of sudden infant death syndrome (SIDS). A depressed ventilatory response to hypoxia (HVR) and hypercapnia (HCVR) is thought to be responsible for the pathogenesis of SIDS and the carotid body is critically involved in these responses. We have recently reported that prenatal nicotinic exposure (PNE) over the full gestation induces depressed HVR in rat pups. Here, we asked whether PNE (1) depressed not only HVR but also HCVR that were dependent on the carotid body, (2) affected some important receptors and neurochemicals expressed in the carotid body, such as tyrosine hydroxylase (TH), neurokinin-1 receptor (NK1R), and α7 nicotinic acetylcholine receptor (α7nAChR), and (3) blunted the ventilatory responses to activation of these receptors. To this end, HVR and HCVR in Ctrl and PNE pups were measured with plethysmography before and after carotid body ablation (Series I), mRNA expression and/or immunoreactivity (IR) of TH, NK1R, and α7nAChR in the carotid body were examined by RT-PCR and immunohistochemistry (Series II), and the ventilatory responses were tested before and after intracarotid injection of substance P (NK1R agonist) and AR-R17779 (α7nAChR agonist) (Series III). Our results showed that PNE (1) significantly depressed both HVR and HCVR and these depressions were abolished by carotid body ablation, (2) reduced the relative population of glomus cells, mRNA NK1R, and α7nAChR and IR of NK1R and TH in the carotid body, and (3) decreased ventilatory responses to intracarotid injection of substance P or AR-R17779. These results suggest that PNE acting via the carotid body could strikingly blunt HVR and HCVR, likely through downregulating TH and NK1R.

H5N1 virus infection results in ~60% mortality in patients primarily due to respiratory failure, but the underlying causes of mortality are unclear. The goal of this study is to reveal respiratory disorders occurring at the early stage of infection that may be responsible for subsequent respiratory failure and death. BALB/c mice were intranasally infected with one of two H5N1 virus strains: HK483 (lethal) or HK486 (non-lethal) virus. Pulmonary ventilation and the responses to hypoxia (HVR; 7% O2 for 3 min) and hypercapnia (HCVR; 7% CO2 for 5 min) were measured daily at 2 days prior and 1, 2, and 3 days postinfection (dpi) and compared to mortality typically by 8 dpi. At 1, 2, and 3 dpi, immunoreactivities (IR) of substance P (SP-IR) in the nodose ganglion or tyrosine hydroxylase (TH-IR) in the carotid body coupled with the nucleoprotein of influenza A (NP-IR) was examined in some mice, while arterial blood was collected in others. Our results showed that at 2 and 3 dpi: 1) both viral infections failed to alter body temperature and weight, [Formula: see text], or induce viremia while producing similarly high lung viral titers; 2) HK483, but not HK486, virus induced tachypnea and depressed HVR and HCVR without changes in arterial blood pH and gases; and 3) only HK483 virus led to NP-IR in vagal SP-IR neurons, but not in the carotid body, and increased density of vagal SP-IR neurons. In addition, all HK483, rather than HK486, mice died at 6 to 8 dpi and the earlier death was correlated with more severe depression of HVR and HCVR. Our data suggest that tachypnea and depressed HVR/HCVR occur at the early stage of lethal H5N1 viral infection associated with viral replication and increased SP-IR density in vagal neurons, which may contribute to the respiratory failure and death.

Our previous study has shown that activating peripheral μ-receptors is necessary for switching the bronchopulmonary C-fibers (PCFs)-mediated rapid shallow breathing (RSB) into an apnea by systemic administration of fentanyl. The brainstem nuclei, such as the medial nucleus tractus solitarius (mNTS) and the pre-Botzinger complex (PBC), are required for completing the PCF-mediated respiratory reflexes. Moreover, these areas contain abundant μ-receptors and their activation prolongs expiratory duration (TE). Thus, we asked if central μ-receptors, especially those in the mNTS and PBC, are involved in fully expressing this RSB-apnea switch by fentanyl. In anesthetized rats, the cardiorespiratory responses to right atrial injection of phenylbiguanide (PBG, 3–6 μg/kg) were repeated after: (1) fentanyl (iv), a μ-receptor agonist, alone (8 μg/kg, iv); (2) fentanyl following microinjection of naloxone methiodide (NXM, an opioid receptor antagonist) into the cisterna magna (10 μg/4 μl); (3) the bilateral mNTS (10 mM, 20 nl); or (4) PBC (10 mM, 20 nl). Our results showed that PBG shortened TE by 37 ± 6% (RSB, from 0.41 ± 0.05 to 0.26 ± 0.03 s, P < 0.01), but it markedly prolonged TE by 5.8-fold (an apnea, from 0.50 ± 0.04 s to 2.9 ± 0.57 s, P < 0.01) after fentanyl (iv). Pretreatment with NXM injected into the cisterna magna or the PBC, but not the mNTS, prevented the fentanyl-induced switch. This study, along with our previous results mentioned above, suggests that although peripheral μ-receptors are essential for triggering the fentanyl-induced switch, central μ-receptors, especially those in the PBC, are required to fully exhibit such switch. Summary statement: Our results suggest that the activation of central μ-receptors, especially those in the pre-Botzinger complex, is required for switching the pulmonary C-fiber-mediated rapid shallow breathing into an apnea by systemic administration of fentanyl.

Passive limb movement (PLM) in humans induces a phasic hyperpnea, but the underlying physiological mechanisms remain unclear. We asked whether PLM in anesthetized rats would produce a similar phasic hyperpnea associated with an augmented ventilatory (V(E)) response to CO(2) that is dependent on sciatic afferents. The animals underwent 5 min threshold PLM, 3 min hypercapnia (5% CO(2)), and their combination (CO(2) exposure at the end of 2nd min of 5-min PLM) before and after bilateral transection of the sciatic nerves. We found that a threshold PLM evoked a phasic hyperpnea, similar to that denoted in humans, and an augmented V(E) response to CO(2). Both responses were greatly diminished by sciatic nerve transection. Moreover, similar responses were also evoked by electrically stimulating the central end of the transected sciatic nerve. Our findings suggest an ability of the sciatic afferents to augment the V(E) response to CO(2) that likely contributes to the PLM-induced hyperpnea.

It has been reported that the degree of emphysema induced by chronic cigarette smoke (CS) is greater in female C3H/HeN mice as compared to other mouse strains. We hypothesized that these mice would develop the similar major characteristics seen in hypercapnic patients with chronic obstructive pulmonary disease (COPD), including emphysema, pulmonary inflammation, hypercapnia/hypoxemia, rapid breathing, and attenuated ventilatory response (AVR). Mice were exposed either to CS or filtered air (FA) for 16 weeks. After exposure, arterial blood gases and minute ventilation were measured before and during chemical challenges in anesthetized and spontaneously breathing mice. We found that as compared to FA, CS exposure caused emphysema and pulmonary inflammation associated with: (1) hypercapnia and hypoxemia, (2) rapid breathing, and (3) AVR to 25 breaths of pure N2, 5% CO2 alone, and 5% CO2 coupled with 10% O2. The similarity of these pathophysiological characteristics between our mouse model and COPD patients suggests that this model could be effectively applied to study COPD pathophysiology, especially central mechanisms of the AVR genesis.

Children with acute respiratory syncytial virus (RSV) infection often develop sequelae of persistent airway inflammation and wheezing. Pulmonary C fibers (PCFs) are involved in the generation of airway inflammation and resistance; however, their role in persistent airway diseases after RSV is unexplored. Here, we elucidated the pathogenesis of PCF activation in RSV-induced persistent airway disorders. PCF-degenerated and intact mice were used in the current study. Airway inflammation and airway resistance were evaluated. MMP408 and FSLLRY-NH2 were the selective antagonists for MMP-12 and PAR2, respectively, to investigate the roles of MMP-12 and PAR2 in PCFs mediating airway diseases. As a result, PCF degeneration significantly reduced the following responses to RSV infection: augmenting of inflammatory cells, especially macrophages, and infiltrating of inflammatory cells in lung tissues; specific airway resistance (sRaw) response to methacholine; and upregulation of MMP-12 and PAR2 expression. Moreover, the inhibition of MMP-12 reduced the total number of cells and macrophages in bronchiolar lavage fluid (BALF), as well infiltrating inflammatory cells, and decreased the sRaw response to methacholine. In addition, PAR2 was upregulated especially at the later stage of RSV infection. Downregulation of PAR2 ameliorated airway inflammation and resistance following RSV infection and suppressed the level of MMP-12. In all, the results suggest that PCF involvement in long-term airway inflammation and airway hyperresponsiveness occurred at least partially via modulating MMP-12, and the activation of PAR2 might be related to PCF-modulated MMP-12 production. Our initial findings indicated that the inhibition of PCF activity would be targeted therapeutically for virus infection-induced long-term airway disorders. IMPORTANCE The current study is critical to understanding that PCFs are involved in long-term airway inflammation and airway resistance after RSV infection through mediating MMP-12 production via PAR2, indicating that the inhibition of PCF activity can be targeted therapeutically for virus infection-induced long-term airway disorders.

RSV infection causes acute AI and AHR with the peak response occurring at ~5th day postinfection (PID 5) in humans and animals. Owing to the critical role of PCFs in regulating pulmonary inflammati...

The mutational status of the immunoglobulin heavy chain variable region defines two clinically distinct forms of chronic lymphocytic leukemia (CLL) known as mutated (M-CLL) and unmutated (UM-CLL). To elucidate the molecular mechanisms underlying the adverse clinical outcome associated with UM-CLL, total proteomes from nine UM-CLL and nine M-CLL samples were analyzed by isobaric tags for relative and absolute quantification (iTRAQ)-based mass spectrometry. Based on the expression of 3521 identified proteins, principal component analysis separated CLL samples into two groups corresponding to immunoglobulin heavy chain variable region mutational status. Computational analysis showed that 43 cell migration/adhesion pathways were significantly enriched by 39 differentially expressed proteins, 35 of which were expressed at significantly lower levels in UM-CLL samples. Furthermore, UM-CLL cells underexpressed proteins associated with cytoskeletal remodeling and overexpressed proteins associated with transcriptional and translational activity. Taken together, our findings indicate that UM-CLL cells are less migratory and more adhesive than M-CLL cells, resulting in their retention in lymph nodes, where they are exposed to proliferative stimuli. In keeping with this hypothesis, analysis of an extended cohort of 120 CLL patients revealed a strong and specific association between UM-CLL and lymphadenopathy. Our study illustrates the potential of total proteome analysis to elucidate pathogenetic mechanisms in cancer.

The carotid sinus nerve (CSN), important in cardiorespiratory modulation, mainly contains C fibers (CSCFs). Previous studies have demonstrated that selective stimulation of bronchopulmonary C fibers (PCFs) via right atrial injection of capsaicin (Cap; approximately 0.25 microg) results in an apnea (approximately 3 s) associated with hypotension and bradycardia. The present study was undertaken to determine the effects of activating CSCFs on cardiorespiratory activities. Intracarotid injection of Cap was performed before and after bilateral transection of the CSN in anesthetized and spontaneously breathing rats. Our results showed that 1) low doses of Cap (up to 2 ng) produced an increase in minute ventilation by elevating both tidal volume and respiratory frequency with the threshold dosage at 1.0 ng (P0.05); 2) high doses (4-64 ng) generated an apnea (prolongation of expiratory duration by approximately 8-fold) and hypertension (P0.05); 3) bilateral transection of the CSN reduced excitatory and inhibitory respiratory responses by 30 and 81%, respectively, and increased the hypertension by 88% (P0.05); and 4) the same doses of Cap delivered into the right atrium to stimulate PCFs failed to evoke detectable cardiorespiratory responses. Our results suggest that compared with PCFs, CSCFs are more sensitive to Cap stimulation and that activation of these fibers significantly modulates cardiorespiratory activity in anesthetized rats.

Mcl-1 is essential for normal haematopoiesis, being required for lymphocyte development and maintenance. Its role in haematopoietic differentiation and development is associated with its function as an anti-apoptotic member of the Bcl-2 family of proteins although the underlining mechanism is poorly understood. We have characterized caspase cleavage of the Mcl-1 protein during apoptosis. Caspase cleavage resulted in the removal of the PEST regions from the protein and generation of a fragment containing the BH-1, -2 and -3 homology domains. Removal of the PEST regions did not appear to alter Mcl-1 stability, suggesting that these regions are not responsible for Mcl-1's short half-life. In addition, unlike cleavage of Bcl-2 and Bcl-X(L), which resulted in pro-apoptotic fragments, cleaved forms of Mcl-1 were unable to induce apoptosis. This novel regulation of Mcl-1 may have important implications not only for its role in apoptosis but also for the essential role it plays in the differentiation and development of haematopoietic cells.

Activation of the vestibular system can either increase or decrease ventilation. The objectives of the present study were to clarify whether these different responses are the result of activating different vestibular subnuclei, by addressing three questions. Do neurones within the medial, lateral and spinal vestibular nuclei (VN(M), VN(L) and VN(S), respectively) function differently in respiratory modulation? Is the ventral medullary nucleus gigantocellularis (NGC) required to fully express the VN-mediated respiratory responses? Is glutamate, by acting on N-methyl-D-aspartic acid (NMDA) receptors in the vestibular subnuclei, capable of modulating respiration? In anaesthetized, tracheotomized and spontaneously breathing rats, electrical stimuli (10 s) applied in the VN(L) and VN(S) significantly elevated ventilation by 35 % and 30 % (P0.05), respectively. However, VN(M) stimulation produced statistically significant (P0.05) changes that differed depending upon the stimulation site: either ventilatory inhibition (by 40 % in 57 % of the trials) or excitation (by 55 % in 43 % of trials), and which were often accompanied by a pressor response. These electrical-stimulation-evoked cardiorespiratory responses were almost eliminated following microinjection of ibotenic acid into the stimulation sites (P0.05) or bilaterally into the NGC (P0.05). As compared to vehicle, microinjection of NMDA into the unilateral VN(M), VN(L) and VN(S) significantly increased ventilation to 74 %, 58 % and 60 % (P0.05), respectively, with no effect on arterial blood pressure. These data suggest that neurones within the vestibular subnuclei play different roles in cardiorespiratory modulation, and that the integrity of the NGC is essential for the full expression of these VN-mediated responses. The evoked respiratory excitatory responses are probably mediated by glutamate acting on NMDA receptors, whereas the neurotransmitters involved in VN(M)-mediated respiratory inhibition and hypertension remain unknown.

Myoglobin, a protein with an important role in muscle oxidative metabolism, is increased in high altitude residents. In the closely related hemoglobins, mutations cause or contribute to human disease. Furthermore, heme-containing proteins may be involved in oxygen sensing. We therefore tested the hypotheses that myoglobin allele frequencies differed in Tibetans, a long-resident human high-altitude population, compared with sea-level residents, and varied in relation to altitude among Tibetans. We obtained the sequence of exon 2 of the myoglobin gene in 146 Tibetans with greater than three generations of stable residence at altitude in rural Tibet. We compared the frequency of known polymorphic sites in this gene among Tibetans living at altitudes of 3000, 3700, and 4500 m and to allele frequencies previously obtained in 525 residents of Dallas, Texas. We also examined the association between different myoglobin genotypes and hemoglobin concentration, used as an index of myoglobin levels. The frequency of the myoglobin 79A allele was higher in the high altitude compared with the sea-level residents, but unchanged with increasing altitude among Tibetans. There was no significant deviation from Hardy-Weinberg equilibrium in any of the Tibetan altitude groups, nor was there any association between myoglobin genotype and hemoglobin concentration. Screening of exon 2 of the myoglobin gene in high altitude Tibetans does not show novel polymorphism or selection for specific myoglobin alleles as a function of altitude of residence or hypoxic challenge.

Despite recent advances in therapy, chronic lymphocytic leukaemia (CLL) remains incurable and new treatment strategies are therefore urgently required. Inhibitor of apoptosis proteins (IAPs) are over-expressed in CLL, suggesting both a role in disease pathogenesis and the potential for therapeutic targeting. To explore these questions, we evaluated the effects on primary CLL cells of AZD5582, a novel potent and selective inhibitor of IAPs. AZD5582 at nanomolar concentrations induced extensive degradation of cIAP-1 and cIAP-2, but minimally of X chromosome-linked IAP (XIAP). However, these effects of AZD5582 produced little or no direct cytotoxicity, nor did they sensitize CLL cells to p53-dependent killing by fludarabine or p53-independent killing by dexamethasone. In contrast, AZD5582 significantly enhanced apoptosis induced by the death receptor (DR) agonist tumour necrosis factor-related apoptosis-inducing ligand (TRAIL). Importantly, killing by TRAIL plus AZD5582 was independent of adverse prognostic features including TP53 deletion which is strongly associated with chemoresistance in CLL. Coculture experiments involving transfected mouse fibroblasts expressing human CD40L (CD154) to mimic the effect of T cells at sites of tissue involvement showed that CD40 stimulation almost completely prevented the killing of CLL cells by TRAIL plus AZD5582 despite up-regulating TRAIL receptors 1 and 2. In conclusion, our findings confirm the rate-limiting, upstream involvement of IAPs in the extrinsic but not intrinsic apoptotic pathway of CLL cells and suggest that drug combinations that simultaneously activate DRs and inhibit IAPs may have therapeutic potential in patients with CLL who have failed T-cell-depleting chemotherapy.

In this study, we asked whether a “full term” prenatal nicotinic exposure (fPNE, 6 mg·kg−1·day−1 nicotinic delivery) over the full gestation, compared to a traditional PNE (tPNE) over the last two‐thirds of the gestation, caused a higher mortality following a remarkable depressed hypoxic ventilatory response (dHVR) independent of brain and pulmonary edema and change in serum corticosterone. P12‐14 pups pretreated with tPNE, fPNE or their vehicle (tCtrl and fCtrl) were exposed to 5% O2 for up to 60 min followed by harvesting the brain and lungs or anesthetized to collect blood for detecting arterial blood pH/gases and serum cotinine and corticosterone levels. We found that fPNE had little effect on baseline VE and heart rate, but consistently induced a dHVR and prolonged apnea that were rarely observed after tPNE. The severity of the dHVR in PNE pups were closely correlated to an earlier appearance of lethal ventilatory arrest (the hypoxia‐induced mortality). PNE did not induce brain and pulmonary edema, but significantly increased serum corticosterone levels similarly in tPNE and fPNE pups. Moreover, the accumulated nicotinic dose given to the individual was significantly higher in fPNE than tPNE pups, though there was no difference in serum cotinine levels and arterial blood pH/gases between the two groups. Our results suggest that nicotinic exposure at the early stage of gestation achieved by fPNE, rather than tPNE, is critical in generating the dHVR and subsequent death occurring independently of brain/pulmonary edema and changes in arterial blood pH/gases and serum corticosterone., Our results suggest that nicotinic exposure at the early stage of gestation achieved by “full term” prenatal nicotinic exposure (fPNE), rather than traditional prenatal nicotinic exposure (tPNE), is critical in generating the depressed hypoxic ventilatory response (dHVR) and subsequent death. The fPNE‐induced cardiorespiratory impairement is independent of brain/pulmonary edema and changes in arterial blood pH/gases and serum corticosterone.

Activation of cNTS MORs blocks HVR and moderately depresses HCVR (↓30%) in anesthetized rats (Zhang et al, Anesthesiology 2011) in agreement with the cNTS synaptically receiving carotid body affere...

High-altitude reduces infant birth weight as a result of intrauterine growth restriction (IUGR) and is associated with increased neonatal mortality. We hypothesized that babies born to Tibetan compared to Han (Chinese) high-altitude residents were protected from IUGR as the result of increased maternal O(2) transport due, in turn, to increased uterine artery (UA) blood flow. We studied 68 nonpregnant or pregnant Tibetan or Han residents of Lhasa, Tibet Autonomous Region, China (3,658 m). The pregnant women had higher hypoxic ventilatory responses (HVR A) and resting ventilations (V(E)) than their nonpregnant counterparts (Tib HVR = 134 +/- 16 (SEM) vs. 30 +/- 8, Han HVR = 134 +/- 16 vs. 66 +/- 18 A units; Tib V(E) = 11.8 +/- 0.3 vs. 10.1 +/- 0.5, Han V(E) = 10.7 +/- 0.5 vs. 9.4 +/- 0.5 l BTPS/min; all P < 0.05). Pregnancy did not change hemoglobin concentration in the Han but lowered values more than 2 g/dl in the Tibetans, serving to reduce arterial O(2) content below Han values (15.4 +/- 0.3 vs. 17.4 +/- 0.5 ml O(2)/100 ml whole blood, P < 0.05). Compared with the Han, the pregnant Tibetans had higher UA blood flow velocity (58.5 +/- 2.9 vs. 49.1 +/- 3.2, P < 0. 05) and distributed a higher portion of common iliac (CI) blood flow to the UA (4.8 +/- 0.4 vs. 3.3 +/- 0.3, P < 0.05). Birth weights averaged 635 g greater in the Tibetan than Han high-altitude residents (3,280 +/- 78 vs. 2,645 +/- 96 g, P < 0.01), or 694 g more when adjusted for maternal age, parity, height, and near-term body weight. Heavier birth weight babies were born to women with higher V(E) (r = 0.62, P < 0.01) and greater distribution of CI blood flow to the UA (r = 0.42, P < 0.05). We conclude that increased UA blood flow, and not higher arterial O(2) content, permits Tibetan women to increase uteroplacental O(2) delivery and protect their infants from altitude-associated IUGR.

In order to compare the prevalence of electrocardiographic (ECG) abnormalities suggestive of right ventricular hypertrophy in native and imigrant populations residing at high altitude, a retrospective review was undertaken of data obtained from a random survey of healthy volunteers and persons with chronic mountain sickness (CMS). All persons included in the survey were ambulatory volunteers from the general community who were evaluated at the Tibet Institute of Medical Science in Lhasa, where the elevation is 3,658 meters. The 74 residents of Lhasa, whose ECGs were studied, included 30 healthy Tibetan natives of Lhasa; 24 healthy Han (Chinese) immigrants, born at or near sea level, who had migrated to high altitude as children or adults; and 20 persons with symptoms of CMS. The ECGs of all subjects were reviewed for predetermined criteria suggestive of right ventricular hypertrophy, which were found to be present in 17% of healthy Tibetan natives, 29% of healthy Han immigrants, and 50% of CMS patients. The Han subjects who had migrated as children presented evidence of right ventricular hypertrophy more commonly than did adult imigrants. The overwhelming majority (90%) of persons with CMS were Han. Thus, the frequency of ECG abnormalities consistent with right ventricular hypertrophy was similar in healthy young Tibetan and Han men, but these abnormalities were less common in Tibetan natives than in Han who had migrated to high altitude as children or in CMS patients. The prevalence of ECG evidence of right ventricular hypertrophy increased with duration of high altitude residence among Han.

Apoptosis is a programmed form of cell death characterized by biochemical and morphological changes affecting the nucleus, cytoplasm, and plasma membrane. These changes in various cellular compartments are widely regarded as mechanistically linked events in a single "program" in which activation of caspases and proteolysis of intracellular substrates represent a final common pathway leading to cell death. To date there has been very limited exploration of the linkage of this program to the plasma membrane changes, which bring about swift recognition, uptake, and safe degradation of apoptotic cells by phagocytes. Using the mitochondrial inhibitors antimycin A and oligomycin in human monocytic THP.1 cells triggered into apoptosis, we report the uncoupling of plasma membrane changes from other features of apoptosis. These inhibitors blocked increased plasma membrane permeability, externalization of phosphatidylserine, and recognition by two classes of phagocytes but not activation of caspase-3, cleavage of poly(ADP-ribose) polymerase and DNA fragmentation. Externalization of phosphatidylserine in apoptotic human leukemic U937 cells was also dissociated from caspase activation. Thus changes governing safe clearance of apoptotic cells may be regulated by an independent pathway to those bringing about caspase activation. This finding could have important consequences for attempts to manipulate cell death for therapeutic gain in vivo.

Few environments challenge human populations more than high altitude, since the accompanying low oxygen pressures (hypoxia) are pervasive and impervious to cultural modification. Work capacity is an important factor in a population's ability to thrive in such an environment. The performance of work or exercise is a measure of the integrated functioning of the O2 transport system, with maximal O2 uptake (.VO2max) a convenient index of that function. Hypoxia limits the ability to transport oxygen: maximal O2 uptake decreases with ascent to high altitude, and years of high altitude residence do not restore sea level .VO2max values. Since Tibetans live and work at some of the highest altitudes in the world, their ability to exercise at very high altitude (>4,000 m) may define the limits of human adaptation to hypoxia. We transported 20 Tibetan lifelong residents of > or =4,400 m down to 3,658 m in order to compare them with 16 previously studied Tibetan residents of Lhasa (3,658 m). The two groups of Tibetans were matched for age, weight, and height. All studies were performed in Lhasa within 3 days of the 4,400 m Tibetans' arrival. Standard test protocol and criteria were used for attaining .VO2max on a Monark bicycle ergometer, while measuring oxygen uptake (.VO2, ml/kg - min STPD), heart rate (bpm), minute ventilation (VE, 1/min BTPS), and arterial oxygen saturation (SaO2, %). The 4,400 m compared with 3,658 m residents had, at maximal effort, similar .VO2 (48.5 +/- 1.2 vs. 51.2 +/- 1.4 ml/kg - min, P = NS), higher workload attained (211 +/- 6 vs. 177 +/- 7 watts, P < 0.01), lower heart rate(176 +/- 2 vs. 191 +/- 2 bpm, P < 0.01), lower ventilation (127 +/- 5 vs. 149 +/- 5 l/min BTPS, P < 0.01), and similar SaO2(81.9 +/- 1.0 vs. 83.7 +/- 1.2%, P = NS). Furthermore, over the range of submaximal workloads, 4,400 m compared with 3,658 m Tibetans had lower .VO2 (P < 0.01), lower heart rates (P < 0.01), and lower ventilation (P < 0.01) and SaO2 (P < 0.05). We conclude that Tibetans living at 4,400 m compared with those residing at 3,658 m achieve greater work performance for a given .VO2 at submaximal and maximal workloads with less cardiorespiratory effort.

A previous study by the authors has shown that isoflurane (ISO), a commonly used volatile anesthetic, has an excitatory effect on bronchopulmonary C-fibers (PCFs). Since selective stimulation of PCFs by action on local 5-HT 3 receptors could evoke an apnea, this current study addresses whether inhalation of ISO would facilitate the PCF 5-HT 3 receptor-mediated apneic response and, if so, how. In anesthetized and spontaneously breathing rats, inhalation of 5% ISO markedly inhibited the apneic response to intra-atrium injection of phenylbiguanide (PBG, 25 μg/kg), a 5-HT 3 receptor agonist, which was contrary to the hypothesis. Extracellular recording of the nodose ganglion neurons in anesthetized, paralyzed and ventilated rats revealed that ISO attenuated the PBG-elicited excitation of pulmonary C neurons. Furthermore, using the patch clamp technique, it was found that ISO depressed the PBG-induced inward current of the pulmonary C neurons labeled with 1,1′-dioctadecyl-3,3,3′,3′-tetramethylindocarbocyanine perchlorate (DiI) instilled previously into the lungs. These results suggest that ISO inhibits PCF 5-HT 3 channel functions, and thereby attenuates PCF excitatory response to PBG, likely contributing to the diminution of the PBG-induced apnea by ISO in rats.

Previous studies have indicated that native Tibetans have a larger lung capacity and better maintain arterial O2 saturation during exercise than Han ("Chinese") acclimatized lowlanders. To test if differences in ventilation or alveolar-arterial O2 gradient (A-aDO2) were responsible, we compared 10 lifelong Tibetan and 9 Han acclimatized newcomer residents of Lhasa (3658 m) at rest and during progressive exercise. Resting blood gas tensions and arterial O2 saturation in the two groups were similar. During exercise the Tibetans had lower total ventilation and higher arterial CO2 tensions than the Han (both P < 0.01) and markedly lower A-aDO2 (7 +/- 1 vs. 11 +/- 1, 13 +/- 1 vs. 18 +/- 1, and 14 +/- 1 vs. 20 +/- 1 mmHg at light, medium, and heavy workloads respectively, all P < 0.01). The Tibetans' narrower A-aDO2 compensated for their lower exercise ventilation such that arterial O2 tension and saturation were raised above acclimatized newcomer values and better maintained during exercise. We concluded that the Tibetans exhibited more efficient pulmonary gas exchange which compensated for reduced ventilation and lessened respiratory effort.

Inhalation of isoflurane (ISO), a widely used volatile anesthetic, can produce clinical tachypnea. In dogs, this response is reportedly mediated by bronchopulmonary C-fibers (PCFs), but the relevant mechanisms remain unclear. Activation of transient A-type potassium current ( I A ) channels and delayed rectifier potassium current ( I K ) channels hyperpolarizes neurons, and inhibition of both channels by ISO increases neural firing. Due to the presence of these channels in the cell bodies of rat PCFs, we determined whether ISO could stimulate PCFs to produce tachypnea in anesthetized rats, and, if so, whether this response resulted from ISO-induced depolarization of the pulmonary C neurons via the inhibition of I A and I K . We recorded ventilatory responses to 5% ISO exposure in anesthetized rats before and after blocking PCF conduction and the responses of pulmonary C neurons (extracellularly recorded) to ISO exposure. ISO-induced (1 mM) changes in pulmonary C neuron membrane potential and I A / I K were tested using the perforated patch clamp technique. We found that: (1) ISO inhalation evoked a brief tachypnea (∼7 s) and that this response disappeared after blocking PCF conduction; (2) the ISO significantly elevated (by 138%) the firing rate of most pulmonary C neurons (17 out of 21) in the nodose ganglion; and (3) ISO perfusion depolarized the pulmonary C neurons in the vitro and inhibited both I A and I K , and this evoked-depolarization was largely diminished after blocking both I A and I K . Our results suggest that ISO is able to stimulate PCFs to elicit tachypnea in rats, at least partly, via inhibiting I A and I K , thereby depolarizing the pulmonary C neurons.

Reduced oxygen availability at high altitude is associated with increased neonatal and infant mortality. We hypothesized that native Tibetan infants, whose ancestors have inhabited the Himalayan Plateau for approximately 25,000 years, are better able to maintain adequate oxygenation at high altitude than Han infants, whose ancestors moved to Tibet from lowland areas of China after the Chinese military entered Tibet in 1951.We compared arterial oxygen saturation, signs of hypoxemia, and other indexes of neonatal wellbeing at birth and during the first four months of life in 15 Tibetan infants and 15 Han infants at 3658 m above sea level in Lhasa, Tibet. The Han mothers had migrated from lowland China about two years previously. A pulse oximeter was placed on each infant's foot to provide measurements of arterial oxygen saturation distal to the ductus arteriosus.The two groups had similar gestational ages (about 38.9 weeks) and Apgar scores. The Han infants had lower birth weights (2773 +/- 92 g) than the Tibetan infants (3067 +/- 107 g), higher concentrations of cord-blood hemoglobin (18.6 +/- 0.8 g per deciliter, vs. 16.7 +/- 0.4 in the Tibetans), and higher hematocrit values (58.5 +/- 2.4 percent, vs. 51.4 +/- 1.2 percent in the Tibetans). In both groups, arterial oxygen saturation was highest in the first two days after birth and was lower when the infants were asleep than when they were awake. Oxygen saturation values were lower in the Han than in the Tibetan infants at all times and under all conditions during all activities. The values declined in the Han infants from 92 +/- 3 percent while they were awake and 90 +/- 5 percent during quiet sleep at birth to 85 +/- 4 percent while awake and 76 +/- 5 percent during quiet sleep at four months of age. In the Tibetan infants, oxygen saturation values averaged 94 +/- 2 percent while they were awake and 94 +/- 3 percent during quiet sleep at birth and 88 +/- 2 percent while awake and 86 +/- 5 percent during quiet sleep at four months. Han infants had clinical signs of hypoxemia--such as cyanosis during sleep and while feeding--more frequently than Tibetans.In Lhasa, Tibet, we found that Tibetan newborns had higher arterial oxygen saturation at birth and during the first four months of life than Han newborns. Genetic adaptations may permit adequate oxygenation and confer resistance to the syndrome of pulmonary hypertension and right-heart failure (subacute infantile mountain sickness).

Lifelong Tibetan residents of 3658 m ventilate as much and have hypoxic and hypercapnic ventilatory responsiveness as least as great as acclimatized newcomers, and likely greater than lifelong North or South American high-altitude residents. To determine whether Tibetans residing at altitudes > 3658 m maintained similar levels of ventilation, hypoxic and hypercapnic ventilatory responses, we transported 20 lifelong residents of ≥ 4400 m to 3658m for comparison with 27 similarly-aged male Tibetan residents of 3658 m. At 3658 m, the 4400 m compared with the 3658 m Tibetans had similar levels of minute ventilation and arterial O 2 saturation, higher respiratory quotients but lower hypoxic ventilatory responses. We concluded that Tibetan residents of ≥ 4400 m ventilate as much as Tibetan residents of 3658 m despite an altitude-associated blunting of their hypoxic ventilatory responses. Thus, factors other than hypoxic ventilatory chemosensitivity are likely to be important contributors to resting ventilation among Tibetan high altitude residents.

Glucocorticoids (GCs) represent an important component of modern treatment regimens for fludarabine-refractory or TP53-defective chronic lymphocytic leukemia (CLL). However, GC therapy is not effective in all patients. The molecular mechanisms responsible for GC-induced apoptosis and resistance were therefore investigated in primary malignant cells obtained from a cohort of 46 patients with CLL. Dexamethasone-induced apoptosis was unaffected by p53 dysfunction and more pronounced in cases with unmutated IGHV genes. Cross-resistance was observed between dexamethasone and other GCs but not fludarabine, indicating non-identical resistance mechanisms. GC treatment resulted in the upregulation of Bim mRNA and protein, but to comparable levels in both GC-resistant and sensitive cells. Pre-incubation with Bim siRNAs reduced GC-induced upregulation of Bim protein and conferred resistance to GC-induced apoptosis in previously GC-sensitive cells. GC-induced upregulation of Bim was associated with the activation of Bax and Bak in GC-sensitive but not -resistant CLL samples. Co-immunoprecipitation experiments showed that Bim does not interact directly with Bax or Bak, but is almost exclusively bound to Bcl-2 regardless of GC treatment. Taken together, these findings suggest that the GC-induced killing of CLL cells results from the indirect activation of Bax and Bak by upregulated Bim/Bcl-2 complexes, and that GC resistance results from the failure of such activation to occur.

Intravenous bolus injection of morphine causes a vagal-mediated brief apnea (∼3 s), while continuous injection, via action upon central μ-opioid receptor (MOR), arrests ventilation (>20 s) that is eliminated by stimulating central 5-hydroxytryptamine 1A receptors (5HT1ARs). Bronchopulmonary C-fibers (PCFs) are essential for triggering a brief apnea, and their afferents terminate at the caudomedial region of the nucleus tractus solitarius (mNTS) that densely expresses 5HT1ARs. Thus we asked whether the vagal-mediated apneic response to MOR agonists was PCF dependent, and if so, whether this apnea was abolished by systemic administration of 8-hydroxy-2-(di- n-propylamino)tetral (8-OH-DPAT) largely through action upon mNTS 5HT1ARs. Right atrial bolus injection of fentanyl (5.0 μg/kg, a MOR agonist) was performed in the anesthetized and spontaneously breathing rats before and after: 1) selective blockade of PCFs' conduction and subsequent bivagotomy; 2) intravenous administration of 5HT1AR agonist 8-OH-DPAT; 3) intra-mNTS injection of 8-OH-DPAT; and 4) intra-mNTS injection of 5HT1AR antagonist WAY-100635 followed by 8-OH-DPAT (iv). We found the following: First, fentanyl evoked an immediate apnea (2.5 ± 0.4 s, ∼6-fold longer than the baseline expiratory duration, TE), which was abolished by either blocking PCFs' conduction or bivagotomy. Second, this apnea was prevented by systemic 8-OH-DPAT challenge. Third, intra-mNTS injection of 8-OH-DPAT greatly attenuated the apnea by 64%. Finally, intra-mNTS microinjection of WAY-100635 significantly attenuated (58%) the apneic blockade by 8-OH-DPAT (iv). We conclude that the vagal-mediated apneic response to MOR activation depends on PCFs, which is fully antagonized by systemic 8-OH-DPAT challenge largely via acting on mNTS 5HT1ARs.

Mitochondrial DNAs (mtDNAs) of 54 Tibetans residing at altitudes ranging from 3,000–4,500 m were amplified by polymerase chain reaction (PCR), examined by high-resolution restriction endonuclease analysis, and compared with those previously described in 10 other Asian and Siberian populations. This comparison revealed that more than 50% of Asian mtDNAs belong to a unique mtDNA lineage which is found only among Mongoloids, suggesting that this lineage most likely originated in Asia at an early stage of the human colonization of that continent. Within the Tibetan mtDNAs, sets of additional linked polymorphic sites defined seven minor lineages of related mtDNA haplotypes (haplogroups). The frequency and distribution of these haplogroups in modern Asian populations are supportive of previous genetic evidence that Tibetans, although located in southern Asia, share common ancestral origins with northern Mongoloid populations. This analysis of Tibetan mtDNAs also suggests that mtDNA mutations are unlikely to play a major role in the adaptation of Tibetans to high altitudes. © 1994 Wiley-Liss, Inc.

Background : The commissural subnucleus of the nucleus tractus solitarius (comNTS) is a key region in the brainstem responsible for the hypoxic ventilatory response (HVR) because it contains the input terminals of the carotid chemoreceptor. Because opioids inhibit the HVR via activating central μ-receptors that are expressed abundantly in the comNTS, the authors of the current study asked whether activating local μ-receptors attenuated the carotid body-mediated HVR. Methods : To primarily stimulate the carotid body, brief hypoxia (100% N2) and hypercapnia (15% CO2) for 10 s and/or intracarotid injection of NaCN (10 μg/100 μl) were performed in anesthetized and spontaneously breathing rats. These stimulations were repeated after: (1) microinjecting three doses of μ-receptor agonist [d-Ala2, N-Me-Phe4, Gly-ol]-Enkephalin (DAMGO) (approximately 3.5 nl) into the comNTS; (2) carotid body denervation; and (3) systemic administration of DAMGO (300 μg/kg) without and with previous intracomNTS injection of d-Phe-Cys-Tyr-d-Trp-Arg-Thr-Pen-Thr-NH2, a μ-receptor antagonist. Results : Study results showed that DAMGO at 0.25 and 2.5, but not 0.025 mM, caused a similar decrease in baseline ventilation (approximately 12%). DAMGO at 0.25 mM largely reduced (64%) the HVR, whereas DAMGO at 2.5 mM abolished the HVR (and the VE response to NaCN) and moderately attenuated (31%) the hypercapnic ventilatory response. Interestingly, similar HVR abolition and depression of the hypercapnic ventilatory response were observed after carotid body denervation. Blocking comNTS μ-receptors by d-Phe-Cys-Tyr-d-Trp-Arg-Thr-Pen-Thr-NH2 significantly attenuated the HVR depression by systemic DAMGO with little change in the DAMGO modulatory effects on baseline ventilation and the hypercapnic ventilatory response. Conclusion : The data suggest that opioids within the comNTS, via acting on μ-receptors, are able to abolish the HVR by affecting the afferent pathway of the carotid chemoreceptor.

To test the hypothesis that native high-altitude residents have less beta-sympathetic and more parasympathetic tone than newcomers, we compared the effects of beta-sympathetic and parasympathetic blockade in 10 Tibetan and 9 Han acclimatized male residents of Lhasa, Tibet Autonomous Region, China (elevation 3,658 m). Each subject was studied during cycle ergometer exercise at 70, 132, and 191 W after placebo (normal saline), beta-sympathetic (propranolol, 0.2 mg/kg iv), or parasympathetic (atropine, 0.04 mg/kg iv) blockade in random order on different days. At rest, the fall in resting heart rate with propranolol and the rise with atropine were equal in Tibetan and Han subjects. During exercise, the fall in heart rate with propranolol relative to placebo values was greater in the Han than in the Tibetan group, whereas the rise in heart rate with atropine was greater in the Tibetans. Propranolol or atropine administration did not change minute ventilation per unit O2 consumption in either group. At the highest level of exercise on the placebo day, the Tibetans achieved a higher work load and level of O2 consumption than the Han subjects. Propranolol or atropine reduced O2 consumption and work load similarly in the two groups at the highest exercise level. The results supported our hypothesis that native Tibetan residents of high altitude exhibit more para-sympathetic and less beta-sympathetic tone during exercise. Neither relatively greater parasympathetic nor less sympathetic activation appeared implicated in the greater exercise capacity of Tibetans compared with that of acclimatized newcomer residents of high altitude.

Lifelong high-altitude residents of North and South America acquire blunted hypoxic ventilatory responses and exhibit decreased ventilation compared with acclimatized newcomers. The ventilatory characteristics of Himalayan high-altitude residents are of interest in the light of their reportedly lower hemoglobin levels and legendary exercise performance. Until recently, Sherpas have been the only Himalayan population available for study. To determine whether Tibetans exhibited levels of ventilation and hypoxic ventilatory drives that were as great as acclimatized newcomers, we compared 27 lifelong Tibetan residents of Lhasa, Tibet, China (3,658 m) with 30 acclimatized Han ("Chinese") newcomers matched for age, body size, and extent of exercise training. During room air breathing, minute ventilation was greater in the Tibetan than in the Han young men because of an increased respiratory frequency, but arterial O2 saturation and end-tidal PCO2 did not differ, indicating similar levels of effective alveolar ventilation. The Tibetan subjects had higher hypoxic ventilatory response shape parameter A values and hypercapnic ventilatory responsiveness than the Han subjects. Among the Han subjects, duration of high-altitude residence correlated with the degree of blunting of the hypoxic ventilatory drive. Paradoxically, hyperoxia (inspired O2 fraction 0.70) increased minute ventilation and decreased end-tidal PCO2 in the Tibetan but not in the Han men. We concluded that lifelong Tibetan residents of high altitude neither hypoventilated nor exhibited blunted hypoxic ventilatory responses compared with acclimatized Han newcomers, suggesting that the effects of lifelong high-altitude residence on ventilation and ventilatory response to hypoxia differ in Tibetan compared with other high-altitude populations. Lifelong high-altitude residents of North and South America acquire blunted hypoxic ventilatory responses and exhibit decreased ventilation compared with acclimatized newcomers. The ventilatory characteristics of Himalayan high-altitude residents are of interest in the light of their reportedly lower hemoglobin levels and legendary exercise performance. Until recently, Sherpas have been the only Himalayan population available for study. To determine whether Tibetans exhibited levels of ventilation and hypoxic ventilatory drives that were as great as acclimatized newcomers, we compared 27 lifelong Tibetan residents of Lhasa, Tibet, China (3,658 m) with 30 acclimatized Han ("Chinese") newcomers matched for age, body size, and extent of exercise training. During room air breathing, minute ventilation was greater in the Tibetan than in the Han young men because of an increased respiratory frequency, but arterial O2 saturation and end-tidal PCO2 did not differ, indicating similar levels of effective alveolar ventilation. The Tibetan subjects had higher hypoxic ventilatory response shape parameter A values and hypercapnic ventilatory responsiveness than the Han subjects. Among the Han subjects, duration of high-altitude residence correlated with the degree of blunting of the hypoxic ventilatory drive. Paradoxically, hyperoxia (inspired O2 fraction 0.70) increased minute ventilation and decreased end-tidal PCO2 in the Tibetan but not in the Han men. We concluded that lifelong Tibetan residents of high altitude neither hypoventilated nor exhibited blunted hypoxic ventilatory responses compared with acclimatized Han newcomers, suggesting that the effects of lifelong high-altitude residence on ventilation and ventilatory response to hypoxia differ in Tibetan compared with other high-altitude populations. Lifelong high-altitude residents of North and South America acquire blunted hypoxic ventilatory responses and exhibit decreased ventilation compared with acclimatized newcomers. The ventilatory characteristics of Himalayan high-altitude residents are of interest in the light of their reportedly lower hemoglobin levels and legendary exercise performance. Until recently, Sherpas have been the only Himalayan population available for study. To determine whether Tibetans exhibited levels of ventilation and hypoxic ventilatory drives that were as great as acclimatized newcomers, we compared 27 lifelong Tibetan residents of Lhasa, Tibet, China (3,658 m) with 30 acclimatized Han ("Chinese") newcomers matched for age, body size, and extent of exercise training. During room air breathing, minute ventilation was greater in the Tibetan than in the Han young men because of an increased respiratory frequency, but arterial O2 saturation and end-tidal PCO2 did not differ, indicating similar levels of effective alveolar ventilation. The Tibetan subjects had higher hypoxic ventilatory response shape parameter A values and hypercapnic ventilatory responsiveness than the Han subjects. Among the Han subjects, duration of high-altitude residence correlated with the degree of blunting of the hypoxic ventilatory drive. Paradoxically, hyperoxia (inspired O2 fraction 0.70) increased minute ventilation and decreased end-tidal PCO2 in the Tibetan but not in the Han men. We concluded that lifelong Tibetan residents of high altitude neither hypoventilated nor exhibited blunted hypoxic ventilatory responses compared with acclimatized Han newcomers, suggesting that the effects of lifelong high-altitude residence on ventilation and ventilatory response to hypoxia differ in Tibetan compared with other high-altitude populations. Lifelong high-altitude residents of North and South America acquire blunted hypoxic ventilatory responses and exhibit decreased ventilation compared with acclimatized newcomers. The ventilatory characteristics of Himalayan high-altitude residents are of interest in the light of their reportedly lower hemoglobin levels and legendary exercise performance. Until recently, Sherpas have been the only Himalayan population available for study. To determine whether Tibetans exhibited levels of ventilation and hypoxic ventilatory drives that were as great as acclimatized newcomers, we compared 27 lifelong Tibetan residents of Lhasa, Tibet, China (3,658 m) with 30 acclimatized Han ("Chinese") newcomers matched for age, body size, and extent of exercise training. During room air breathing, minute ventilation was greater in the Tibetan than in the Han young men because of an increased respiratory frequency, but arterial O2 saturation and end-tidal PCO2 did not differ, indicating similar levels of effective alveolar ventilation. The Tibetan subjects had higher hypoxic ventilatory response shape parameter A values and hypercapnic ventilatory responsiveness than the Han subjects. Among the Han subjects, duration of high-altitude residence correlated with the degree of blunting of the hypoxic ventilatory drive. Paradoxically, hyperoxia (inspired O2 fraction 0.70) increased minute ventilation and decreased end-tidal PCO2 in the Tibetan but not in the Han men. We concluded that lifelong Tibetan residents of high altitude neither hypoventilated nor exhibited blunted hypoxic ventilatory responses compared with acclimatized Han newcomers, suggesting that the effects of lifelong high-altitude residence on ventilation and ventilatory response to hypoxia differ in Tibetan compared with other high-altitude populations.