Reversal of Nicotine-Induced Alveolar Lipofibroblast-to-Myofibroblast Transdifferentiation by Stimulants of Parathyroid Hormone-Related Protein Signaling

Nicotine exposure disrupts the parathyroid hormone-related protein (PTHrP)-driven alveolar epithelial-mesenchymal paracrine-signaling pathway, resulting in the transdifferentiation of pulmonary lipofibroblasts (LIFs) to myofibroblasts (MYFs), which seems to be central to altered pulmonary development and function in infants born to mothers who smoke during pregnancy. Modulation of PTHrP-driven signaling can almost completely prevent nicotine-induced LIF-to-MYF transdifferentiation. However, once this process has occurred, whether it can be reversed is not known. Our objective was to determine if nicotine-induced LIF-to-MYF transdifferentiation could be reversed by specifically targeting the PTHrP-mediated alveolar epithelial-mesenchymal paracrine signaling. WI38 cells, a human embryonic pulmonary fibroblast cell line, were initially treated with nicotine for 7 days and LIF-to-MYF transdifferentiation was confirmed by determining the downregulation of the key lipogenic marker, peroxisome proliferator-activated receptor γ (PPARγ) and upregulation of the key myogenic marker, α-smooth muscle actin (αSMA). Because downregulation of the PPARγ signaling pathway is the key determinant of LIF-to-MYF transdifferentiation, cells were treated with three agonists of this pathway, PTHrP, dibutryl cAMP (DBcAMP), or rosiglitazone (RGZ) for 7 days, and the expression of the PTHrP receptor, PPARγ, αSMA, and calponin was determined by Western analysis and immunohistochemistry. Simultaneously, fibroblast function was characterized by measuring their capacity to take up triglycerides. Nicotine-induced LIF-to-MYF transdifferentiation was almost completely reversed by treatment with RGZ, PTHrP, or DBcAMP, as determined by protein and functional assays. Using a specific molecular approach and targeting specific molecular intermediates in the PTHrP signaling pathway, to our knowledge, this for the first time, demonstrates the reversibility of nicotine-induced LIF-to-MYF transdifferentiation, suggesting not only the possibility of prevention but also the potential for reversal of nicotine-induced lung injury. This work was supported in part by grants from the American Heart Association (0265127Y), the National Institutes of Health (HL075405 and HL55268), Philip Morris USA, Inc. and Philip Morris International (11108−02), and the Tobacco-Related Disease Research Program (14RT-0073 and 15IT-0250). Presented in part at the Pediatric Academic Societies’ Meeting, San Francisco, CA, May 2006.     

烟雾暴露对大鼠肺血管细胞间黏附分子-1和基质金属蛋白酶-9表达的影响

目的 观察不同烟雾暴露量及断烟对大鼠肺血管形态、炎症和重塑的影响.方法 8周龄清洁级雄性Wistar大鼠32只,随机数字表法分为对照组、烟雾1组、烟雾2组和断烟组,每组8只.建立大鼠被动吸烟模型.分别测量各组大鼠肺血管管肇厚度占血管外径的百分率(WT%)及管壁面积占血管总面积的百分率(WA%);免疫组织化学染色检测细胞间黏附分子-1(ICAM-1)和基质金属蛋白酶9(MMP-9)在肺血管壁的表达,原位杂交法检测ICAM-1及MMP-9 mRNA在肺血管壁的表达,并分析各指标的相关性.结果 烟雾1组和烟雾2组肺血管的WT%[(15.3±2.1)%、(18.0 ±2.0)%]、WA%[(41±7)%、(50±7)%]均明显高于断烟组[(11.0±1.3)%、(35±5)%]和对照组[(10.4±2.0)%、(30±4)%],差异均有统计学意义(q值为4.93～11.16,P<0.05);烟雾1组和烟雾2组肺血管ICAM-1蛋白表达的阳性单位比值[(12.9±2.3)、(19.2±2.3)]及mRNA表达[(10.3±2.2)、(18.3±2.4)]均明显高于断烟组[(7.9±3.2)、(6.2±3.0)]和对照组[(4.7±2.3)、(2.7±1.7)],差异均有统计学意义(q值为3.28～15.76,P<0.05);烟雾1组和烟雾2组肺血管MMP-9蛋白表达的阳性单位比值[(16.1±2.8)、(22.5±3.5)]及mRNA表达[(12.5±1.8)、(20.0±3.1)]均明显高于断烟组[(12.0±2.8)、(7.0±3.4)]和对照组[(7.8±3.0)、(3.2±2.8)],差异均有统计学意义(q值为3.19～14.22,P<0.05);肺血管ICAM-1和MMP-9 mRNA表达与WT%和WA%均呈显著正相关(r值为0.619～0.703,P<0.05).结论 烟雾暴露可导致大鼠肺血管管壁增厚,上调肺血管细胞ICAM-1、MMP-9的表达,介导肺血管炎症及重塑,参与肺动脉高压的发生.戒烟后上述肺血管损害有所改善.     

Free-base nicotine in tobacco products. Part I. Determination of free-base nicotine in the particulate phase of mainstream cigarette smoke and the relevance of these findings to product design parameters

The free-base nicotine (FBN) content of mainstream cigarette smoke (MSS) has been discussed in the peer-reviewed literature and popular press. It has been alleged that manufacturers adjust product design features to increase the percentage of total nicotine (TN) in the MSS gas–vapor phase that is unprotonated [P_g,nic(%)] and/or the fraction of nicotine in the MSS total particulate matter (TPM) that is unprotonated (FBN/TN). Our research showed the Health Canada Intensive smoking conditions negated the effects of blend and cigarette design features reported to raise the pH of TPM collected under ISO or US FTC conditions. Our research also showed that when additive-free Canadian cigarettes were smoked under ISO conditions, the FBN/TN ratio increased as the tar/nicotine ratio decreased. Our findings are in line with other studies that have questioned allegations of a relationship between use of ammonia and its compounds as tobacco additives and amounts of unprotonated nicotine in MSS. In addition, the experimental work demonstrated how use of solid-phase microextraction to estimate FBN can yield erroneously high results due to improper conditioning and/or smoking of the cigarettes. Our research showed that there is no longer any scientific support for regulators to require smoke pH and FBN determinations on cigarette products.     

Association between Parental Cotinine-verified Smoking Status and Childhood Asthma: a Population-based Nationally Representative Analysis

BackgroundEnvironmental tobacco smoke exposure due to parents is a modifiable risk factor for childhood asthma, but many studies have evaluated parental smoking using self-reported data. Therefore, we aimed to analyze the relationship between parental cotinine-verified smoking status and asthma in their children.MethodsThis population-based cross-sectional study used data from the Korean National Health and Nutrition Examination Survey from 2014 to 2017. Participants aged 0 to 18 years with complete self-reported physician-diagnosed childhood asthma and measurement of their parental urinary cotinine levels were included. Parental urinary cotinine-verified smoking status was defined using both urinary cotinine levels and self-report, as active, passive, and non-smoker. Sample weights were applied to all statistical analyses because of a complex, multistage and clustered survey design. Logistic regression model was used to analyze the relationship between childhood asthma and parental smoking.ResultsA total of 5,264 subjects aged < 19 years were included. The prevalence of asthma was 3.4%. The proportions of paternal and maternal urinary cotinine-verified active smokers during the study period were 50.4% and 16.9%, respectively. When parental urinary cotinine level increased, the proportion of parental low household income was increased (P < 0.001). There was no significant association between the parental urinary cotinine-verified smoking group and childhood asthma group. However, the adjusted odds ratios of childhood asthma in the middle and highest tertile of paternal urinary cotinine levels compared with those in lowest tertile were 1.95 (95% confidence interval [CI], 0.98–3.89) and 2.34 (95% CI, 1.21–4.54), respectively.ConclusionThere seems to be a dose-related association between paternal urinary cotinine levels and the risk of childhood asthma. Because of the high rate of paternal smoking, further studies are needed to develop a targeted strategy to reduce parental smoking for childhood asthma.     

A comparative study of the mutagenicity of various types of tobacco products

Toxicological data are an important aspect of tobacco product characterization. In this study, TPM (Total Particulate Matter) (three replicates) was collected from cigarettes [five brands, ISO conditions: puff volume, 35 mL; duration, 2s; interval, 60s (35/2/60)], cigars (two brands, 45/2/30), cigarillos (two brands, 35/2/60), bidis (two brands, 45/2/30), and pipe tobacco (two brands, 50/2/12). TPM was extracted from the Cambridge filter pad using dimethyl sulfoxide (DMSO). Smokeless tobacco (ST) (six brands) was extracted with DMSO using an ultrasonic homogenizer. Both types of extracts were filtered and stored at -80 degrees C. All extracts were analyzed for humectants, water and nicotine. Mutagenic activity was assessed per OECD guideline 471 using Salmonella typhimurium TA98+S9 and TA100+S9. TA98+S9 response (specific activity expressed as revertants/mg nicotine) was greatest for the cigarette fabricated with dark, air-cured tobaccos. Average product responses with TA98+S9 based on nicotine and relative to cigarettes (excluding dark tobacco) were cigars, 242%; cigarillos, 238%; bidis, 91%; and pipe tobacco, 44%. ST response was not significant for TA98+S9. Corresponding values for TA100+S9 were cigars, 189%; cigarillos, 155%; pipe tobacco, 130%; bidis, 114% and ST, 34%. ST TA100+S9 response ranged from a low of 501 to a high of 8547 revertants/mg nicotine, depending on ST composition.     

Difference between smokers and non-smokers in the corpus callosum volume

The purpose of this study was to analyze the effects of smoking on corpus callosum volume. In addition, the relationships between smoking duration, smoking frequency, and corpus callosum volume were analyzed. Magnetic resonance brain images were acquired for 58 normal Korean men (30 smokers (age 32.82 ± 14.12 years) and 28 non-smokers (age 35.49 ± 13.11 years)). The corpus callosum volume was measured using Brain Voyager 2000 S/W and was normalized by intracranical volume, which was calculated using cerebral sizes. The corpus callosum volume for smokers was significantly smaller than that for non-smokers. Also, there was a negative correlation between corpus callosum volume and smoking duration. The change of white matter volume (e.g., corpus callosum) might be a primary factor for characterizing the effects of smoking.     

诸暨市推进公共场所控烟工作的思考

诸暨市以“健康诸暨”建设为契机,通过政府出台禁烟令、部门把禁烟政策融入日常工作管理、市民积极响应并参与公共场所禁烟,合力推进全市公共场所全面禁烟。本文就诸暨市将健康融入所有政策,合力推进公共场所室内全面禁烟的背景、做法与思路、成效与产出、总结与经验进行综述,为相关研究提供参考。     

Smoke inhalation injury during enclosed-space fires: an update

In view of the tragic fire at a nightclub in the city of Santa Maria, Brazil, which culminated in the sudden death of 232 young people, we decided to review the literature regarding smoke inhalation injury caused by enclosed-space fires, which can be divided into direct thermal damage, carbon monoxide poisoning, and cyanide poisoning. Such injuries often call for immediate orotracheal intubation, either due to acute airway obstruction or due to a reduced level of consciousness. The diagnosis and the severity of the thermal injury can be determined by fiberoptic bronchoscopy. The levels of gases and gas by-products in the bloodstream should be assessed as rapidly as possible, even while still at the scene of the incident. First responders can also treat carbon monoxide poisoning, with immediate administration of oxygen at 100%, as well as cyanide poisoning, with oxygen therapy and hydroxocobalamin injection     

Chronic Maternal Tobacco Smoke Exposure and/or Alpha-Lipoic Acid Treatment Causes Long-Term Deterioration of Testis and Sexual Behavior in Adult Male Rats

BackgroundTobacco use during pregnancy is known to have several negative effects on the offspring's reproductive health in the long term. The use of alpha-lipoic acid (ALA) as a dietary supplement during pregnancy has increased greatly in recent years and has been known to have positive effects on various pregnancy outcomes including miscarriage, diabetic embryopathy, preterm delivery, and congenital malformations.AimTo evaluate the effects of tobacco smoke exposure (TSE) on sexual behavior, reproductive parameters, and testicles in adult male rats and to reveal the possible role of ALA administration on these parameters.MethodsPregnant rats (n = 7 per group) were treated with tobacco smoke (TS), ALA (20 mg/kg), and TS + ALA for a total of 11 weeks. The following parameters were compared with 8 control rats: puberty parameters, sexual behavior; levels of serum gonadotropins and testosterone, total antioxidant status, and total oxidant status; the expression of the apoptotic protease-activating factor-1 and caspase 9 mRNA levels in the testis; and assessment of immunohistochemistry and terminal deoxynucleotidyl transferase dUTP nick end labeling assay of testis.Main Outcome MeasureSexual behavior, changes in puberty parameters, and hormonal and genetic alterations were the outcomes analyzed in this study.ResultsMaternal TSE caused a significant decrease in the number of intromissions compared to the control group. Similarly, ALA decreased erectile function in sexual behavior by decreasing the number of intromissions and intromission ratio in the ALA group compared to the control group. In addition, TSE and ALA treatment caused an impairment of some consummatory sexual behaviors. Also, in parallel with this inhibitory effect, the age of pubertal onset was significantly delayed in the TS + ALA group compared to other groups. Also, histopathological changes in testicular tissue, oxidative stress markers, apoptotic index, and mRNA levels of apoptosis-related genes increased in all treatment groups.Clinical ImplicationsThe use of ALA and/or tobacco products during pregnancy may adversely affect the reproductive health of male newborns in the long term.Strengths & LimitationsTo the best of our knowledge, this study is the first to show the effects of maternal ALA treatment and/or TSE on the sexual behavior and reproductive parameters in male rats; however, the study is based on an animal model, and the present findings partially reflect the characteristics of human sexual behavior.ConclusionMaternal TSE and/or ALA treatment may impair sexual behavior in adulthood in male rats because of testicular damage caused by oxidative stress during gonadal development.Yardimci A, Akkoc RF, Tektemur A, et al. Chronic Maternal Tobacco Smoke Exposure and/or Alpha-Lipoic Acid Treatment Causes Long-Term Deterioration of Testis and Sexual Behavior in Adult Male Rats. J Sex Med 2020;17:1835–1847.     

30例重度烟雾吸入性损伤老年人机械通气的“平衡”护理研究

目的 探讨重度烟雾吸人性损伤并发急性呼吸功能衰竭综合征(acute respiration dysfunction syndrome,ARDS)老年人机械通气的护理方法.方法 介绍30例重度烟雾吸人性损伤并发急性呼吸衰竭综合征的老年人机械通气的“平衡”护理方法.结果 30例老年人都抢救成功.结论 重度烟雾吸人性损伤老年人机械通气的护理方法与年轻人不同,必须根据老年人重度烟雾吸人性损伤后呼吸系统(respiratory system)的生理及病理的特点来制定.