Experimental Myocardial Infarction Induces Altered Regulatory T Cell Hemostasis,and Adoptive Transfer Attenuates Subsequent Remodeling

Background

Ischemic cardiac damage is associated with upregulation of cardiac pro-inflammatory cytokines, as well as invasion of lymphocytes into the heart. Regulatory T cells (Tregs) are known to exert a suppressive effect on several immune cell types. We sought to determine whether the Treg pool is influenced by myocardial damage and whether Tregs transfer and deletion affect cardiac remodeling.

Methods and Results

The number and functional suppressive activity of Tregs were assayed in mice subjected to experimental myocardial infarction. The numbers of splenocyte-derived Tregs in the ischemic mice were significantly higher after the injury than in the controls, and their suppressive properties were significantly compromised. Compared with PBS, adoptive Treg transfer to mice with experimental infarction reduced infarct size and improved LV remodeling and functional performance by echocardiography. Treg deletion with blocking anti-CD25 antibodies did not influence infarct size or echocardiographic features of cardiac remodeling.

Conclusion

Treg numbers are increased whereas their function is compromised in mice with that underwent experimental infarction. Transfer of exogeneous Tregs results in attenuation of myocardial remodeling whereas their ablation has no effect. Thus, Tregs may serve as interesting potential interventional targets for attenuating left ventricular remodeling.     

Pulmonary gas exchange during exercise in women: effects of exercise type and work increment.

Exercise-induced arterial hypoxemia (EIAH) has been reported in male athletes, particularly during fast-increment treadmill exercise protocols. Recent reports suggest a higher incidence in women. We hypothesized that 1-min incremental (fast) running (R) protocols would result in a lower arterial PO(2) (Pa(O(2))) than 5-min increment protocols (slow) or cycling exercise (C) and that women would experience greater EIAH than previously reported for men. Arterial blood gases, cardiac output, and metabolic data were obtained in 17 active women [mean maximal O(2) uptake (VO(2 max)) = 51 ml. kg(-1). min(-1)]. They were studied in random order (C or R), with a fast VO(2 max) protocol. After recovery, the women performed 5 min of exercise at 30, 60, and 90% of VO(2 max) (slow). One week later, the other exercise mode (R or C) was similarly studied. There were no significant differences in VO(2 max) between R and C. Pulmonary gas exchange was similar at rest, 30%, and 60% of VO(2 max). At 90% of VO(2 max), Pa(O(2)) was lower during R (mean +/- SE = 94 +/- 2 Torr) than during C (105 +/- 2 Torr, P < 0.0001), as was ventilation (85.2 +/- 3.8 vs. 98.2 +/- 4.4 l/min BTPS, P < 0.0001) and cardiac output (19.1 +/- 0.6 vs. 21.1 +/- 1.0 l/min, P < 0.001). Arterial PCO(2) (32.0 +/- 0.5 vs. 30.0 +/- 0.6 Torr, P < 0.001) and alveolar-arterial O(2) difference (A-aDO(2); 22 +/- 2 vs. 16 +/- 2 Torr, P < 0.0001) were greater during R. Pa(O(2)) and A-aDO(2) were similar between slow and fast. Nadir Pa(O(2)) was 相似文献   

Thermal drive contributes to hyperventilation during exercise in sheep

The etiology of exercise hypocapnia is unknown.The contributions of exercise intensity (ExInt), lactic acid,environmental temperature, rectal temperature(T_re), and physicalconditioning to the variance in arterialCO₂ tension(Pa_CO2) in the exercising sheep werequantified. We hypothesized that thermal drive contributes tohyperventilation. Four unshorn sheep were exercised at ~30, 50, and70% of maximal O₂ consumption for30 min, or until exhaustion, both before and after 5 wk of physicalconditioning. In addition, two of the sheep were shorn and exercised ateach intensity in a cold (<15°C) environment.T_re andO₂ consumption were measured continuously. Lactic acid and Pa_CO2 weremeasured at 5- to 10-min intervals. Data wereanalyzed by multiple regression onPa_CO2. During exercise,T_re rose andPa_CO2 fell, except at the lowest ExIntin the cold environment. T_reexplained 77% of the variance in Pa_CO2,and ExInt explained 5%. All other variables were insignificant. Weconclude that, in sheep, thermal drive contributes to hyperventilation during exercise.

     

Measurement of cardiac output during exercise by open-circuit acetylene uptake.

Noninvasive measurement of cardiac output (QT) is problematic during heavy exercise. We report a new approach that avoids unpleasant rebreathing and resultant changes in alveolar PO(2) or PCO(2) by measuring short-term acetylene (C(2)H(2)) uptake by an open-circuit technique, with application of mass balance for the calculation of QT. The method assumes that alveolar and arterial C(2)H(2) pressures are the same, and we account for C(2)H(2) recirculation by extrapolating end-tidal C(2)H(2) back to breath 1 of the maneuver. We correct for incomplete gas mixing by using He in the inspired mixture. The maneuver involves switching the subject to air containing trace amounts of C(2)H(2) and He; ventilation and pressures of He, C(2)H(2), and CO(2) are measured continuously (the latter by mass spectrometer) for 20-25 breaths. Data from three subjects for whom multiple Fick O(2) measurements of QT were available showed that measurement of QT by the Fick method and by the C(2)H(2) technique was statistically similar from rest to 90% of maximal O(2) consumption (VO(2 max)). Data from 12 active women and 12 elite male athletes at rest and 90% of VO(2 max) fell on a single linear relationship, with O(2) consumption (VO(2)) predicting QT values of 9.13, 15.9, 22.6, and 29.4 l/min at VO(2) of 1, 2, 3, and 4 l/min. Mixed venous PO(2) predicted from C(2)H(2)-determined QT, measured VO(2), and arterial O(2) concentration was approximately 20-25 Torr at 90% of VO(2 max) during air breathing and 10-15 Torr during 13% O(2) breathing. This modification of previous gas uptake methods, to avoid rebreathing, produces reasonable data from rest to heavy exercise in normal subjects.     

Effect of locomotor respiratory coupling on respiratory evaporative heat loss in the sheep.

During galloping, many animals display 1:1 coupling of breaths and strides. Locomotor respiratory coupling (LRC) may limit respiratory evaporative heat loss (REHL) by constraining respiratory frequency (f). Five sheep were exercised twice each, according to a five-step protocol: 5 min at the walk, 5 min at the trot (trot1), 10 min at the gallop, 5 min at the trot (trot2), and 5 min at the walk. Rectal temperature (T(re)), stride frequency, f, REHL, and arterial CO(2) tension and pH were measured at each step. Tidal volume (VT) was calculated. LRC was observed only during galloping. The coupling ratio remained at 1:1 while VT increased continuously during galloping, causing REHL to increase from 2.9 +/- 0.2 (SE) W/kg at the end of trot1 to a peak of 5.3 +/- 0.3 W/kg. T(re) rose from 39.0 +/- 0.1 degrees C preexercise to 40.2 +/- 0.2 degrees C at the end of galloping. At the gallop-trot2 transition, VT fell and f rose, despite a continued rise in T(re). Arterial CO(2) tension fell from 36.5 +/- 1.1 Torr preexercise to 31.8 +/- 1.4 Torr by the end of trot1 and then further to 21.5 +/- 1.2 Torr by the end of galloping, resulting in alkalosis. In conclusion, LRC did not prevent increases in REHL in sheep because VT increased. The increased VT caused hypocapnia and presumably elevated the cost of breathing.     

Reduction of the Pa(CO2) set point during hyperthermic exercise in the sheep

In animals that rely on the respiratory system for both gas exchange and heat loss, exercise can generate conflict between chemoregulation and thermoregulation. We hypothesized that in panting animals, hypocapnia during hyperthermic exercise reflects a reduction in the arterial CO2 tension (Pa(CO2)) set point. To test this hypothesis, five sheep were subjected to tracheal insufflations of CO2 or air (control) at 3-4 L min(-1) in 3 min bouts at 5 min intervals over 31 min of exercise. During exercise, rectal temperature and minute ventilation (V(E)) rose continuously while Pa(CO2) fell from 35.4+/-3.1 to 18.6+/-2.9 Torr and 34.3+/-2.4 to 18.7+/-1.5 Torr in air and CO2 trials, respectively. Air insufflations did not affect V(E) or Pa(CO2). V(E) increased during CO2 insufflations via a shift to higher tidal volume and lower frequency. CO2 insufflations also increased Pa(CO2), although not above the pre-exercise level. Within 5 min after each CO2 insufflation, Pa(CO2) had decreased to match that following the equivalent air insufflation. These results are consistent with a reduced Pa(CO2) set point or an increased gain of the Pa(CO2) regulatory system during hyperthermic exercise. Either change in the control of Pa(CO2) could facilitate respiratory evaporative heat loss by mitigating homeostatic conflict.