Mitochondrial dysfunction in chronic ischemia and peripheral vascular disease

In peripheral vascular disease, impaired muscle energy metabolism is assumed to be due mainly to defective vascular O2 supply, the resulting cellular hypoxia inhibiting oxidative ATP synthesis. Older work suggested a compensatory increase in muscle aerobic enzymes, but more recent studies suggest a relative decrease in some mitochondrial components and an accumulation of damage in mitochondrial DNA, perhaps due to reactive oxygen species. However, to establish whether in vivo muscle mitochondria suffer from anything other than a low concentration of O2 will require more knowledge of the mitochondrial behaviour at low PO2, and the actual cell PO2 during exercise.     

Increased hyaluronan fragmentation during pulmonary ischemia

Hyaluronan (HA), a glycosaminoglycan critical to the lung extracellular matrix, has been shown to dissociate into low-molecular-weight (LMW) HA fragments following exposure to injurious stimuli. In the present study we questioned whether lung HA changed during ischemia and whether changes had an effect on subsequent angiogenesis. After left pulmonary artery ligation (LPAL) in mice, we analyzed left lung homogenates immediately after the onset of ischemia (0 h) and intermittently for 14 days. The relative expression of HA synthase (HAS)1, HAS2, and HAS3 was determined by real-time RT-PCR, total HA in the lung was measured by an ELISA-like assay, gel electrophoresis was performed to determine changes in HA size distribution, and the activity of hyaluronidases was determined by zymography. A 50% increase in total HA was measured 16 h after the onset of ischemia and remained elevated for up to 7 days. Furthermore, a fourfold increase in LMW HA fragments (495-30 kDa) was observed by 4 h after LPAL. Both HAS1 and HAS2 showed increased expression 4-16 h after LPAL, yet no changes were seen in hyaluronidase activity. These results suggest that both HA fragmentation and activation of HA synthesis contribute to increased HA levels during lung ischemia. Delivery of LMW HA fragments in an in vitro tube formation assay or directly to the ischemic mouse lung in vivo both resulted in increased angiogenesis. We conclude that ischemic injury results in matrix fragmentation, which leads to stimulation of neovascularization.     

Systemic oxygen extraction during incremental exercise in patients with severe chronic obstructive pulmonary disease

To determine if decreased systemic oxygen (O₂) extraction contributes to the exercise limit in severe chronic obstructive pulmonary disease (COPD), 40 consecutive incremental cycle ergometer exercise tests performed by such patients, from which a “log-log” lactate threshold (LT) was identified, were compared to those of 8 patients with left ventricular failure (LVF) and 10 normal controls. Pulmonary gas exchange and minute ventilation were measured continuously and arterial blood gas tensions, pH, and lactate concentrations were sampled each minute. Cardiac output (Q˙ _c) was measured by first-pass radionuclide ventriculography. The systemic O₂ extraction ratio (O₂ER) was calculated as arterial − mixed venous O₂ content difference (C _aO₂ − C _vO₂)/C _aO₂. Peak exercise O₂ uptake (V˙O_2peak) was markedly reduced in both COPD and LVF [41 (3) and 42 (3)% predicted, respectively], compared to controls [89 (2)% predicted, P < 0.0001 for each]. Similarly, the LT occurred at a low percentage of predicted maximal oxygen consumption in both COPD and LVF [25 (2) and 27 (3)%] compared to normals [46 (3)%, P < 0.0001 for each]. The systemic O₂ER at peak exercise was severely reduced in COPD [0.36 (0.02)] compared to the other groups [P < 0.0001 for each], for whom it was nearly identical [0.58 (0.03) vs 0.63 (0.04), LVF vs control, P > 0.05]. In the COPD group, an early LT correlated with reduced systemic O₂ER at peak exercise (r = 0.64, P < 0.0001), but not with any index of systemic O₂ delivery. These data suggest that lactic acidemia during exercise in patients with severe COPD is better related to abnormal systemic O₂ extraction than to its delivery and contributes to the exercise limit. Accepted: 10 March 1998     

肺微生物组与慢性阻塞性肺疾病的研究进展

慢性阻塞性肺疾病（COPD）是一种慢性炎症性呼吸道疾病,其特征是持续气流受限和肺部炎症反应异常。气道内微生物是COPD恶化的主要原因,并且使气道中的炎症反应持续存在而促成COPD进展,这导致肺功能的进一步损害和巨大的医疗保健成本。近年来随着高通量测序技术的发展和运用,人类肺微生物组的研究逐渐成为热点。大量研究表明,COPD患者肺内存在明显不同的微生物群落,而且与COPD的疾病严重程度及恶化状态有关。肺微生物组学的研究有助于人们更全面地理解COPD患者肺内的微生态系统及其在该病恶化和进展中的作用。本文就肺微生物组在COPD中的研究进展作一综述,并探讨未来的研究前景。     

miR-21 regulates chronic hypoxia-induced pulmonary vascular remodeling

Chronic hypoxia causes pulmonary vascular remodeling leading to pulmonary hypertension (PH) and right ventricle (RV) hypertrophy. Aberrant expression of microRNA (miRNA) is closely associated with a number of pathophysiologic processes. However, the role of miRNAs in chronic hypoxia-induced pulmonary vascular remodeling and PH has not been well characterized. In this study, we found increased expression of miR-21 in distal small arteries in the lungs of hypoxia-exposed mice. Putative miR-21 targets, including bone morphogenetic protein receptor (BMPR2), WWP1, SATB1, and YOD1, were downregulated in the lungs of hypoxia-exposed mice and in human pulmonary artery smooth muscle cells (PASMCs) overexpressing miR-21. We found that sequestration of miR-21, either before or after hypoxia exposure, diminished chronic hypoxia-induced PH and attenuated hypoxia-induced pulmonary vascular remodeling, likely through relieving the suppressed expression of miR-21 targets in the lungs of hypoxia-exposed mice. Overexpression of miR-21 enhanced, whereas downregulation of miR-21 diminished, the proliferation of human PASMCs in vitro and the expression of cell proliferation associated proteins, such as proliferating cell nuclear antigen, cyclin D1, and Bcl-xL. Our data suggest that miR-21 plays an important role in the pathogenesis of chronic hypoxia-induced pulmonary vascular remodeling and also suggest that miR-21 is a potential target for novel therapeutics to treat chronic hypoxia associated pulmonary diseases.     

Glucose and pyruvate metabolism in severe chronic obstructive pulmonary disease

The mechanisms leading to weight loss in patients with chronic obstructive pulmonary disease (COPD) are poorly understood but may involve alterations in macronutrient metabolism. Changes in muscle oxidative capacity and lactate production during exercise suggest glucose metabolism may be altered in COPD subjects. The objective of this study was to determine differences in the rates of glucose production and clearance, the rate of glycolysis (pyruvate production), and oxidative and nonoxidative pyruvate disposal in subjects with severe COPD compared with healthy controls. The in vivo rates of glucose production and clearance were measured in 14 stable outpatients with severe COPD (seven with low and seven with preserved body mass indexes) and 7 healthy controls using an intravenous infusion of [(2)H(2)]glucose. Additionally, pyruvate production and oxidative and non-oxidative pyruvate disposal were measured using intravenous infusions of [(13)C]bicarbonate and [(13)C]pyruvate. Endogenous glucose flux and glucose clearance were significantly faster in the combined COPD subjects (P = 0.002 and P < 0.001, respectively). This difference remained significant when COPD subjects were separated by body mass index. Pyruvate flux and oxidation were significantly higher in the combined COPD subjects than controls (P = 0.02 for both), but there was no difference in nonoxidative pyruvate disposal or plasma lactate concentrations between the two groups. In subjects with severe COPD, there are alterations in glucose metabolism leading to increased glucose production and faster glucose metabolism by glycolysis and oxidation compared with controls. However, no difference in glucose conversion to lactate via pyruvate reduction is observed.     

Age-dependent effects of chronic hypoxia on pulmonary vascular reactivity

Effects of age on the pulmonary vascular responses to histamine (HIST), norepinephrine (NE), 5-hydroxytryptamine (5-HT), and KCl were studied in isolated, perfused lungs from juvenile (7-wk-old), adult (14-wk-old), and mature adult (28-wk-old) normoxic rats and compared with age-matched rats exposed to chronic hypoxia for either 14 or 28 days. Chronic hypoxia changed vasoconstriction to HIST and NE to vasodilation in lungs from juvenile and adult rats. Mature adult lungs only vasoconstricted to these amines in both control and hypoxic animals. Pressor responses to 5-HT were not affected by chronic hypoxia regardless of age group. Pressor responses to KCl were also not altered by hypoxia, but lungs from older rats showed greater control responsiveness to KCl compared with lungs from juveniles. Only lungs from juvenile animals developed significant elevations of base-line resistance as a result of hypoxic exposure. To investigate the contribution of H1-, H2-, and beta-receptors in these changes, we employed chlorpheniramine, metiamide, and propranolol, respectively, as blocking agents in another series of experiments. Chlorpheniramine either reduced vasoconstriction or increased vasodilation to HIST in lungs from both control and hypoxic animals, whereas metiamide was without effect. Propranolol either increased vasoconstriction or reversed vasodilation to HIST and NE in all lungs studied. The present data demonstrate the important interaction between chronic hypoxia and age that can alter pulmonary vascular tone and reactivity. The inverse relationship between age and elevation of pulmonary vascular resistance after chronic hypoxic exposure may be the key element that changes pulmonary vascular reactivity observed during hypoxia.(ABSTRACT TRUNCATED AT 250 WORDS)     

Improved pulmonary artery buffering function during phenylephrine-induced pulmonary hypertension

The goal of this study was to determine the in vivo pulmonary arterial buffering function (BF) during acute and moderate pulmonary hypertension achieved by phenylephrine-induced smooth muscle activation.Pulmonary pressure (Konigsberg P7) and diameter (sonomicrometry) were measured in nine anesthetized sheep. Transit pulmonary arterial hypertension was induced by mechanical occlusion of the pulmonary artery (HP) and by phenylephrine infusion (5 g/kg/min) (PHE). A viscoelastic Kelvin-Voigt model was used. By increasing the values of the viscous modulus, the pressure-diameter hysteresis area was reduced to a minimum in order to obtain the purely elastic pressure-diameter relationship. The elastic index (E) was calculated as the first derivative of the exponential model of the purely elastic pressure-diameter relationship at the mean pressure point.Systolic, diastolic, mean and pulse pressures were similar during HP and PHE, but significantly higher with regard to control steady state. In HP, E and arterial diameter (both its minimum and maximum values) increased significantly. In contrast, when pulmonary hypertension was induced by VSM activation, E was maintained concomitantly with pulmonary artery vasoconstriction.Pulmonary hypertension produced by occlusion of the pulmonary artery increases elasticity. Smooth muscle activation may offset the deleterious effect of pulmonary hypertension on arterial wall elasticity by reducing E and impeding arterial dilatation and collagen recruitment, maintaining BF during pulmonary hypertension.     

Stem cell function during plant vascular development

While many regulatory mechanisms controlling the development and function of root and shoot apical meristems have been revealed, our knowledge of similar processes in lateral meristems, including the vascular cambium, is still limited. Our understanding of even the anatomy and development of lateral meristems (procambium or vascular cambium) is still relatively incomplete, let alone their genetic regulation. Research into this particular tissue type has been mostly hindered by a lack of suitable molecular markers, as well as the fact that thus far very few mutants affecting plant secondary development have been described. The development of suitable molecular markers is a high priority in order to help define the anatomy, especially the location and identity of cambial stem cells and the developmental phases and molecular regulatory mechanisms of the cambial zone. To date, most of the advances have been obtained by studying the role of the major plant hormones in vascular development. Thus far auxin, cytokinin, gibberellin and ethylene have been implicated in regulating the maintenance and activity of cambial stem cells; the most logical question in research would be how these hormones interact during the various phases of cambial development.     

Lung function and breathing pattern in subjects developing high altitude pulmonary edema

Introduction

The purpose of the study was to comprehensively evaluate physiologic changes associated with development of high altitude pulmonary edema (HAPE). We tested whether changes in pulmonary function and breathing pattern would herald clinically overt HAPE at an early stage.

Methods

In 18 mountaineers, spirometry, diffusing capacity, nitrogen washout, nocturnal ventilation and pulse oximetry were recorded at 490 m and during 3 days after rapid ascent to 4559 m. Findings were compared among subjects developing HAPE and those remaining well (controls).

Results

In 8 subjects subsequently developing radiographically documented HAPE at 4559 m, median FVC declined to 82% of low altitude baseline while closing volume increased to 164% of baseline (P<0.05, both instances). In 10 controls, FVC decreased slightly (to 93% baseline, P<0.05) but significantly less than in subjects with HAPE and closing volume remained unchanged. Sniff nasal pressure was reduced in both subjects with and without subsequent HAPE. During nights at 4559 m, mean nocturnal oxygen saturation dropped to lower values while minute ventilation, the number of periodic breathing cycles and heart rate were higher (60%; 8.6 L/min; 97 cycles/h; 94 beats/min, respectively) in subjects subsequently developing HAPE than in controls (73%; 5.1 L/min; 48 cycles/h; 79 beats/min; P<0.05 vs. HAPE, all instances).

Conclusion

The results comprehensively represent the pattern of physiologic alterations that precede overt HAPE. The changes in lung function are consistent with reduced lung compliance and impaired gas exchange. Pronounced nocturnal hypoxemia, ventilatory control instability and sympathetic stimulation are further signs of subsequent overt HAPE.

Registration

ClinicalTrials.gov identifier: {"type":"clinical-trial","attrs":{"text":"NCT00274430","term_id":"NCT00274430"}}NCT00274430     

Comparison of pulmonary vascular function and structure in early and established hypoxic pulmonary hypertension in rats

In pulmonary hypertension, changes in pulmonary vascular structure and function contribute to the elevation in pulmonary artery pressure. The time-courses for changes in function, unlike structure, are not well characterised. Medial hypertrophy and neomuscularisation and reactivity to vasoactive agents were examined in parallel in main and intralobar pulmonary arteries and salt-perfused lungs from rats exposed to hypoxia (10% O2) for 1 and 4 weeks (early and established pulmonary hypertension, respectively). After 1 week of hypoxia, in isolated main and intralobar arteries, contractions to 5-hydroxytryptamine and U46619 (thromboxane-mimetic) were increased whereas contractions to angiotensins I and II and relaxations to acetylcholine were reduced. These alterations varied quantitatively between main and intralobar arteries and, in many instances, regressed between 1 and 4 weeks. The alterations in reactivity did not necessarily link chronologically with alterations in structure. In perfused lungs, constrictor responses to acute alveolar hypoxia were unchanged after 1 week but were increased after 4 weeks, in conjunction with the neomuscularisation of distal alveolar arteries. The data suggest that in hypoxic pulmonary hypertension, the contribution of altered pulmonary vascular reactivity to the increase in pulmonary artery pressure may be particularly important in the early stages of the disease.     

Lung function during and after prolonged head-down bed rest.

We determined the effects of prolonged head-down tilt bed rest (HDT) on lung mechanics and gas exchange. Six subjects were studied in supine and upright postures before (control), during [day 113 (D113)], and after (R + number of days of recovery) 120 days of HDT. Peak expiratory flow (PF) never differed between positions at any time and never differed from controls. Maximal midexpiratory flow (FEF(25-75%)) was lower in the supine than in the upright posture before HDT and was reduced in the supine posture by about 20% between baseline and D113, R + 0, and R + 3. The diffusing capacity for carbon monoxide corrected to a standardized alveolar volume (volume-corrected DL(CO)) was lower in the upright than in the supine posture and decreased in both postures by 20% between baseline and R + 0 and by 15% between baseline and R + 15. Pulmonary blood flow (Q(C)) increased from R + 0 to R + 3 by 20 (supine) and 35% (upright). As PF is mostly effort dependent, our data speak against major respiratory muscle deconditioning after 120 days of HDT. The decrease in FEF(25-75%) suggests a reduction in elastic recoil. Time courses of volume-corrected DL(CO) and Q(C) could be explained by a decrease in central blood volume during and immediately after HDT.     

eNOS-deficient mice show reduced pulmonary vascular proliferation and remodeling to chronic hypoxia

Pulmonary hypertension is characterized by structural and morphological changes to the lung vasculature. To determine the potential role of nitric oxide in the vascular remodeling induced by hypoxia, we exposed wild-type [WT(+/+)] and endothelial nitric oxide synthase (eNOS)-deficient [(-/-)] mice to normoxia or hypoxia (10% O(2)) for 2, 4, and 6 days or for 3 wk. Smooth muscle alpha-actin and von Willebrand factor immunohistochemistry revealed significantly less muscularization of small vessels in hypoxic eNOS(-/-) mouse lungs than in WT(+/+) mouse lungs at early time points, a finding that correlated with decreases in proliferating vascular cells (5-bromo-2'-deoxyuridine positive) at 4 and 6 days of hypoxia in the eNOS(-/-) mice. After 3 wk of hypoxia, both mouse types exhibited similar percentages of muscularized small vessels; however, only the WT(+/+) mice exhibited an increase in the percentage of fully muscularized vessels and increased vessel wall thickness. eNOS protein expression was increased in hypoxic WT(+/+) mouse lung homogenates at all time points examined, with significantly increased percentages of small vessels expressing eNOS protein after 3 wk. These results indicate that eNOS deficiency causes decreased muscularization of small pulmonary vessels in hypoxia, likely attributable to the decrease in vascular cell proliferation observed in these mice.