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1.
Treatment of allergic asthma with inhaled corticosteroids results in local down-regulation of proinflammatory cytokine synthesis
and in marked decrease in tissue eosinophilia. Blood concentrations of inhaled corticosteroids, although significantly lower
than those measured in the lung, may still have antiinflammatory effects on circulating eosinophils, reducing their ability
to migrate. The aim of our study was to evaluate in vitro the activity of budesonide on blood eosinophils by measuring their
chemotactic response, eosinophil cationic protein (ECP) release, and hydrogen peroxide (H 2O 2) production in the presence of different drug concentrations similar to those obtained at airway level (10 −8 and 10 −7 M) and at blood level (10 −10 and 10 −9 M). Partially purified blood eosinophils, isolated from 23 asthmatic subjects, were used to evaluate the activity of budesonide
on: (1) chemotaxis toward the activated fifth component of complement (C5a, 0.1 μg/ml) or recombinant human (rh) interleukin
(IL)-5 (200 pg/ml), (2) ECP release by cells stimulated with tetradecanoylphorbol acetate (TPA) and (3) H 2O 2 production by TPA-activated cells. The chemotactic response to C5a was down-regulated significantly by budesonide only by
the highest concentrations tested (10 −8 and 10 −7 M); differently, budesonide was effective in inhibiting eosinophil migration toward rhIL-5, at all concentrations tested
( p < 0.01, each comparison). By contrast, no drug-induced modifications were observed in ECP release or in H 2O 2 production ( p > 0.05, each comparison). We conclude that concentrations of budesonide similar to those obtained in vivo are effective in
inhibiting eosinophil locomotion but not in down-regulating the release of reactive oxygen species and granule-associated
proteins.
Accepted for publication: 11 February 1999 相似文献
2.
Reactive oxygen species (ROS) may play an important role in the chronic pulmonary morbidity of preterm infants. We therefore
studied the magnitude and mechanisms of oxidative inactivation of a natural lung surfactant (NLS) and of two surfactants used
for treatment of respiratory distress syndrome, beractant and KL 4 surfactant (KL 4). Incubation with Fenton reagents, 2-4 mM peroxynitrite (ONOO −) or 0.5 mM hypochlorous acid (OCl −), resulted in an increased minimum surface tension (MST) of all surfactants; the order of effect on MST was beractant > KL 4 > NLS. After incubation with Fenton reagents, NLS contained a higher concentration of conjugated dienes ( p < 0.01) but lower concentration of malondialdehyde ( p < 0.001) than beractant. Protein carbonyl concentrations after treatment with Fenton reagents were higher in NLS and KL 4 than in beractant ( p < 0.05). Surface area cycling for 24 h with 2 mM ONOO − or 0.5 mM OCl − caused both beractant and KL 4 to increase the proportion of light subtypes from 8–10% to 26–29%; with Fenton reagents, there was disappearance of the light
subtype and formation of ultraheavy subtype 74–91% with poor MST. Natural and therapeutic surfactants differ markedly in their
sensitivity to ROS, which may be important for surfactants in therapeutic use because oxidative inactivation may limit their
effect. Oxidation of natural surfactant may result in reduced function and contribute to chronic lung disease.
Accepted for publication: 8 January 1999 相似文献
3.
The inhibitory effects of reactive oxygen species (ROS) on the surface tension-lowering abilities of three surfactants were
compared: natural lung surfactant (NLS), KL 4 surfactant containing synthetic peptide resembling the hydrophobic/hydrophilic domains of SP-B in an aqueous dispersion of
phospholipids, and Survanta? (SUR) containing SP-B and SP-C. The inhibitory concentrations of Fenton reactants (i.e. 0.65
mM FeCl 2, 0.65 mM EDTA, 30 mM H 2O 2), deduced from dose-response plots of FeCl 2 on minimum surface tension (MST) of SUR, were used to assess the Fenton effect on biophysical properties of various surfactants.
Neither H 2O 2 (30 mM) nor FeCl 2 with EDTA (both 0.65 mM) alone affected surfactant function, but when mixed together significantly increased ( p < 0.01) the MST of SUR compared with KL 4 ( p < 0.05) in a FeCl 2 concentration-dependent manner. This effect on NLS was not significant ( p= 0.05) at similar phospholipid concentrations. Also, the range of increases in surface adsorption in mN/m at equilibrium
surface tension (EST) was 27–40 for SUR, 36–44 for KL 4, and 24–25 for NLS. We speculate that the presence of SP-A and the catalase content in NLS may have protective effects on
inactivation of NLS by ROS. We conclude that the in vitro Fenton effect could be a valuable test system for comparing the
inactivation range of surfactants by oxyradicals.
Accepted for publication: 20 May 1997 相似文献
4.
Superoxide dismutases play an important protective role in the lung defense against the pro-oxidative effect of fibrous dusts
(e.g. crocidolite fibers). Particularly crocidolite, but also other asbestos fibers, are known to induce cellular antioxidant
defense. Although rockwool, a man-made fiber made from rock, is used widely for insulation purposes, its effects on the superoxide
dismutases in bronchoepithelial cells have not been investigated. Thus, the purpose of this study was to determine whether
human bronchoepithelial cells (BEAS 2B) respond to rockwool fibers (115-4 experimental rockwool fiber) by induction of MnSOD
mRNA and an increase of MnSOD activity levels. The results were compared with BEAS 2B cells exposed to silica (α-quartz: DQ12;
SiO 2) and UICC (Union Internationale Contre le Cancer) crocidolite (concentrations of all dusts: 0, 2, 5, 10, 25, 50 μg/cm 2= 0, 2.4, 6, 12, 30, 60 μg/ml; 24-h exposure) as control fibers. Scanning electron microscopy confirmed close dust cell contact
under all experimental settings. Very low MnSOD mRNA baseline levels rose significantly ( p < 0.001) in BEAS 2B cells exposed to all three dusts at 2 μg/cm 2. However, at >25 μg/cm 2 MnSOD mRNA levels in silica- and crocidolite- but not in rockwool-exposed cells decreased. Slight (no significance) increases
of MnSOD activity were observed which decreased at higher dust (>5 μg/cm 2) concentrations. These results suggest that: (1) like crocidolite and silica, rockwool accelerates MnSOD gene expression
in bronchoepithelial cells; (2) an increase of MnSOD mRNA levels is not accompanied by MnSOD activity elevation; (3) in contrast
to rockwool, high concentrations (≥25 μg/cm 2) of crocidolite and silica reduced MnSOD activity and MnSOD mRNA levels. Because oxidants (H 2O 2) and crocidolite fibers were shown to reduce SOD activity, lack of active MnSOD protein may be caused by inactivation on
a post-translational level. Furthermore, the decline of MnSOD mRNA and MnSOD activity levels coincides with increasing cytotoxicity.
In conclusion, rockwool was demonstrated to induce MnSOD gene expression, perhaps because of its pro-oxidative effect in bronchoepithelial
cells. In contrast to crocidolite and silica, rockwool fibers are not cytotoxic in this experimental setting.
Accepted for publication: 21 August 1997 相似文献
5.
It has recently been demonstrated that purified NAD(P)H:quinone oxidoreductase 1 (NQO1) is able to scavenge superoxide (O 2•−) though the rate of reaction of O 2•− with NQO1 is much lower than the rate of enzymatic dismutation catalyzed by superoxide dismutase (SOD). This study was undertaken
to determine if the endogenously expressed NQO1 in cardiovascular cells could scavenge O 2•−. We observed that NQO1 was highly expressed in cardiovascular cells, including rat aortic smooth muscle A10 and cardiac H9c2
cells, as well as normal human aortic smooth muscle and endothelial cells. NQO1, but not SOD in the cardiovascular cells was
highly inducible by 3 H-1,2-dithiole-3-thione (D3T). Cytosols from H9c2 and human aortic smooth muscle cells (HASMCs) were isolated to determine
the O 2•− scavenging ability of the endogenously expressed NQO1 by using pyrogallol autooxidation assay. We showed that cytosols from
the above cells inhibited pyrogallol autooxidation in an NADPH or NADH-dependent manner. The NADH/NADPH-dependent inhibition
of pyrogallol autooxidation by the cytosols was completely abolished by the NQO1-specific inhibitor, ES936, suggesting that
the endogenously expressed NQO1 could scavenge O 2•−. In the presence of NADH/NADPH, cytosols from D3T-treated cells showed increased ability to scavenge O 2•− as compared to cytosols from untreated cells. This increased ability to scavenge O 2•− was also completely reversed by ES936. 5-(Diethoxyphosphoryl)-5-methyl-1-pyrroline- N-oxide spin-trapping experiments using potassium superoxide as a O 2•− generator further confirmed the ability of NQO1 from HASMCs to scavenge O 2•−. The spin-trapping experiments also showed that induction of NQO1 by D3T in HASMCs augmented the O 2•− scavenging ability. Taken together, these results demonstrate that the highly expressed and inducible endogenous NQO1 in
cardiovascular cells may act as a potential O 2•− scavenger. 相似文献
6.
To determine whether the slope of a maximal bronchial challenge test (in which FEV 1 falls by over 50%) could be extrapolated from a standard bronchial challenge test (in which FEV 1 falls up to 20%), 14 asthmatic children performed a single maximal bronchial challenge test with methacholine (dose range:
0.097–30.08 μmol) by the dosimeter method. Maximal dose-response curves were included according to the following criteria:
(1) at least one more dose beyond a ΔFEV 1≥ 20%; and (2) a MFEV 1≥ 50%. PD 20 FEV 1 was calculated, and the slopes of the early part of the dose-response curve (standard dose-response slopes) and of the entire
curve (maximal dose-response slopes) were calculated by two methods: the two-point slope (DRR) and the least squares method
(LSS) in % ΔFEV 1×μmol −1. Maximal dose-response slopes were compared with the corresponding standard dose-response slopes by a paired Student's t test after logarithmic transformation of the data; the goodness of fit of the LSS was also determined. Maximal dose-response
slopes were significantly different ( p < 0.0001) from those calculated on the early part of the curve: DRR 20% (91.2 ± 2.7 ΔFEV 1% ·μmol −1) was 2.88 times higher than DRR 50% (31.6 ± 3.4 ΔFEV 1% ·μmol −1), and the LSS 20% (89.1 ± 2.8% ΔFEV 1·μmol −1) was 3.10 times higher than LSS 50% (28.8 ± 1.5% ΔFEV 1·μmol −1). The goodness of fit of LSS 50% was significant in all cases, whereas LSS 20% failed to be significant in one. These results suggest that maximal dose-response slopes cannot be predicted from the data
of standard bronchial challenge tests.
Accepted for publication: 12 December 1996 相似文献
7.
To characterize the cellular inflammation at the bronchial and bronchoalveolar levels, we evaluated 43 patients with asthma
who were sensitized to house dust mites. On 2 consecutive days patients underwent methacholine challenge and allergen bronchial
challenge. In addition, 6, 24, or 72 h after allergen challenge, fiberoptic bronchoscopy with bronchial lavage (BL) and bronchoalveolar
lavage (BAL) was performed. Patients belonging to the 6-h, 24-h, or 72-h group were divided further into two subgroups: those
with isolated early response to allergen (LAR −), and those with dual response to allergen (LAR +). The percentage of eosinophils and of epithelial cells in BAL fluid was significantly higher in LAR + than in LAR − patients in the 6-h group ( p < 0.05, each comparison), but not 24 or 72 h after ( p > 0.05, each comparison). Similarly, the proportion of BL eosinophils was also higher in LAR + than in LAR − patients, both in the 6-h and in the 24-h group ( p < 0.05, each comparison). In addition, increased proportions of BL neutrophils were present in the LAR + patients belonging to the 24-h group ( p < 0.05). Comparing ``proximal' = BL vs ``distal' = BAL data, we found a significantly higher proportion of epithelial cells
in BL compared with BAL, in both LAR − and LAR + subjects, either 6, or 24, or 72 h after challenge ( p < 0.01, each comparison) and increased percentages of BL neutrophils and eosinophils in LAR + patients ( p < 0.05, each comparison), but not in LAR − patients, in the 24-h group. The percentages of BL or BAL macrophages and lymphocytes did not differ significantly among
the different patient groups. These data indicate that the development of LAR after allergen inhalation challenge is associated
with an early recruitment of eosinophils and with epithelial desquamation in the airways. In addition, after allergen challenge
epithelial desquamation is more pronounced in the proximal than in the distal airways, independently of the type of bronchial
response.
Accepted for publication: 7 January 1997 相似文献
8.
N6-(2-hydroxyethyl)-adenosine (HEA), is one of the active molecule found in Cordyceps cicadae. The protective effect of HEA against H2O2 induced oxidative damage in PC12 cells and the mechanism of action was investigated. The cells were exposed to varying concentrations of HEA (5–40 μM) for a period of 24 h and further incubated with 100 μM of H2O2 for an another 12 h. Cell viability, LDH release, MMP collapse, Ca2+ overload, antioxidant parameters (reactive oxygen species generation (ROS), malondialdehyde (MDA), superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), inflammatory mediators (interleukins 6 and 1β (IL-6 and IL-1β), tumor necrosis factor alpha (TNF-α) and NF-kB were evaluated. The results obtained showed that cells exposed to H2O2 toxicity showed reduced cell viability, increased LDH, ROS and Ca2+ overload. However, prior treatment of PC12 cells with HEA increased cell viability, reduced LDH release, MMP collapse, Ca2+ overload and ROS generation induced by H2O2 toxicity. Furthermore, HEA also increased the activities of antioxidant enzymes and inhibited lipid peroxidation as well as reduced IL-6, IL-1β, TNF-α and NF-kB. Thus, our results provided insight into the attenuative effect of HEA against H2O2 induced cell death through its antioxidant action by reducing ROS generation, oxidative stress and protecting mitochondrial function. 相似文献
9.
Sulfite (bisulfite/sulfite) can affect voltage-gated sodium (Na +) channels (VGSC) in a concentration-dependent manner in isolated rat ventricular myocytes. In this study, the effect of epigallocatechin-3-gallate
(EGCG) on VGSC in isolated ventricular myocytes was studied. Ventricular myocytes were exposed to 10 μM bisulfite/sulfite
for 10 min, and EGCG was then administered in different concentrations (10, 30, 50 μg ml −1). Decreased activity of superoxide dismutase, catalase (CAT) and glutathione peroxidase (GPx) was observed after bisulfite/sulfite
exposure, with significant increase in Na + currents ( I
Na) and alterations in half-activation voltage and half-inactivation voltage. Intracellular reactive oxygen species (ROS) such
as hydrogen peroxide (H 2O 2), hydroxyl (OH ·), and superoxide anion (O 2·−) were increased. After EGCG treatment, activity of the aforementioned enzymes increased while the ROS level decreased. The
effects progressed with increasing amounts of EGCG, up to a level similar to blank control at the dose of 50 μg ml −1 EGCG, EGCG also reduced the I
Na and reversed the alterations in half-activation voltage and half-inactivation voltage. In conclusion, EGCG could protect
Na + channels in rat ventricular myocytes against the oxidative damage induced by sulfite as a scavenger of the ROS. 相似文献
10.
Pretreatment with inhaled fuorsemide has been shown to protect against bronchoconstrictive stimuli that indirectly activate
airway smooth muscle. However, it is controversial as to whether furosemide acts directly on airway smooth muscle. To investigate
this we studied the effect of furosemide on both methacholine (MCh)- and serotonin (5-HT)-induced bronchoconstriction in explanted
rat airways. Lungs from 21 Sprague-Dawley rats (269 ± 15 g) were excised, inflated with agarose solution at 37°C (1% w/v,
48 ml/kg), embedded in 4% agarose, and refrigerated to gel the agarose. Lung slices (0.5–1.0 mm thick) were cultured overnight
at 37°C. Explants were placed on a dissecting video microscope, and airway area was measured with an image analysis system.
MCh or 5-HT was administered directly to explanted airways (final concentrations 3.8 × 10 −6 M and 3.8 × 10 −5 M, respectively). Five min later furosemide (3.7 × 10 −5 M or 3.7 × 10 −4 M) was added and airway area monitored 5, 10, 15, 30, and 60 min later. Results were expressed as a percentage of the maximal
response. Significant bronchodilation was seen after 30 min in airways preconstricted with MCh and after 15 min in those preconstricted
with 5-HT following 3.7 × 10 −4 M furosemide ( p < 0.05). 3.7 × 10 −5 M furosemide caused bronchodilation only at 60 min in airways constricted with 5-HT. The effect was blocked by a 30-min incubation
of explants with 10 −6 M indomethacin. The furosemide-induced bronchodilation effect was not observed in airways strongly constricted with 3.8 ×
10 −5 M MCh. These findings indicate that in the rat at least, furosemide induces a weak bronchodilator effect present only at
high doses, which seems to be dependent on the production of prostaglandins. This effect may be relevant to the observed therapeutic
action of furosemide in asthmatics.
Accepted for publication: 27 September 1996 相似文献
11.
The rate of oxidative phosphorylation was investigated in isolated mitochondria from hindlimb muscles of young (4.5 mo) and
old (26.5 mo) male Fischer 344 rats with or without endurance training. Further, the susceptibility of the muscle mitochondria
to exogenous reactive oxygen species was examined. State 3 and 4 respiration, as well as the respiratory control index (RCI),
were significantly lower in muscle mitochondria from aged vs. young rats (P<0.05), using either the site 1 substrates malate-pyruvate
(M-P) and 2-oxoglutarate (2-OG), or the site 2 substrate succinate. In both young and old rats, training increased state 4
respiration with M-P, but had no effect on state 3 respiration, resulting in a reduction of RCI. Training also increased state
4 respiration with 2-OG and decreased RCI in young rats. When muscle mitochondria were exposed to superoxide radicals (O 2
·−) and hydrogen peroxide (H 2O 2) generated by xanthine oxidase and hypoxanthine, or H 2O 2 alone in vitro, state 3 respiration and RCI in both age groups were severely hampered, but those from the old rats were inhibited to a less
extent than the young rats. In contrast, state 4 respiration was impaired by O 2
·− and/or H 2O 2 to a greater extent in the old rats. Muscle mitochondria from trained young rats showed a greater resistance to the O 2
· − and/or H 2O 2-induced state 3 and RCI inhibition than those from untrained young rats. Muscle from aged rats had significantly higher total
activities of superoxide dismutase (SOD), catalase, glutathione peroxidase (GPX), and glutathione reductase than that from
young rats, however, training increased SOD and GPX activities in young but not old rats. The results of this study suggest
that mitochondrial capacity for oxidative phosphorylation is compromised in aging skeletal muscle. Further, the increased
mitochondrial resistance to reactive oxygen species demonstrated in aged and young trained muscles may be attributed to enhanced
antioxidant enzyme activities. 相似文献
12.
Synthesis and release of 1,25-dihydroxycholecalciferol (1,25-(OH) 2D 2) by alveolar macrophages (AM) have been shown to be increased in granulomatous lung disease. ICAM-1 plays a major part in
leukocyte homing to sites of chronic inflammation, which is a crucial step during the inflammatory response. Whether 1,25-(OH) 2D 2 alters the ICAM-1 expression of AM in humans has not been studied. Bronchoalveolar lavage (BAL) was performed in 12 healthy
volunteers, in 13 patients with sarcoidosis (active disease n= 8, inactive disease n= 5), and in 9 patients with chronic bronchitis. AM were incubated with different concentrations of 1,25-(OH) 2D 2 (10 −11 to 10 −6 M) with and without priming with interferon-γ (IFN-γ) and with and without preincubation with 10 −8 M dexamethasone. In addition, the metabolites of vitamin D, 24,25-dihydroxycholecalciferol and 25-hydroxycholecalciferol,
were used. The AM expression of ICAM-1 (cELISA) and the release of tumor necrosis factor-α (TNF-α) (bioassay) by AM were determined.
In healthy volunteers the ICAM-1 expression on AM was significantly and dose-dependently increased by 1,25-(OH) 2D 2, but not by 24,25-dihydroxycholecalciferol and 25-hydroxycholecalciferol. Priming with IFN-γ resulted in an additive effect.
Preincubation with dexamethasone inhibited ICAM-1 expression. Addition of 1,25-(OH) 2D 2 after inhibition by dexamethasone increased ICAM-1 expression significantly. TNF-α secretion of AM from healthy volunteers
was significantly reduced by 1,25-(OH) 2D 2. In sarcoidosis patients ICAM-1 expression was significantly higher compared with healthy volunteers. Incubation with 1,25-(OH) 2D 2 resulted in a further significant increase of ICAM-1 expression. TNF-α secretion of AM was increased compared with healthy
volunteers. 1,25-(OH) 2D 2 reduced TNF-α secretion; however, this difference was not significant. 1,25-(OH) 2D 2 has an immunomodulating effect on human AM both in healthy volunteers and in sarcoidosis patients with enhanced expression
of ICAM-1. It may serve as an autocrine mediator in inflammatory lung disease.
Accepted for publication: 5 November 1998 相似文献
13.
Oxygen-derived free radicals have been demonstrated to contribute to the pathogenesis of myocardial dysfunction, although
the underlying mechanism remains not fully understood. This study was designed to examine the role of the superoxide generator
pyrogallol on cardiac contractile function and possible intervention with herbal medicines anisodamine and tetramethylpyrazine
(TMP) on pyrogallol-induced cardiac contractile response. Adult rat ventricular myocytes were isolated and stimulated to contract
at 0.5 Hz. Mechanical properties were evaluated using an lonOptix system including peak shortening (PS), time-to-PS (TPS),
time-to-90% relengthening (TR 90), and maximal velocity of shortening/relengthening (±dL/dt). A 10-min exposure of pyrogallol (0 to 10 −2
M) did not affect cardiac contractile mechanics. However, longer duration of pyrogallol exposure (1, 3, and 6 h) significantly
shortened resting cell length, reduced PS and ±dL/dt, and prolonged TPS and TR 90 in time- and concentration-dependent manners. The pyrogallol (10 −4
M with 6-h incubation)-induced mechanical defects were prevented by the p38 mitogen-activated protein (MAP) kinase inhibitor
SB203580 (1 μ M) and superoxide dismutase (SOD, 500 U/mL) with the exception that pyrogallol-induced PS depression was unaffected by SOD.
Interestingly, incubation of herbal antioxidants anisodamine (10 −7
M) and TMP (10 −7
M) effectively attenuated the pyrogallol-induced cardiac mechanical defects with the exception of PS unaffected by TMP. Our
data demonstrate a direct inhibitory effect of pyrogallol on cardiac contraction, probably in a superoxide- and p38 MAP kinase-dependent
manner. The antioxidant medicines anisodamine and TMP may be useful in the treatment of oxygen free radical-induced myocardial
dysfunction. 相似文献
14.
Bafilomycin A 1, a selective inhibitor of V-type H +-translocating ATPase (V-ATPase), may be a useful adjunct in cancer chemotherapy (Altan et al. [1998] J Exp Med 187:1583–1598).
Therapeutic uses of the enzyme inhibitor need to consider the agent's potential effects on normal (nontumor) cells. This study
determined the effects of bafilomycin A 1 on resident alveolar macrophages (mφ). Treatment of alveolar mφ with bafilomycin A 1 (10 μM, 1 h) caused a significant decrement in cytosolic pH. This was accompanied by marked alteration of mφ bactericidal
capabilities. The enzyme inhibitor caused a marginal reduction in the phagocytosis of opsonized Staphylococcus aureus and significantly suppressed intracellular killing of the phagocytosed bacteria. In keeping with the effects on intracellular
killing, bafilomycin A 1 significantly reduced the production of reactive oxygen species (ROS). On the other hand, cell spreading was enhanced significantly
by bafilomycin A 1. Comparable changes in ROS generation and mφ spreading were produced by altering cytosolic pH through changes in extracellular
pH (pH o) in the absence of bafilomycin A 1. These findings suggest that the agent's effects on ROS production and mφ spreading were related to the accompanying changes
in cytosolic pH. The enzyme inhibitor also altered mφ morphology, leading to the shortening of microvilli and focal loss of
surface ruffles. These morphologic effects differed from those produced by altering cytosolic pH by changes in pH o. The results demonstrate that V-ATPase activity is an important determinant of mφ functioning and structure. Therapeutic
use of V-ATPase inhibitors might be expected to compromise the bactericidal activity of alveolar mφ.
Accepted for publication: 20 January 2000 相似文献
15.
The symptom of breathlessness is an important outcome measure in the management of patients with chronic obstructive pulmonary
disease (COPD). Clinical ratings of dyspnea and routine lung function are weakly related to each other. However, in the clinical
setting breathlessness in COPD is encountered under conditions of increased respiratory effort, impeded respiratory muscle
action, or functional weakness. Thus, the present study was carried out to determine whether and to what extent clinical ratings
of dyspnea and respiratory muscle dysfunction relate to each other. In 21 patients with COPD two methods were used to rate
dyspnea: a modified Medical Research Council Scale (MRC) and the Baseline Dyspnea Index (BDI), which is a multidimensional
instrument for measuring dyspnea based on three components: magnitude of task, magnitude of effort, and functional impairment.
A baseline focal score was obtained as the sum of the three components. Measures were: pulmonary volumes; arterial blood gases;
maximal voluntary ventilation (MVV); maximal inspiratory and expiratory pressures (MIP and MEP, respectively); and breathing
patterns ventilation (V E), tidal volume (V T), and respiratory frequency (R f). In 15 patients pleural pressure was also measured during both quiet breathing (Ppl sw) and maximal inspiratory sniff maneuver at FRC (Pplsn). BDI and MRC ratings related to each other and showed comparable weak
associations with standard parameters (FEV 1, Pa co
2, V
T), MIP, and MEP. In contrast, MVV closely and similarly related to both ratings. Ppl sw (%Ppl sn), a measure of respiratory effort, and Ppl sw (%Ppl sn)/ V
T(%VC), an index of neuroventilatory dissociation, related significantly to both the BDI ( r
2=−0.77 and r
2=−0.75, respectively) and the MRC ( r
2= 0.81 and r
2= 0.74, respectively). Using MVV, Ppl sw (%Ppl sn), and Ppl sw (%Ppl sn)/ V
T(%VC) in a stepwise multiple regression as independent variables with BDI rating as dependent variable, MVV explained an additional
14.5% of the variance of the BDI over the 67.8% predicted by Ppl sw (%Ppl sn). Our results demonstrate that the level of chronic exertional dyspnea in COPD increases as the ventilatory muscle derangement
increases. The level of the relationships among dyspnea ratings and MVV and respiratory effort helps to explain some of the
mechanisms of chronic dyspnea of COPD. These measures should be considered for therapeutic intervention to reduce dyspnea.
Accepted for publication: 30 December 1996 相似文献
16.
Objective To explore the role of reactive oxygen species (ROS) in the in vitro activation of skin fibroblasts from patients with systemic sclerosis (SSc). Methods Fibroblasts were obtained from involved skin of patients with limited or diffuse SSc. Oxidative activity imaging in living cells was carried out using confocal microscopy. Levels of O2− and H2O2 released from fibroblasts were estimated by the superoxide dismutase (SOD)–inhibitable cytochrome c reduction and homovanilic acid assays, respectively. To verify NADPH oxidase activation, the light membrane of fibroblasts was immunoblotted with an anti‐p47phox–specific antibody. Fibroblasts were stimulated with various cytokines and growth factors to determine whether any of these factors modulate ROS generation. Cell proliferation was estimated by 3H‐thymidine incorporation. Northern blot analysis was used to study α1 and α2 type I collagen gene expression. Results Unstimulated skin fibroblasts from SSc patients released more O2− and H2O2 in vitro through the NADPH oxidase complex pathway than did normal fibroblasts, since incubation of SSc fibroblasts with diphenylene iodonium, a flavoprotein inhibitor, suppressed the generation of ROS. This suppression was not seen with rotenone, a mitochondrial oxidase inhibitor, or allopurinol, a xanthine oxidase inhibitor. Furthermore, the cytosolic component of NADPH oxidase, p47phox, was translocated to the plasma membrane of resting SSc fibroblasts. A transient increase in ROS production was induced in normal but not in SSc fibroblasts by interleukin‐1β (IL‐1β), platelet‐derived growth factor type BB (PDGF‐BB), transforming growth factor β1 (TGFβ1), and H2O2. Treatment of normal and SSc fibroblasts with tumor necrosis factor α (TNFα), IL‐2, IL‐4, IL‐6, IL‐10, interferon‐α (IFNα), IFNγ, granulocyte–macrophage colony‐stimulating factor (GM‐CSP), G‐CSF, or connective tissue growth factor (CTGF) had no effect on ROS generation. Constitutive ROS production by SSc fibroblasts was not inhibited when these cells were treated with catalase, SOD, IL‐1 receptor antagonist, or antibodies blocking the effect of TGFβ1, PDGF‐BB, and other agonists (IL‐4, IL‐6, TNFα, CTGF). In contrast, treatment of SSc fibroblasts with the membrane‐permeant antioxidant N‐acetyl‐L ‐cysteine inhibited ROS production, and this was accompanied by decreased proliferation of these cells and down‐regulation of α1(I) and α2(I) collagen messenger RNA. Conclusion The constitutive intracellular production of ROS by SSc fibroblasts derives from the activation of an NADPH oxidase–like system and is essential to fibroblast proliferation and expression of type I collagen genes in SSc cells. Our results also exclude O2−, H2O2, IL‐1β, TGFβ1, PDGF‐BB, IL‐4, IL‐6, TNFα, or CTGF as mediators of a positive, autocrine feedback mechanism of ROS generation. 相似文献
17.
To determine the site of action of inhaled nitric oxide (iNO) in the newborn pig lung, lungs were isolated and perfused at
constant flow for microfocal x-ray angiography. Measurements of pulmonary arterial diameters were made on arteries in the
100–2500 μm diameter range under control conditions, during vasoconstriction caused by hypoxia (decreasing PO 2 from ∼120 to ∼50 Torr), or N ω-nitro-L-arginine methylester (L-NAME 10 −4 M) administration, with or without vasodilation induced by iNO (40 ppm) or by the NO donor S-nitroso-N-acetylpenicillamine
(SNAP 5 × 10 −6 M) given intravascularly. Hypoxia caused constriction only in smaller arteries whereas L-NAME constricted arteries throughout
the size range studied. iNO dilated the smaller arteries more than the larger arteries under all study conditions. SNAP was
used to provide an intravascular source of NO for comparison to iNO. SNAP also dilated smaller arteries more than larger arteries,
but it had a significantly greater effect on the large arteries than did iNO. This suggests that differential accessibility
of the vascular smooth muscle to NO between sources, air and blood, is a factor in the diameter dependence of the responses.
Accepted for publication: 13 March 2001 相似文献
18.
To determine whether functional atypical β-adrenoceptors (β 3-adrenoceptors) are present in pulmonary vascular smooth muscle, we studied isolated canine pulmonary arterial rings under
isometric conditions in vitro. Addition of β-adrenoceptor agonists produced a concentration-dependent relaxation of noradrenaline-precontracted
tissues, a rank order potency being isoproterenol (1) > salbutamol (0.95) > selective β 3-adrenoceptor agonists, CL 316243 (0.85), and BRL 37344 (0.83). A marked desensitization to salbutamol occurred by pretreatment
with salbutamol but not with CL 316243. When β 1-adrenoceptors had been blocked, the relaxant responses to salbutamol were competitively antagonized by the β 2-adrenoceptor antagonist ICI 118551 with a pA 2 value of 7.67 ± 0.21 (mean ± S.E.), but the response to CL 316243 was weekly antagonized by ICI 118551 only at a high concentration
of 10 −5 M, where an apparent pA 2 value was 5.24. In contrast, cyanopindolol, a nonselective β-adrenoceptor antagonist, antagonized CL 316243–induced relaxation
in a competitive manner with a pA 2 of 6.10 ± 0.11. This pA 2 value was lower than that when salbutamol was used as an agonist (6.69 ± 0.14, p < 0.01). Intracellular 3′,5′-cyclic adenosine monophosphate (cAMP) levels were increased by CL 316243 in a concentration-dependent
fashion, an effect that was not altered by ICI 118551. These results suggest that β 3-adrenoceptors may exist in canine pulmonary artery smooth muscle and that stimulation of this atypical receptor causes vasodilation
through a cAMP-dependent pathway.
Accepted for publication: 17 June 1999 相似文献
19.
Tannin, isolated from cotton bracts and implicated in the pathogenesis of byssinosis, inhibits isoproterenol and forskolin-stimulated
cAMP release from airway cells in part by decreasing cell surface β-adrenergic receptor number and uncoupling the β-adrenergic
receptor from its stimulatory G-protein (G s) and in part by inhibiting adenylyl cyclase activity. We have hypothesized that cotton tannin, because of its long polymer
length, interacts with the hydrophobic binding pocket of the β-adrenergic receptor and alters β-adrenergic receptor binding
and G s coupling. In these studies, tannins of three different polymer lengths and molecular masses were isolated from cotton bracts
using sequential Amicon ultrafiltration [molecular mass > 10,000 (YM10 retentate), 1,000–10,000 (YM10 filtrate), and 1,000–5,000
Da (YM2 retentate)]. The YM10 retentate (25 μg/ml) decreased chloride secretion (Jnet = 1.11 ± 0.28 (control) to 0.59 ± 0.18
μEq/cm 2·h, p < 0.05, n= 6), decreased cell surface β-adrenergic receptor number (18.0 ± 1.8 (control) to 10.6 ± 0.9 fmol/mg protein, p < 0.02, n= 4), and inhibited forskolin-stimulated cAMP release (5,254 ± 1,290 (control) to 2,968 ± 620 pmol/mg protein, p < 0.01, n= 8). In contrast, neither the YM10 filtrate nor the YM2 retentate had any effect on net chloride secretion, β-adrenergic
cell surface receptor number, or forskolin-stimulated cAMP release. We conclude that polymer length is essential for the effect
of tannin on the β-adrenergic receptor and on adenylyl cyclase.
Accepted for publication: 28 June 1998 相似文献
20.
Our novel proposal is that TNFα exerts a direct effect on mitochondrial respiratory function in the heart, independently of
its cell surface receptors. TNFα-induced cardioprotection is known to involve reactive oxygen species (ROS) and sphingolipids.
We therefore further propose that this direct mitochondrial effect is mediated via ROS and sphingolipids. The protective concentration
of TNFα (0.5 ng/ml) was added to isolated heart mitochondria from black 6 × 129 mice (WT) and double TNF receptor knockout
mice (TNFR1&2 −/−). Respiratory parameters and inner mitochondrial membrane potential were analyzed in the presence/absence of two antioxidants,
N-acetyl- l-cysteine or N-tert-butyl-α-(2-sulfophenyl)nitrone or two antagonists of the sphingolipid pathway, N-oleoylethanolamine (NOE) or imipramine. In WT, TNFα reduced State 3 respiration from 279.3 ± 3 to 119.3 ± 2 (nmol O 2/mg protein/min), increased proton leak from 15.7 ± 0.6% (control) to 36.6 ± 4.4%, and decreased membrane potential by 20.5 ± 3.1%
compared to control groups. In TNFR1&2 −/− mice, TNFα reduced State 3 respiration from 205.2 ± 4 to 75.7 ± 1 ( p < 0.05 vs. respective control). In WT mice, both antioxidants added with TNFα restored State 3 respiration to 269.2 ± 2 and
257.6 ± 2, respectively. Imipramine and NOE also restored State 3 respiration to 248.4 ± 2 and 249.0 ± 2, respectively ( p < 0.01 vs. TNFα alone). Similarly, both antioxidant and inhibitors of the sphingolipid pathway restored the proton leak to
pre-TNF values. TNFα-treated mitochondria or isolated cardiac muscle fibers showed an increase in respiration after anoxia–reoxygenation,
but this effect was lost in the presence of an antioxidant or NOE. Similar data were obtained in TNFR1&2 −/− mice. TNFα exerts a protective effect on respiratory function in isolated mitochondria subjected to an anoxia–reoxygenation
insult. This effect appears to be independent of its cell surface receptors, but is likely to be mediated by ROS and sphingolipids. 相似文献
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