Short-term inhalation exposure to cigarette smoke induces oxidative stress and inflammation in lungs without systemic oxidative stress in mice.

Smoking is a well-established risk factor for various pathologies, including pulmonary diseases, cardiovascular disorders, and cancers. The toxic effects of cigarette smoke (CS) are mediated through multiple pathways and diverse mechanisms. A key pathogenic factor is oxidative stress, primarily induced by excessive formation of reactive oxygen species. However, it remains unclear whether smoking directly induces systemic oxidative stress or if such stress is a secondary consequence. This study aimed to determine whether short-term inhalation exposure to CS induces oxidative stress in extrapulmonary organs in addition to the lung in a murine model. In the experiment, 3R4F reference cigarettes were used to generate CS, and 8-week-old male BALB/c mice were exposed to CS at a total particulate matter concentration of either 0 or 800 µg/L for four consecutive days. CS exposure led to an increase in neutrophils, eosinophils, and total cell counts in bronchoalveolar lavage fluid. It also elevated levels of lactate dehydrogenase and malondialdehyde (MDA), markers indicative of tissue damage and oxidative stress, respectively. Conversely, no significant changes were observed in systemic oxidative stress markers such as total oxidant scavenging capacity, MDA, glutathione (GSH), and the GSH/GSSG ratio in blood samples. In line with these findings, CS exposure elevated NADPH oxidase (NOX)-dependent superoxide generation in the lung but not in other organs like the liver, kidney, heart, aorta, and brain. Collectively, our results indicate that short-term exposure to CS induces inflammation and oxidative stress in the lung without significantly affecting oxidative stress in extrapulmonary organs under the current experimental conditions. NOX may play a role in these pulmonary-specific events.

Inhalation exposure to cigarette smoke induces endothelial nitric oxide synthase uncoupling and enhances vascular collagen deposition in streptozotocin-induced diabetic rats.

Smoking is an acknowledged risk factor for vascular disorders, and vascular complication is a main outcome of diabetes. Hence, we investigated the impact of cigarette smoke on blood vessels in diabetes, postulating that smoking might aggravate diabetic vascular impairment. Sprague-Dawley rats were divided into four groups: control, cigarette smoke-exposed, diabetic, and cigarette smoke-exposed diabetic groups. Streptozotocin-induced diabetic rats were exposed to cigarette smoke by inhalation at total particulate matter concentration of 200 µg/L for 4 h/day, 5 day/week for a total of 4 weeks. Diabetes caused structural change of aorta, but additional cigarette smoke exposure did not induce further alteration. Collagen, a marker for fibrosis, was increased in media of diabetic aorta, and this increase was augmented by cigarette smoke. Cigarette smoke induced endothelial nitric oxide synthase (eNOS) uncoupling in the diabetic group. Malondialdehyde was increased and glutathione was decreased in blood from diabetes, but these effects were not exaggerated by cigarette smoke. Cigarette smoke caused NADPH oxidase (NOX) 2 expression in diabetic aorta and enhanced diabetes-induced NOX4 expression in aorta. Taken together, cigarette smoke exposure can aggravate vascular fibrosis and induce eNOS uncoupling in diabetes under experimental condition, suggesting that smoking might exacerbate diabetic vascular impairments.

Comparative In Vitro Toxicity Study of Docetaxel and Nanoxel, a Docetaxel-Loaded Micellar Formulation Using Cultured and Blood Cells.

Nanoxel-PMTM (Nanoxel) is a docetaxel-loaded methoxy-poly(ethylene glycol)-block-poly(D,L-lactide) (mPEG-PDLLA). This newly developed and marketed nanoformulation exhibits an improved pharmacokinetic profile, efficacy, and safety. Although the safety of Nanoxel to docetaxel as well as its bioequivalence must be clinically confirmed, all biological activities have not been examined in in vitro or in vivo studies. Here, the toxicity in a cultured cell system and the effects on blood cells were tested with Nanoxel and docetaxel. The in vitro cytotoxicity of Nanoxel was found to be comparable to or slightly lower than that of docetaxel depending on the concentrations tested or the cell types. Neither docetaxel nor Nanoxel induced erythrocytes hemolysis and produced reactive oxygen species up to 100 µM. However, Nanoxel was able to enhance the aggregatory response of platelets to collagen, whereas docetaxel attenuated such aggregation in a range of 50-100 µM, while thrombin-induced aggregation was not affected by either of them. Docetaxel or Nanoxel did not alter basal level of Ca2+ and 5-hydroxytryptamine-evoked Ca2+ transient in vascular smooth muscle cells. These results suggest that the mPEG-PDLLA micellar formulation alters the toxicological properties of docetaxel, and that extra cautions are needed when evaluating the safety of nanomedicine.

Concealed resuscitation-related injuries as reversible cause of recurrent arrest following extracorporeal cardiopulmonary resuscitation.

A life-threatening cardiopulmonary resuscitation (CPR)-related injury can cause recurrent arrest after return of circulation. Such injuries are difficult to identify during resuscitation, and their contribution to failed resuscitation can be missed given the limitations of conventional CPR. Extracorporeal cardiopulmonary resuscitation (ECPR), increasingly being considered for selected patients with potentially reversible etiology of arrest, may identify previously occult CPR-related injuries by restoring arterial pressure and flow. Herein, we describe two cases of severe CPR-related injuries contributing to recurrent arrest. Each case had ECPR implemented within 60 minutes of the start of CPR. After the presumed cardiac etiology had been addressed with percutaneous coronary intervention, life-threatening cardiovascular injuries with recurrent arrest were noted, and resuscitative thoracotomy was performed under ECPR. One patient survived to hospital discharge. ECPR may provide an opportunity to identify and correct severe resuscitation-related injuries causing recurrent arrest. Chest compression depth >6 cm, especially in older women, may contribute to these injuries.

Differential Effects between Cigarette Total Particulate Matter and Cigarette Smoke Extract on Blood and Blood Vessel.

The generation and collection of cigarette smoke (CS) is a prerequisite for any toxicology study on smoking, especially an in vitro CS exposure study. In this study, the effects on blood and vascular function were tested with two widely used CS preparations to compare the biological effects of CS with respect to the CS preparation used. CS was prepared in the form of total particulate matter (TPM), which is CS trapped in a Cambridge filter pad, and cigarette smoke extract (CSE), which is CS trapped in phosphate-buffered saline. TPM potentiated platelet reactivity to thrombin and thus increased aggregation at a concentration of 25~100 µg/mL, whereas 2.5~10% CSE decreased platelet aggregation by thrombin. Both TPM and CSE inhibited vascular contraction by phenylephrine at 50~100 µg/mL and 10%, respectively. TPM inhibited acetylcholine-induced vasorelaxation at 10~100 µg/mL, but CSE exhibited a minimal effect on relaxation at the concentration that affects vasoconstriction. Neither TPM nor CSE induced hemolysis of erythrocytes or influenced plasma coagulation, as assessed by prothrombin time (PT) and activated partial thromboplastin time (aPTT). Taken together, CS affects platelet activity and deteriorates vasomotor functions in vitro. However, the effect on blood and blood vessels may vary depending on the CS preparation. Therefore, the results of experiments conducted with CS preparations should be interpreted with caution.