PURPOSE: Removal of CO₂ is much efficient during high-frequency oscillatory ventilation (HFOV) for preterm infants. However, an optimal carbon dioxide diffusion coefficient (DCO₂) and tidal volume (VT) have not yet been established due to much individual variance. This study aimed to analyze DCO₂ values, VT, and minute volume in very-low-birth-weight (VLBW) infants using HFOV and correlates with plasma CO₂ (pCO₂). MATERIALS AND METHODS: Daily respiratory mechanics and ventilator settings from twenty VLBW infants and their two hundred seventeen results of blood gas analysis were collected. Patients were treated with the Dräger Babylog VN500 ventilator (Drägerwerk Ag & Co.) in HFOV mode. The normocapnia was indicated as pCO₂ ranging from 45 mm Hg to 55 mm Hg. RESULTS: The measured VT was 1.7 mL/kg, minute volume was 0.7 mL/kg, and DCO₂ was 43.5 mL²/s. Mean results of the blood gas test were as follows: pH, 7.31; pCO₂, 52.6 mm Hg; and SpO₂, 90.5%. In normocapnic state, the mean VT was significantly higher than in hypercapnic state (2.1±0.5 mL/kg vs. 1.6±0.3 mL/kg), and the mean DCO₂ showed significant difference (68.4±32.7 mL²/s vs. 32.4±15.7 mL²/s). The DCO₂ was significantly correlated with the pCO₂ (p=0.024). In the receiver operating curve analysis, the estimated optimal cut-off point to predict the remaining normocapnic status was a VT of 1.75 mL/kg (sensitivity 73%, specificity 80%). CONCLUSION: In VLBW infants treated with HFOV, VT of 1.75 mL/kg is recommended for maintaining proper ventilation.
Blood Gas Analysis ; Carbon Dioxide/analysis ; Female ; High-Frequency Ventilation ; Humans ; Hypercapnia/physiopathology ; Incidence ; Infant ; Infant, Newborn ; Infant, Very Low Birth Weight/physiology ; Male ; ROC Curve ; Tidal Volume

The present study was to investigate the role of TRPC6 in pulmonary artery smooth muscle cells (PASMCs) proliferation and apoptosis under hypoxia and hypercapnia. PASMCs were isolated from chloral hydrate-anesthetized male Sprague-Dawley (SD) rats. Cellular purity was assessed by immunofluorescence staining for smooth muscle α-actin under fluorescence microscopy. Passage 4-6 PASMCs were starved for 24 h in serum-free DMEM and divided into 5 groups randomly: normoxia, hypoxia and hypercapnia, DMSO, TRPC6 inhibitor SKF-96365 and TRPC6 activator OAG groups. The normoxic group was incubated under normoxia (5% CO, 21% O, 37 °C) for 24 h, and the others were incubated with corresponding drugs under hypoxic and hypercapnic (6% CO, 5% O, 37 °C) atmosphere for 24 h. TRPC6 mRNA was detected by reverse transcription-PCR. TRPC6 protein was detected by Western blotting. The proliferation of PASMCs was performed by CCK-8 kit. Apoptosis of the PASMCs was detected using TUNEL assay. The [Ca]in the PASMCs was measured using Fura 2-AM fluorescence. The results showed that the expressions of TRPC6 mRNA and protein, and [Ca]were upregulated under hypoxic and hypercapnic conditions. Hypoxia and hypercapnia promoted cellular proliferation and inhibited apoptosis in the PASMCs. OAG enhanced the above-mentioned effects of hypoxia and hypercapnia, whereas SKF-96365 reversed these effects. These results suggest that TRPC6 may play a role in PASMCs proliferation and apoptosis under hypoxia and hypercapnia by regulating [Ca].
Actins ; Animals ; Apoptosis ; Calcium ; metabolism ; Cell Hypoxia ; Cell Proliferation ; Cells, Cultured ; Hypercapnia ; physiopathology ; Imidazoles ; Male ; Muscle, Smooth, Vascular ; cytology ; Myocytes, Smooth Muscle ; metabolism ; Pulmonary Artery ; cytology ; Rats ; Rats, Sprague-Dawley ; TRPC Cation Channels ; metabolism

OBJECTIVETo investigate the role and significance of ATP-sensitive K+ channels in the pathological process of hypoxia hypercapnia-induced pulmonary vasoconstriction (HHPV) and the relationship with ERK1/2 signal pathway in rats.

METHODSWe made the third pulmonary artery rings of SD rats, used the model of pulmonary artery rings perfusion in vitro. Under acute hypoxia hypercapnia condition, and observed the effects of the three stages of HHPV incubated by glybenclamide(Gly) and the combined application of Gly and U0126. At the same time, the values of rings' tension changes were recorded via the method of hypoxia hypercapnia conditions reactivity.

RESULTSUnder the normoxia condition, the values of the third pulmonary artery rings tension were relatively stable, but under the hypoxia hypercapnia condition, we observed a biphasic pulmonary artery contractile response compared with N group (P < 0.05, P < 0.01). When the third pulmonary artery rings incubated by Gly, it's phase II persistent vasoconstriction was enhanced compared with the H group (P < 0.05, P < 0.01), and the phase I vasoconstriction was also heightened. Moreover, under the hypoxia hypercapnia condition, U0126 could significantly relieve the phase II persistent vasoconstriction compared with HD group (P < 0.05, P < 0.01) induced by Gly, but the phase I acute vasoconstriction and the phase I vasodilation had no changes (P > 0.05).

CONCLUSIONGly may mediate HHPV via activating ERK1/2 signal transduction pathway.

Animals ; Glyburide ; pharmacology ; Hypercapnia ; metabolism ; physiopathology ; Hypoxia ; metabolism ; physiopathology ; In Vitro Techniques ; MAP Kinase Signaling System ; physiology ; Male ; Pulmonary Artery ; drug effects ; metabolism ; physiology ; Rats ; Rats, Sprague-Dawley ; Vasoconstriction ; drug effects

OBJECTIVETo investigate the effect of chloride channel blocker--niflumic acid (NFA) on the pathological process of hypoxia hypercapnia-induced pulmonary vasoconstriction in rats.

METHODSWe used the model of hypoxia hypercapnia-induced pulmonary vasoconstriction rats, and divided the second, third branch pulmonary artery rings randomly into four groups (n = 8): control group (N group), hypoxia hypercapnia group (H group), DMSO incubation group (HD group), niflumic acid group (NFA group). Under acute hypoxia hypercapnia conditions, we observed the effects of the three stages of hypoxia hypercapnia-induced pulmonary vasoconstriction (HHPV) incubated by NFA in the second, third brach pulmonary artery rings. At the same time, the values of rings' tension changings were recorded via the method of hypoxia hypercapnia conditions reactivity. And investigated the effect of NFA to HHPV.

RESULTS(1) Under the hypoxia hypercapnia condition, we observed a biphasic pulmonary artery contractile (the phase I rapid contraction and vasodilation; the phase II sustained contraction) response in both the second and the third branch pulmonary artery rings compared with the control group (P < 0.05 , P < 0.01); (2) The second and third pulmonary artery rings incubated by NFA which phase II persistent vasoconstriction were significantly attenuated compared with the H group (P < 0.05 , P < 0.01).

CONCLUSIONThe blocker of the chloride channels attenuates the second and third branch pulmonary artery rings constriction in rat, especially the phase II persistent vasoconstriction, so then have an antagonistic effect on HHPV.

Animals ; Chloride Channels ; antagonists & inhibitors ; Hypercapnia ; physiopathology ; Hypoxia ; physiopathology ; Niflumic Acid ; pharmacology ; Pulmonary Artery ; physiopathology ; Pulmonary Circulation ; Rats ; Vasoconstriction ; drug effects

OBJECTIVETo investigate the mechanism of how curcumin improves pulmonary vascular remodeling associated with chronic pulmonary arterial hypertension.

METHODSThe model of chromic hypoxia hypercapniapulmoary remodeling was made. Twenty-four male rats were randomly divided into 4 groups (n = 6): group I (normoxia control group), group II (hypxia and hypercapnia model group), group II (disodium cromoglycate control group), group IV (curcumin treated group). The last 3 group rats were put in a hypoxia cabin where the concentrate of O2 was 8% - 11% and the concentrate of CO2 was 3% - 5%, for 8 h a day and lasting 4 w in total. Group III rats were intraperitoneally injected with disodium cromoglycate (20 mg/kg) and group IV rats were administrated with curcumin by gavage (150 mg/kg). The morphological changes of pulmonary vessel walls and the ultrastructure of mast cells were observed by the optics microscope and the transmission electron microscope. Mast cells and its degranulation state were measured by toluidine blue staining and immunohistochemistry. Data were expressed as means ± SD (standard deviation) and analyzed with SPSS17.0 software.

RESULTS(1) By optics microscopy observation, the value of WA/TA was significantly higher in II group than other groups (P < 0.05). (2) Electron microscope showed that the endothelial cells of pulmonary arterioles in III and IV group were near to I group and the proliferation of pulmonary arterial media smooth cell layer and collagen fibers in adventitia was much lighter than those in II group. The membrane of mast cells was more intact in I, III, IV group than II group. (3) The number of mast cells, the degranulation rate of master cells and the number of positive tryptase stained cells in II group were significantly more than those in other groups. (P < 0.05).

CONCLUSIONCurcumin may inhibit the remodeling of pulmonary vessel induced by chronic hypoxia hypercapnia by mast cell regulation.

Animals ; Cell Degranulation ; Curcumin ; pharmacology ; Hypercapnia ; physiopathology ; Hypertension, Pulmonary ; drug therapy ; Hypoxia ; physiopathology ; Lung ; pathology ; Male ; Mast Cells ; physiology ; ultrastructure ; Pulmonary Artery ; drug effects ; Rats ; Rats, Sprague-Dawley ; Vascular Remodeling ; drug effects

OBJECTIVETo explore the effects of safflower injection on prevention and treatment of hypoxic pulmonary hypertension and clarify the function of the endoplasmic reticulum stress apoptosis pathway during the process.

METHODSThirty male SD rats were randomly grouped as normal control group, hypoxia-hypercapnia group and hypoxia+safflower group. The latter two groups were put in the cabin with oxygen concentration ranged from 9% to 11% and carbon dioxide concentration from 5% to 6%. The pulmonary artery pressure and the index of right ventricular hypertrophy were determined after hypoxia exposure (8 h/dx28 d). Changes in morphology of lung tissue were observed by electron microscopy. To explore the possible mechanisms, we also detected apoptosis and apoptosis-related genes/proteins in lung tissue by TUNEL reactivity and PCR and Western blot.

RESULTSCompared with the normal control group, pulmonary artery pressure and the index of right ventricular hypertrophy in hypoxia group were 45% and 33.4% higher, respectively. Tiny blood vessel wall of lungs was thickened and edema, and proliferation of collagen fibers was obvious under the electron microscope. TUNEL staining of apoptotic cells in lung tissues showed more high brightness green fluorescence (+-++), but less green fluorescence showed in the pulmonary vascular smooth muscle cell layer, and apoptosis index (AI) value was 150% higher; gene and protein expression levels of endoplasmic reticulum stress pathway were increased. Compared with hypoxia-hypercapnia group, pulmonary artery pressure and the index of right ventricular hypertrophy in the hypoxia+safflower group were 18% and 15.6% lower, respectively; collagen fibers were decreased, and smooth muscle cells and epithelial cells were got apoptotic-like changes under the electron microscope. TUNEL staining of apoptotic cells in lung tissues showed brighter green fluorescence (++-+++); the high brightness green fluorescence showed in pulmonary vascular smooth muscle cell layer, and apoptotic index (Al) value was 40% higher; gene and protein expressions of endoplasmic reticulum stress pathway were significantly upregulated.

CONCLUSIONOur findings demonstrate that safflower injection could activate endoplasmic reticulum stress-induced apoptosis and especially promote apoptosis in pulmonary vascular smooth muscle cells.

Animals ; Apoptosis ; drug effects ; Carthamus tinctorius ; chemistry ; Endoplasmic Reticulum Stress ; drug effects ; Hypercapnia ; physiopathology ; Hypertension, Pulmonary ; drug therapy ; physiopathology ; Hypoxia ; physiopathology ; Lung ; cytology ; physiopathology ; Male ; Myocytes, Smooth Muscle ; drug effects ; Rats ; Rats, Sprague-Dawley

A reduction in diaphragm mobility has been identified in patients with chronic obstructive pulmonary disease (COPD) and has been associated with a decline in pulmonary function parameters. However, little information exists regarding the potential role of diaphragm mobility on hypercapnia in COPD. A new method of assessing the mobility of the diaphragm, using ultrasound, has recently been validated. The purpose of the present study was to investigate the relationship between diaphragm mobility and pulmonary function parameters, as well as that between arterial blood gas values and diaphragm mobility, in COPD patients. Thirty seven COPD patients were recruited for pulmonary function test, arterial blood gas analysis and diaphragm mobility using ultrasound to measure the craniocaudal displacement of the left branch of the portal vein. There were significant negative correlations between diaphragmatic mobility and PaCO2 (r = -0.373, P = 0.030). Diaphragmatic mobility correlated with airway obstruction (FEV1, r = 0.415, P = 0.011) and with ventilatory capacity (FVC, r = 0.302, P = 0.029; MVV, r = 0.481, P = 0.003). Diaphragmatic mobility also correlated significantly with pulmonary hyperinflation. No relationship was observed between diaphragm mobility and PaO2 (r = -0.028, P = 0.873). These findings support a possibility that the reduction in diaphragm mobility relates to hypercapnia in COPD patients.
Aged ; Airway Resistance/physiology ; Carbon Dioxide/blood/physiology ; Diaphragm/physiopathology/*ultrasonography ; Female ; Humans ; Hypercapnia/complications/*physiopathology ; Male ; Middle Aged ; Portal Vein ; Pulmonary Disease, Chronic Obstructive/complications/*physiopathology/ultrasonography ; Pulmonary Gas Exchange ; Respiratory Muscles/physiopathology

OBJECTIVETo study the effect of celecoxib on chronic hypoxia and hypercapnic pulmonary hypertension.

METHODSSD rats were randomly divided into normal control group (A), hypoxic hypercapnic group (B), hypoxic hypercapnia+ celecoxib group (C). The content of TXB2 and 6-keto-PGF1alpha in plasma and lung were detected by the technique of radioimmunology.

RESULTS(1) Mean pulmonary arteria pressure(mPAP) was significantly higher in rats of B group than those of A group. mPAP was significantly higher in rats of C group than those of B group. Differences of mPAP were not significant in three groups. (2) The content of TXB2 in plasma and lung and the ratio of TXB2/6-keto-PGF1alpha were significantly higher in rats of B group than those of A group. The ratio of TXB2/6-keto-PGF1alpha was significantly higher and the content of 6-keto-PGF1alpha in plasma and lung was significantly lower in rats of C group than those of B group. (3) Light microscopy showed that WA/TA (vessel wall area/total area) and PAMT (the thickness of medial smooth cell layer) were significantly higher in rats of B group than those of A group. WA/TA and PAMT were significantly higher in rats of C group than those of B group. (4) Electron microscopy showed the thickening of vessel wall and the proliferation of collagen fiber in B group and augmentation of smooth muscle cell and abundance of myofilament in pulmonary arterioles in C group.

CONCLUSIONCelecoxib can aggravate hypoxic hypercapnia pulmonary hypertension and pulmonary vessel remodeling by increasing the ratio of TXA2/PGI2.

Animals ; Celecoxib ; Chronic Disease ; Cyclooxygenase 2 Inhibitors ; adverse effects ; pharmacology ; Epoprostenol ; blood ; Hypercapnia ; complications ; Hypertension, Pulmonary ; etiology ; physiopathology ; Hypoxia ; complications ; Male ; Pyrazoles ; adverse effects ; pharmacology ; Rats ; Rats, Sprague-Dawley ; Sulfonamides ; adverse effects ; pharmacology ; Thromboxane A2 ; blood

OBJECTIVETo investigate the changes of the endogenous hydrogen sulfide(H2S) system in pulmonary hypertension induced by hypoxic hypercapnia (HHPH) in rats and approach the possible mechanisms.

METHODS20 SD rats were randomly divided into control group (C) and hypoxic hypercapnia group (HH) (n=10). The changes of hemodynamics and the right ventricle/left ventricle + septum (RV/LV + SP) were measured. The ratio of vessel wall area and total area (WA/TA) of arteriae pulmonalis were observed under lightmicroscope. By using TdT-mediated dUTP nick end labeling (TUNEL) and immunocytochemistry techniques, apoptosis index (AI) and expression of Bcl-2, Bax protein in arteriae pulmonalis were tested. Plasma level of H2S and activity of H2S generating enzymes in homogenates of rat lung tissue were evaluated by sensitive modified sulfide electrode method. Cystathionine-gamma-lyase (CSE) mRNA in lung tissues was determined by RT-PCR.

RESULTSThe level of mean pulmonary arterial pressure(mPAP), WA/TA and RV/LV + SP were significantly higher in HH group than those in C group (P < 0.05 or P < 0.01). Compared with those in C group, the AI of arteriae pulmonalis in HH group were significantly lower; the expression of Bcl-2 protein increased while that of Bax protein decreased, and the ratio of Bax/Bcl-2 went up obviously (all P < 0.01). Plasma level of H2S, the activity of H2S generating enzymes and CSE mRNA in HH group were significantly lower than those in C group (all P < 0.01). Plasma level of H2S, the activity of H2S generating enzymes, CSE mRNA each was closely positively related to Al while inversely related to mPAP and Bcl-2/Bax (all P < 0.01).

CONCLUSIONThe endogenous hydrogen sulfide system is closely related to pulmonary hypertension induced by hypoxic hypercapnia. The depression of the H2S/CSE system in HHPH may help increase the ratio of Bcl-2/Bax, inhibit apoptosis of pulmonary artery smooth muscle cells and finally result in the formation of pulmonary hypertension.

Animals ; Apoptosis ; physiology ; Hydrogen Sulfide ; metabolism ; Hypercapnia ; complications ; physiopathology ; Hypertension, Pulmonary ; etiology ; physiopathology ; Hypoxia ; complications ; physiopathology ; Male ; Muscle, Smooth, Vascular ; pathology ; Proto-Oncogene Proteins c-bcl-2 ; metabolism ; Rats ; Rats, Sprague-Dawley ; bcl-2-Associated X Protein ; metabolism

OBJECTIVETo investigate the changes of endoplasmic reticulum stress-induced apoptosis in pulmonary tissue of rats with hypoxic pulmonary hypertension.

METHODSTwenty two male SD rats were randomly divided into control group and 4-week hypoxia-hypercapnia group (n=11). The mean pulmonary arterial pressure (mPAP) and the mean carotid arterial pressure (mCAP) were monitored, and the weight ratio of right ventricle (RV) to left ventricle plus septum (LV + S) were measured. The rattish pathological model were assessed by mPAP, mCAP, RV/(LV+ S), vessel wall area/total area (WA/TA), vessel cavity area/total area (CA/TA) and media thickness of pulmonary arteriole (PAMT). The pulmonary apoptotic cells were detected by Hoechst staining. RT-PCR was used to study the genetic expression of caspasel2, glucose regulated protein 78 (GRP78) and GRP94 in pulmonary tissue. The expression of GRP94 and GRP78 proteins in pulmonary tissue were determined by using immunohistochemistry.

RESULTS(1) (The mPAP, RV/(LV + S), WA/TA and PAMT were respectively higher by 50.5%, 37.3%, 72.5% and 137% in hypoxic group than those in control group, while CA/TA was lower by 41.9% (all P < 0.01). There was not significant difference of mCAP between the two groups. (2) Hoechst staining showed that the pulmonary apoptotic cells in hypoxic group outnumbered markedly than those in control group, and the apoptotic cells were mainly in pulmonary tissue, while they were rare in pulmonary vascular smooth muscle cell. (3) Compared with control group, the expression of pulmonary caspasel2, GRP78 and GRP94 mRNA in hypoxic group were higher by 144%, 137% and 80.7% (all P < 0.05), respectively. (4) The expression of pulmonary GRP78 and GRP94 proteins were up-regulated in hypoxic group, and these proteins mainly localized in pulmonary vascular endothelial cell.

CONCLUSIONThe endoplasmic reticulum stress-induced apoptosis may be one of the mechanism of hypoxic pulmonary hypertension and pulmonary vascular wall remodeling.

Animals ; Apoptosis ; physiology ; Caspase 12 ; metabolism ; Endoplasmic Reticulum Stress ; physiology ; Heat-Shock Proteins ; metabolism ; Hypercapnia ; physiopathology ; Hypertension, Pulmonary ; etiology ; pathology ; physiopathology ; Hypoxia ; complications ; physiopathology ; Lung ; pathology ; Male ; Membrane Glycoproteins ; metabolism ; Rats ; Rats, Sprague-Dawley