Protective effects of necrostatin-1 on doxorubicin-induced cardiotoxicity in rat heart.

Background: Doxorubicin (Dox) is one of the most effective antineoplastic drugs which has severe cardiotoxic effects, limiting its clinical usage. Though the exact mechanism of doxorubicin-induced cardiotoxicity is yet to be elucidated, it is shown that production of reactive oxygen species (ROS) increases oxidative stress and leads to cardiomyocyte apoptosis and necroptosis which is also defined as a programmed cell death.Purpose: In the present study, we investigate the effects of necrostatin-1 (Nec-1)-an inhibitor of receptor interaction proteins 1 (RIP1) and necroptosis-on doxorubicin-induced cardiotoxicity in rats.Research Design: Hearts were isolated and perfused by the Langendorff system in all four groups. Perfusion pressure (PP), left ventricular developed pressure (LVDP) and heart rate per minute (HR), LV (dP/dt) max, and LV (dP/dt) min which shows cardiac contractility and relaxation were recorded.Results: Results showed that PP significantly increased with Dox treatment and significantly decreased with Nec-1 treatment, while HR, LVDP, LV (dP/dt) max, and LV (dP/dt) min values significantly decreased with the Dox-treated group and significantly increased with Nec-1 treatment. Also with Nec-1 treatment, gene expression levels of anti-apoptotic Bcl-2 significantly increased and pro-apoptotic protein Bax, apoptotic marker caspase-3, and Nox-2 significantly decreased compared to the Dox-treated group. In heart tissues, MDA levels were significantly increased with Dox and decreased with Nec-1 treatment. These results were supported by the histological analysis indicated that Nec-1 reduced doxorubicin-induced cellular injury.Conclusions: In conclusion, our data indicate that Nec-1 ameliorates doxorubicin-induced cardiotoxicity by reducing oxidative stress injury and attenuating apoptosis and necroptosis.

Evaluation of Serum Interleukin-38 Levels in Different Radiographic Grades of Idiopathic Knee Osteoarthritis.

The aim of this study was to assess interleukin-1ß (IL-1ß), IL-1Ra, IL-36, and IL-38 levels together with hs-CRP levels in patients with different radiographic grades of knee osteoarthritis (OA) in comparison to healthy individuals. Consecutive patients aged over 50 years who were admitted to our Orthopaedics and Traumatology department between November 2018 and March 2019 and diagnosed as knee OA according to the American College of Rheumatology criteria were included in this prospective case-control study. Patients with knee OA were staged according to radiographic Kellgren-Lawrence (K-L) classification and 20 patients were assigned to each group. An age and gender matched control group consisted healthy volunteers with no clinical and radiographic sign of arthritis were conducted as the control group. Venous blood samples were collected and assessed for hs-CRP, IL-1ß, IL-1Ra, IL-36, and IL-38 levels using the double-antibody sandwich ELISA method. The hs-CRP, IL-1ß, IL-36 and IL-38 levels did not significantly differ among controls and independent radiographic stage groups except IL-1Ra levels which was significantly higher in K-L grade 4 knee OA groups compared to healthy controls (P = 0.045). When we compared all patients with knee OA and healthy controls, we detected that IL-1 and IL-1Ra were significantly lower and IL-38 levels were significantly higher in healthy control group compared to patients with knee OA (P = <0.001, <0.001, and 0.019, respectively). According to results obtained from our study, IL-1ß, IL-1Ra, and IL-38 levels significantly differed between healthy individuals and patients with knee OA. However, we did not observe a significant difference and correlation between radiographic grade of knee OA and interleukin levels.

Protective effects of ethyl pyruvate in cisplatin-induced nephrotoxicity.

This study was performed to investigate the effect of ethyl pyruvate on changes in renal functions and oxidative stress related renal injury caused by cisplatin (cis-dichlorodiammine platinum-II; CDDP). Male Wistar albino rats were divided into four groups (n = 8): (1) control group (1 ml Ringer's lactate solution i.p.); (2) ethyl pyruvate (EP) group (50 mg/kg Ringer's EP solution (REPS) i.p.); (3) cisplatin group (a single dose of cisplatin (5 mg/kg, i.p.); and (4) cisplatin + EP group (a single dose of cisplatin (5 mg/kg, i.p.) + REPS 50 mg/kg/day, i.p.) for five days. At the sixth day, kidneys of rats were mounted to a Langendorff apparatus. Renal perfusion pressures were recorded. Blood samples were taken for serum urea, creatinine, total oxidant status (TOS), total antioxidant status (TAS) and oxidative stres index (OSI) evaluations. Kidney tissues were obtained for malondialdehyde (MDA) analyses and histopathological examination. Perfusion pressures, serum urea, creatinine, TOS, OSI and tissue MDA levels were found significantly higher, whereas TAS was notably lower in cisplatin group. Histopathological examination showed apparent renal paranchymal injury in cisplatin group. In cisplatin + REPS group, perfusion pressures, serum urea, creatinine and tissue MDA levels were decreased. Moreover, EP co-administration provided less inflammatory cell infiltration, tubular dilatation, whereas TOS, TAS and OSI improved significantly versus cisplatin group. These findings show that EP has protective effects against cisplatin nephrotoxicity.

N-acetylcysteine reduces lung reperfusion injury after deep hypothermia and total circulatory arrest.

OBJECTIVE: We hypothesized that the use of N-acetylcysteine would ameliorate the lung reperfusion injury observed after deep hypothermia and total circulatory arrest (DHTSA). METHODS: Experiments were carried out on 12 adult mongrel dogs of either sex weighing 25 to 30 kg. The animals were randomly divided into two groups of six animals each. All animals were cooled to an esophageal temperature of 15 degrees C during 30 minutes and underwent 60 minutes of DHTSA, followed by the reinstitution of cardiopulmonary bypass (CPB) and rewarming. Before rewarming, while 100 mL physiologic saline solution was added into the pump in group I, 50 mg/kg N-acetylcysteine(NAC) was given in group II. Heart rate, mean arterial pressure, pulmonary arterial pressure, left atrial pressure, central venous pressure, and cardiac output were recorded. To measure lung tissue malondialdehyde (MDA), water content and polymorphonuclear leukocytes (PMNs) count, lung tissue samples were taken before CPB and after weaning CPB. In addition, alveolar-arterial oxygen difference (AaDO(2))()for tissue oxygenation was calculated by obtaining arterial blood gas samples. Dynamic lung compliance (DLC) was measured before CPB and after CPB. RESULTS: MDA levels before CPB of 44.2 +/- 3.9 nmol/g tissue rose to 76.6 +/- 5.6 nmol/g tissue after weaning CPB in group I (p = 0.004). In group II also, the MDA levels increased from 43.5 +/- 4.2 to 57.4 +/- 5.6 nmol MDA/g tissue after weaning CPB (p = 0.006). The MDA increase in group II after CPB was found to be significantly lower than in group I (p = 0.006). The wet-to-dry lung weight ratio in the NAC group was 5.1 +/- 0.2, significantly less than in the control group (5.9 +/- 0.3), (p = 0.004). AaDO(2) significantly increased in the group I and II (p = 0.002 and p = 0.002, respectively); this elevation in group I was significant than in group II (p = 0.044). In histopathological examination, it was observed that neutrophil counts in the lung parenchyma rose significantly after CPB in both groups (p < 0.001). The increase in group I was significantly larger than group II (p < 0.001). CONCLUSIONS: Results represented in our study indicate that addition of NAC into the pump after DHTSA can reduce lung reperfusion injury.

Does sodium nitroprusside reduce lung injury under cardiopulmonary bypass?

OBJECTIVE: We hypothesized that direct pulmonary arterial infusion of sodium nitroprusside (SNP) would ameliorate lung injury under cardiopulmonary bypass. METHODS: Experiments were performed on 12 adult mongrel dogs of both sexes weighing 20-28 kg. The animals were randomly divided into two groups of six animals each. All animals were subjected to total cardiopulmonary bypass (CPB) and moderate hypothermia (28 degrees C core temperature). During total CPB, the aorta was clamped together with the pulmonary artery to prevent any antegrade flow to the lungs. After cardioplegic arrest for 120 min, the animals were rewarmed, weaned from CPB, and their condition stabilized for another 90 min. After the release of the aortic cross-clamp, the dogs received either a 5% glucose solution as a placebo (group I) or SNP (0.5 microg/kg per min) (group II), both infused into the pulmonary arterial line. The infusion was stopped after 60 min. To measure lung tissue malondialdehyde (MDA), water content and polymorphonuclear leukocytes count, lung tissue samples were taken before CPB and after weaning from CPB. In addition, alveolar-arterial oxygen difference (AaDO(2)) for tissue oxygenation was calculated by obtaining arterial blood gas samples. RESULTS: Values of MDA before CPB of 42.0+/-5.3 nmol/g of tissue rose to 67.6+/-5.7 nmol/g of tissue after weaning from CPB in group I (P=0.028). In group II MDA values also increased from 43.1+/-4.3 to 52.4+/-5.7 nmol MDA/g of tissue after weaning from CPB (P=0.046). The MDA increase in group II after CPB was found to be significantly lower than that for group I (P=0.004). The wet-to-dry lung weight ratio in the sodium nitroprusside group was 5.1+/-0.2, significantly lower than in the control group (6.8+/-0.4), (P=0.01). AaDO(2) increased significantly in group I (P=0.028). There was no statistically significant difference (P=0.065) between groups I and II. During histopathological examination it was observed that neutrophil counts in the lung parenchyma rose significantly after CPB in both groups. The increase in group I was significantly larger than that in group II (P<0.001). CONCLUSIONS: The results represented in our study indicate that pulmonary arterial infusion of sodium nitroprusside during reperfusion can reduce lung injury under cardiopulmonary bypass.

The effect of aprotinin on ischemia-reperfusion injury in an in situ normothermic ischemic lung model.

OBJECTIVES: In the context of the physiopathology of damage due to ischemic preservation and reperfusion injury following preservation, we aimed to demonstrate the positive effects of the addition of aprotinin, a serine protease inhibitor, to low potassium dextran (LPD), used as a single-flush solution in normothermic ischemic animal models, on lung protection and the prevention of reperfusion injury. METHODS: In the study, 21 New Zealand white rabbits were used as experimental subjects. The subjects were ventilated with the assistance of a manual mechanical ventilator at 30 breaths/min and 10 ml/kg tidal volume. Lung protection solution was supplied to the pulmonary artery via a catheter. After applying the solution, ischemia was carried out for 120 min. At the end of this period, reperfusion was carried out for 90 min. The subjects were divided into three groups of seven subjects each. In the control group, pulmonary perfusion solution was not employed, whereas in the second group LPD was employed, and in the third group LPD and aprotinin (LPD+A) were perfused. Blood gas analysis, bronchoalveolar lavage (BAL) fluid examination, tissue malondialdehyde (MDA) level analysis and morphological examinations were performed. RESULTS: The LPD+A group showed the significantly highest levels of oxygenation at the 15th and 60th minutes of reperfusion (297+/-76.7 and 327+/-97.4 mmHg) in comparison to the LPD (157+/-20.6 and 170+/-53.6 mmHg) and control (64+/-8.4 and 59+/-7.2 mmHg) groups (P<0.001). The LPD+A group showed the significantly lowest levels of alveolar-arterial oxygen difference at the 60th minute of reperfusion (389+/-15 mmHg) in comparison to the LPD (478+/-19 mmHg) and control (542+/-23) groups (P<0.001). The BAL fluid neutrophil percentage was significantly lower in the LPD+A group (22+/-2.4%) compared to the LPD (31+/-6.1%) and control (38+/-2.4%) groups. MDA levels were significantly lower in the LPD+A group (119.8+/-5.3 nmol MDA/g) when compared to the LPD (145.06+/-9.5 nmol MDA/g) and control (147.3+/-3.9 nmol MDA/g) groups (P<0.05). Morphological examinations revealed pathological lesions and alveolar hemorrhaging in all samples, with the LPD+A group having statistically more significant levels than the LPD and control groups (P<0.005). The LPD+A group had a significantly lower percentage of pathological lesions and alveolar hemorrhage grade values than the LPD and control groups (P<0.005). CONCLUSIONS: It was observed that the addition of aprotinin to LPD solution as a pulmonary flush solution in an in situ normothermic ischemic lung model prevents reperfusion injury by means of various mechanisms and also protects the morphological, functional and biochemical integrity of the lung. In our view, therefore, the addition of aprotinin to lung protection solution will provide positive results in lung transplantation protocols.

Effects of N-acetylcysteine on pulmonary function in patients undergoing coronary artery bypass surgery with cardiopulmonary bypass.

Cardiopulmonary bypass (CPB) has been implicated in causing poor pulmonary gas exchange postoperatively in patients undergoing coronary artery bypass grafting (CABG) procedures. In this prospective, randomized, double-blind, placebo-controlled study, we examined the pulmonary effects of N-acetylcysteine (NAC) in patients undergoing CABG. Twenty patients undergoing elective CABG and early tracheal extubation were randomized into two groups. Group I (ten patients) received a physiologic salt solution as a placebo in a continuous intravenous infusion for one hour before CPB and 24 hours after CPB; Group II (ten patients) received 100 mg/ kg NAC intravenously for one hour before CPB and 40 mg/kg/day at 24 hours after CPB. Perioperative hemodynamic and pulmonary data were recorded. Postoperative tracheal extubation was accomplished at the earliest appropriate time. The postoperative clinical course was similar in the two groups. Both groups exhibited significant postoperative increases in A-a oxygen gradient (p < 0.01), but patients in Group II exhibited significantly lower increases in postoperative A-a oxygen gradient (p < 0.006). Other hemodynamic and pulmonary data (pulmonary capillary wedge pressure, pulmonary vascular resistance (PVR), cardiac index (CI), shunt flow, dynamic lung compliance and static lung compliance) exhibited no differences between the groups. There was no significant difference in terms of intubation time. The malondialdehyde (MDA) increase in Group II following CPB was found to be significantly lower than in Group I (p = 0.043). This clinical study reveals that administration of NAC to patients undergoing elective CABG with CPB improves systemic oxygenation. There was no effect in other pulmonary parameters and in terms of intubation time.