Chronic Cigarette Smoke Research Articles

Using TAPSE versus speckle tracking in assessment of right ventricular function in healthy heavy chronic cigarette smokers

Using TAPSE versus speckle tracking in assessment of right ventricular function in healthy heavy chronic cigarette smokers

Dysregulation of mitochondrial complexes and dynamics by chronic cigarette smoke exposure Utilizing MitoQC reporter mice

Cigarette smoke (CS) is known to cause impaired mitophagy and mitochondrial dysregulation in the pathogenesis of chronic obstructive pulmonary disease (COPD)/emphysema. Mitochondrial complexes and dynamics are affected by acute CS exposure in lung epithelium and mouse lung. We hypothesize that chronic CS exposure (4 months) will induce lung mitochondrial dysregulation and abnormal mitophagy. In this study, we employed the mitoQC reporter mice, a mitochondrial reporter strain, which can reflect the mitophagy based on the fluorescence-tagged mitochondria. Chronic CS exposure induced lung inflammatory cell infiltration, airspace enlargement, and lung cellular senescence. We showed the higher occurrence of mitophagy (GFP/mCherry) in the lung cells by CS exposure, associated with more mitochondrial fluorescence signals (GFP+/mCherry+). After chronic CS exposure, the mitochondrial complexes and function related genes were inhibited, while protein levels of complexes I and III slightly changed. Additionally, chronic CS exposure down-regulated most of the mitochondrial dynamic markers at gene expression level, included mitochondrial fusion/fission and mitochondrial translocate/transfer markers. For the markers related to mitophagy, Pink1 and Parkin, decreased gene and protein levels of Parkin, and decreased gene expression of Pink1, were identified in the CS exposure group. Hence, CS-induced mitophagy is mediated by Pink1-Parkin independent mechanism. Thus, we have shown that the chronic CS epxosure dysregulated mitochondrial complexes and dynamics and induced mitophagy, using the state-of-the art mitoQC reporter mouse model. Our results suggested that dysregulated mitochondrial function and dynamics are associated with CS-induced lung injury and phenotypic development of chronic lung diseases, such as COPD/ emphysema.

The Differential Effects of Chronic Alcohol and Cigarette Smoke Exposures on Cognitive-Behavioral Dysfunction in Long Evans Rats.

Chronic heavy alcohol consumption and daily cigarette smoking are the most prevalent substance use problems in the U.S., including Veterans. Excessive alcohol use causes neurocognitive and behavioral deficits that can be linked to neurodegeneration. Similarly, preclinical and clinical data suggest that smoking also leads to brain atrophy. This study examines the differential and additive effects of alcohol and cigarette smoke (CS) exposures on cognitive-behavioral function. A 4-way experimental model of chronic alcohol and CS exposures was generated using 4-week-old male and female Long Evans rats that were pair-fed with Lieber-deCarli isocaloric liquid diets containing 0% or 24% ethanol for 9 weeks. Half of the rats in the control and ethanol groups were exposed to CS for 4 hours/day and 4 days/week for 9 weeks. All rats were subjected to Morris Water Maze, Open Field, and Novel Object Recognition testing in the last experimental week. Chronic alcohol exposure impaired spatial learning as shown by significantly increased latency to locate the platform, and it caused anxiety-like behavior marked by the significantly reduced percentage of entries to the center of the arena. Chronic CS exposure impaired recognition memory as suggested by significantly less time spent at the novel object. Combined exposures to alcohol and CS did not show any significant additive or interactive effect on cognitive-behavioral function. Chronic alcohol exposure was the main driver of spatial learning, while the effect of secondhand CS exposure was not robust. Future studies need to mimic direct CS exposure effects in humans.

Chronic exposure to cigarette smoke transiently worsens the disease course in a mouse model of pulmonary paracoccidioidomycosis.

Paracoccidioidomycosis (PCM) may present as an acute/subacute clinical form, characterized by a progressive disease arising from the airborne initial infection, or, most often, as an asymptomatic or subclinical infection that may manifest later during an individual's life, the chronic form. Epidemiological studies show the existence of a strong association between smoking and the development of the chronic form. Current evidence demonstrates that cigarette smoke (CS) has immunosuppressive properties that could be implicated in the increasing susceptibility to the chronic form of PCM. To address this issue, we developed a murine model of a non-progressive pulmonary form of PCM that was exposed to CS at a magnitude that mimicked a moderate smoker. The chronic CS exposure started after 2 weeks and lasted up until 20 weeks post-infection, with the aim of mimicking human natural history, since it is estimated that individuals from endemic areas are infected early in life. The control group consisted of infected but not CS-exposed mice. We assessed the lung fungal burden (colony forming units [CFU]) and the area affected by the granulomatous inflammatory response, fungal dissemination to spleen and liver, and, by immunohistochemistry, the presence of CD4 and CD8 lymphocytes, CD68 and MAC-2 macrophages, and IFN-γ, IL-10 and TNF expressing cells within the granulomatous response. We detected a CS effect as early as 2 weeks after exposure (four weeks post-infection) when the lung CFU of exposed animals was significantly higher than in their non-exposed counterparts. At 12 weeks, the CS-exposed animals presented a more severe disease, as witnessed by the persistent higher lung fungal load (although it did not reach statistical significance [ p = 0.054]), greater dissemination to other organs, greater affected area of the lung, decreased IFN-γ/IL-10 ratio, and higher TNF expression within the granulomas, compared with CS-non-exposed mice. The number of CD4 and CD8 lymphocytes infiltrating the granulomas was similar between both mice groups, but there was a decrease in the number of MAC-2+ macrophages. No difference was noted in the CD68+ macrophage number. However, the follow-up in week 20 showed that the immunological effects of exposure to CS ceased, with both CS and NCS mice showing the same infectious features, i.e., a trend for resolution of the infection. In conclusion, we show that chronic CS-exposure alters the course of the disease in an experimental model of subclinical pulmonary PCM, confirming the epidemiological link between CS-exposure and the chronic form of PCM. However, we also show that this effect is transitory, being detected between 4- and 12-weeks post-infection but not thereafter. The possible immune mechanisms that mediate this effect and the reasons for its transitory effect are discussed.

Retinal Microvascular Reactivity in Chronic Cigarette Smokers and Non-smokers: An Observational Cross-Sectional Study.

Purpose: To evaluate the changes in the retinal microvasculature and its reactivity in chronic cigarette smokers.Methods: Thirty-four male chronic cigarette smokers and 18 male non-smokers were enrolled. Optical coherence tomography angiography was used to measure the perfused retinal vessel densities (PVDs) of the peripapillary and parafoveal areas at baseline and during phase IV of the Valsalva maneuver (VM-IV). Systemic blood pressure and intraocular pressure were also measured.Results: The baseline PVD in the peripapillary area of the smokers was significantly lower than the non-smokers (59.56 ± 2.26% vs. 61.67 ± 3.58%, respectively; P = 0.005). However, there was no significant difference in the foveal avascular zone or parafoveal PVD between the two groups. During VM-IV, the peripapillary PVD of the smokers decreased by 1.13 ± 3.50%, which was significantly less than that of the non-smokers (−3.83 ± 4.26%, P < 0.05). Similarly, the parafoveal PVD of the smokers decreased by 5.49 ± 9.70%, which was significantly less than the percentage change of the non-smokers (−13.01 ± 8.39%, P < 0.05). There was no significant difference in the percentage change in systemic blood pressure parameters between the two groups.Conclusion: The retinal microvasculature and its reactivity were impaired in chronic smokers compared with non-smokers. The extent of impairment differed among different regions of the fundus.

Epithelial Ablation of Miro1/Rhot1 GTPase Augments Lung Inflammation by Cigarette Smoke.

Mitochondrial quality control is sustained by Miro1 (Rhot1), a calcium-binding membrane-anchored GTPase during mitophagy. The exact mechanism that operates the interaction of Miro1 with mitophagy machinery and their role in cigarette smoke (CS)-induced mitochondrial dysfunction that often results in lung inflammation is unclear. We hypothesized that Miro1 plays an important role in regulating mitophagy machinery and the resulting lung inflammation by CS exposure to mice. The lung epithelial Rhot1fl/fl (WT) and Rhot1CreCC10 mice were exposed to mainstream CS for 3 days (acute) and 4 months (chronic). Acute CS exposure showed a notable increase in the total inflammatory cells, macrophages, and neutrophils that are associated with inflammatory mediators. Chronic exposure showed increased infiltration of neutrophils versus air controls. The effects of acute and chronic CS exposure were augmented in the Rhot1CreCC10 group, indicating that epithelial Miro1 ablation led to the augmentation of inflammatory cell infiltration with alteration in the inflammatory mediators. Thus, Rhot1/Miro1 plays an important role in regulating CS-induced lung inflammatory responses with implications in mitochondrial quality control.

IL-27 mediates anti-inflammatory effect in cigarette smoke induced emphysema by negatively regulating IFN-γ producing cytotoxic CD8+ T cells in mice.

Chronic airway inflammation mediated by CD8+ T lymphocytes contributes to the pathogenesis of Chronic obstructive pulmonary disease (COPD). Deciphering the fingerprint of the chronic inflammation orchestrated by CD8+ T cells may allow the development of novel approaches to COPD management. Here, the expression of IL-27 and IFN-γ+ CD8+ Tc1 cells were evaluated in patients with COPD and in cigarette smoke-exposed mice. The production of IL-27 by marrow-derived dendritic cells (mDCs) in response to cigarette smoke extract (CSE) was assessed. The role of IL-27 in IFN-γ+ CD8+ Tc1 cells was explored. We demonstrated that elevated IL-27 was accompanied by an exaggerated IFN-γ+ CD8+ Tc1 response in a smoking mouse model of emphysema. We noted that lung dendritic cells were one of the main sources of IL-27 during chronic cigarette smoke exposure. Moreover, CSE directly induced the production of IL-27 by mDCs in vitro. IL-27 negatively regulated the differentiation of IFN-γ+ CD8+ Tc1 cells isolated from cigarette smoke-exposed mice in a STAT1- and STAT3-independent manner. Systemic administration of recombinant IL-27 attenuated IFN-γ+ CD8+ Tc1 response in the late phase of cigarette smoke exposure. Our results uncovered that IL-27 negatively regulates IFN-γ+ CD8+ Tc1 response in the late stage of chronic cigarette smoke exposure, which may provide a new strategy for the anti-inflammatory treatment of smoking-related COPD/emphysema.

Attenuation of the Airway and Cardiovascular Responses to Extubation in Chronic Smokers by Prior Treatment with Dexmedetomidine, Fentanyl, and their Combination

BACKGROUND: Respiratory complications and hemodynamic changes during and after extubation are more common than during tracheal intubation and induction of anesthesia. AIM: The objective of this study was to compare the efficacy of prior treatment with dexmedetomidine, fentanyl, and their combination on the attenuation of the airway and cardiovascular responses to extubation. METHODS: The subjects were adult chronic male smokers, representing the population in which secondary response to extubation is most common. A randomized double-blinded comparative trial was conducted on 66 patients who were 20–60 years of age, chronic male smokers, scheduled for elective surgeries, and divided into three equal groups according to given drug 20 min before the end of surgery. Group A (n = 22) received 1 ug. kg−1 dexmedetomidine, Group B (n = 22) received fentanyl 1 ug. kg−1, and Group C (n = 22) received a mixture of the previously used drugs in the same doses. Time to and quality of extubation, airway and hemodynamic responses, and post-operative agitation and sedation were recorded. RESULTS: Hemodynamic responses and quality of extubation were better in both Groups A and C than patients in Group B at the expense of increasing time to extubation, post-extubation sedation, and delayed recovery in Group C. CONCLUSION: Single-dose dexmedetomidine 1 ug. kg-1 given 15 min before extubation in chronic cigarette smokers provided better attenuation of the airway and cardiovascular responses to extubation and suctioning with better recovery profile when compared to fentanyl 1 ug. kg-1 and dexmedetomidine mixed with fentanyl in the same previous doses.

Muscle-Bone Crosstalk in Chronic Obstructive Pulmonary Disease.

Sarcopenia and osteoporosis are common musculoskeletal comorbidities of chronic obstructive pulmonary disease (COPD) that seriously affect the quality of life and prognosis of the patient. In addition to spatially mechanical interactions, muscle and bone can also serve as endocrine organs by producing myokines and osteokines to regulate muscle and bone functions, respectively. As positive and negative regulators of skeletal muscles, the myokines irisin and myostatin not only promote/inhibit the differentiation and growth of skeletal muscles, but also regulate bone metabolism. Both irisin and myostatin have been shown to be dysregulated and associated with exercise and skeletal muscle dysfunction in COPD. During exercise, skeletal muscles produce a large amount of IL-6 which acts as a myokine, exerting at least two different conflicting functions depending on physiological or pathological conditions. Remarkably, IL-6 is highly expressed in COPD, and considered to be a biomarker of systemic inflammation, which is associated with both sarcopenia and bone loss. For osteokines, receptor activator of nuclear factor kappa-B ligand (RANKL), a classical regulator of bone metabolism, was recently found to play a critical role in skeletal muscle atrophy induced by chronic cigarette smoke (CS) exposure. In this focused review, we described evidence for myokines and osteokines in the pathogenesis of skeletal muscle dysfunction/sarcopenia and osteoporosis in COPD, and proposed muscle-bone crosstalk as an important mechanism underlying the coexistence of muscle and bone diseases in COPD.

Associations between chronic cigarette smoking and taste function: Results from the 2013–2014 national health and nutrition examination survey

We identified associations between cigarette-smoking and taste function in the U.S. NHANES 2013–2014. Adults ≥ 40 years (n = 2849, nearly half former or current smokers) rated whole-mouth and tongue-tip bitter (1 mM quinine) and salt (1 M NaCl, 0.32 M NaCl) intensities and reported smoking history (pack years, PY), dependence (time to first cigarette, TTFC) and menthol/non-menthol use. Perceived intensity on the tongue-tip averaged just below moderate for quinine and moderate to strong for 1 M NaCl. Current chronic smokers (≥ 20 PY) reported lower bitter and salty intensities on the tongue-tip (β: -2.0, 95% CI: -3.7 to -0.4 and β: -3.6, 95% CI: -6.9 to -0.3, respectively) than never smokers. Similarly, compared to never smokers, dependent current smokers (TTFC ≤ 30 min) and dependent chronic smokers (≥ 20 PY, TTFC ≤ 30 min) rated less bitter (β: -2.0, 95% CI: -4.0 to 0.1 and β: -2.9, 95% CI: -4.5 to -1.3, respectively) and salty (β: -5.3, 95% CI: -9.3 to -1.4 and β: -4.7, 95% CI: -8.6 to -0.7, respectively) intensities on the tongue-tip. Depressed tongue-tip intensity in dependent smokers (with/without chronicity) versus never smokers was significant in younger (40–65 years), but not older (> 65 years) adults. Former smokers, non-chronic/less dependent smokers, and menthol smokers were more likely to report elevated whole-mouth quinine and 1 M NaCl intensities. Tongue-tip and whole-mouth taste intensity concordance varied between smokers and never smokers—current dependent smokers were more likely to rate tongue-tip quinine and NaCl lower than their respective whole-mouth tastants (OR: 1.8, 95% CI: 1.0 to 3.1 and OR: 1.8, 95% CI: 1.1 to 2.8, respectively). In summary, these U.S. nationally-representative data show that current smoking with chronicity and/or dependence associates with lower tongue-tip intensity for bitter and salty stimuli. Smokers with greater exposure to nicotine and/or dependence showed greater risk of taste alterations, with implications for diet- and smoking-related health outcomes.

Exploration of the influence of body mass index on intra-network resting-state connectivity in chronic cigarette smokers

BackgroundObesity and cigarette smoking are two leading preventable causes of death. Previous research suggests that comorbid smoking and obesity likely share neurobehavioral underpinnings; however, the influence of body mass index (BMI) on resting-state functional connectivity (rsFC) in smokers remains unknown. In this study, we explore how BMI affects rsFC and associations between rsFC and smoking-related behavior. MethodsTreatment-seeking cigarette smokers (N = 87; 54 % men) completed a BOLD resting-state fMRI scan session. We grouped smokers into BMI groups (N = 23 with obesity, N = 33 with overweight, N = 31 lean) and used independent components analysis (ICA) to identify the resting state networks commonly associated with cigarette smoking: salience network (SN), right and left executive control networks (ECN) and default mode network (DMN). Average rsFC values were extracted (p < 0.001, k = 100) to determine group differences in rsFC and relationship to self-reported smoking and dependence. ResultsAnalyses revealed a significant relationship between BMI and connectivity in the SN and a significant quadratic effect of BMI on DMN connectivity. Heavier smoking was related to greater rsFC in the SN among lean and obese groups but reduced rsFC in the overweight group. ConclusionsFindings build on research suggesting an influence of BMI on the neurobiology of smokers. In particular, dysfunction of SN-DMN-ECN circuitry in smokers with overweight may lead to a failure to modulate attention and behavior and subsequent difficulty quitting smoking. Future research is needed to elucidate the mechanism underlying the interaction of BMI and smoking and its impact on treatment.

Cigarette Smoke Specifically Affects Small Airway Epithelial Cell Populations and Triggers the Expansion of Inflammatory and Squamous Differentiation Associated Basal Cells.

Smoking is a major risk factor for chronic obstructive pulmonary disease (COPD) and causes remodeling of the small airways. However, the exact smoke-induced effects on the different types of small airway epithelial cells (SAECs) are poorly understood. Here, using air–liquid interface (ALI) cultures, single-cell RNA-sequencing reveals previously unrecognized transcriptional heterogeneity within the small airway epithelium and cell type-specific effects upon acute and chronic cigarette smoke exposure. Smoke triggers detoxification and inflammatory responses and aberrantly activates and alters basal cell differentiation. This results in an increase of inflammatory basal-to-secretory cell intermediates and, particularly after chronic smoke exposure, a massive expansion of a rare inflammatory and squamous metaplasia associated KRT6A+ basal cell state and an altered secretory cell landscape. ALI cultures originating from healthy non-smokers and COPD smokers show similar responses to cigarette smoke exposure, although an increased pro-inflammatory profile is conserved in the latter. Taken together, the in vitro models provide high-resolution insights into the smoke-induced remodeling of the small airways resembling the pathological processes in COPD airways. The data may also help to better understand other lung diseases including COVID-19, as the data reflect the smoke-dependent variable induction of SARS-CoV-2 entry factors across SAEC populations.

The Aryl Hydrocarbon Receptor Suppresses Chronic Smoke-Induced Pulmonary Inflammation.

The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor expressed in the lungs that is activated by numerous xenobiotic, endogenous and dietary ligands. Although historically the AhR is known for mediating the deleterious response to the environmental pollutant dioxin, emerging evidence supports a prominent role for the AhR in numerous biological process including inflammation. We have shown that the AhR suppresses pulmonary neutrophilia in response to acute cigarette smoke exposure. Whether the AhR can also prevent lung inflammation from chronic smoke exposure is not known but highly relevant, given that people smoke for decades. Using our preclinical smoke model, we report that exposure to chronic cigarette smoke for 8-weeks or 4 months significantly increased pulmonary inflammation, the response of which was greater in Ahr−/− mice. Notably, there was an increased number of multinucleated giant cells (MNGCs) in smoke-exposed Ahr−/− mice without a change in cytokine levels. These data support a protective role for the AhR against the deleterious effects of cigarette smoke, warranting continued investigation into its therapeutic potential for chronic lung diseases.

Necroptosis Signaling Promotes Inflammation, Airway Remodeling, and Emphysema in Chronic Obstructive Pulmonary Disease.

Rationale: Necroptosis, mediated by RIPK3 (receptor-interacting protein kinase 3) and MLKL (mixed lineage kinase domain-like), is a form of regulated necrosis that can drive tissue inflammation and destruction; however, its contribution to chronic obstructive pulmonary disease (COPD) pathogenesis is poorly understood. Objectives: To determine the role of necroptosis in COPD. Methods: Total and active (phosphorylated) RIPK3 and MLKL were measured in the lung tissue of patients with COPD and control subjects without COPD. Necroptosis-related mRNA and proteins as well as cell death were examined in lungs and pulmonary macrophages of mice with cigarette smoke (CS)-induced experimental COPD. The responses of Ripk3-/- and Mlkl-/- mice to acute and chronic CS exposure were compared with those of wild-type mice. The combined inhibition of apoptosis (with the pan-caspase inhibitor quinoline-Val-Asp-difluorophenoxymethylketone [qVD-OPh]) and necroptosis (with deletion of Mlkl in mice) was assessed. Measurements and Main Results: The total MLKL protein in the epithelium and macrophages and the pRIPK3 and pMLKL in lung tissue were increased in patients with severe COPD compared with never-smokers or smoker control subjects without COPD. Necroptosis-related mRNA and protein levels were increased in the lungs and macrophages in CS-exposed mice and experimental COPD. Ripk3 or Mlkl deletion prevented airway inflammation upon acute CS exposure. Ripk3 deficiency reduced airway inflammation and remodeling as well as the development of emphysematous pathology after chronic CS exposure. Mlkl deletion and qVD-OPh treatment reduced chronic CS-induced airway inflammation, but only Mlkl deletion prevented airway remodeling and emphysema. Ripk3 or Mlkl deletion and qVD-OPh treatment reduced CS-induced lung-cell death. Conclusions: Necroptosis is induced by CS exposure and is increased in the lungs of patients with COPD and in experimental COPD. Inhibiting necroptosis attenuates CS-induced airway inflammation, airway remodeling, and emphysema. Targeted inhibition of necroptosis is a potential therapeutic strategy in COPD.

Peripheral arterial disease: Effects of ethanolic extracts of seed kernels of mango (Mangifera indica .L) on acute hind limb ischemia-reperfusion injury in diabetic rats

Background and aimHind limb ischemia is one of the peripheral arterial diseases affecting majority of the people with atherosclerosis, diabetes and chronic cigarette smokers. Hind limb ischemic-reperfusion injury is also one of the exacerbating events in these peoples, resulting in hind limb dysfunction. The aim of this study was to identify the effects of ethanolic extracts of mangifera indica (EEMI) on reversing hind limb dysfunction in diabetic rats with acute hind limb ischemia-reperfusion injury. Experimental procedureUnilateral femoral artery ligated diabetic rats were orally fed with EEMI (0.2 and 0.4 g/kg) for 14 days. At the end of the study, plasma levels of pro-inflammatory cytokines and relevant biochemical parameters were measured. The isolated gastrocnemius muscles were used for gene expression and histopathological studies. ResultsThere was a significant reduction (p < 0.05) in the plasma levels of pro-inflammatory cytokines, nitric oxide, malondialdehyde; and the expression levels of mRNA of induced nitric oxide synthase and intercellular adhesion molecule −1; and increase in anti-inflammatory cytokine, in isolated gastrocnemius muscles of animals treated with 0.2 and 0.4 g/kg of EEMI in comparison to disease control. In addition, histopathological study of gastrocnemius muscle and hind limb function test indicated the recovery of tissue damage from ischemic reperfusion at 0.2 and 0.4 g/kg of EEMI in comparison to disease control. ConclusionWe conclude that 14-day EEMI treatment of rats with acute hind limb ischemia/reperfusion in diabetic rats recovered from ischemic/reperfusion injury by modulating (decreasing) oxidative stress and inflammation.

Salvadora persica protects libido by reducing corticosterone and elevating the testosterone levels in chronic cigarette smoke exposure rats.

Background & ObjectivesCigarette smoke is associated with several diseased states including defects in reproductive behavior. Salvadora persica (S. persica) known as the toothbrush plant is reported to possess several pharmacological properties including antidepressants and anxiolytics. The present research was done to determine the libido-protective effect of S. persica in chronic cigarette smoke-exposed rats.Materials and MethodsThe decoction of freshly dried roots of S. persica (50, 100, and 200 mg/kg, oral) was administered to the chronic-cigarette smoke-exposed adult rats. The parameters related to libido were recorded using a close-camera circuit (CCTV). Serum corticosterone and testosterone levels were estimated. Further, the phytochemical constituents were identified in the decoction. The data obtained were analyzed using one-way analysis of variance and significance was considered at p < 0.05.ResultsThe observation from the study revealed that cigarette smoke exposure reduces the sexual activity parameters significantly (p < 0.01), besides elevated the serum corticosterone and suppressed the testosterone levels in rats. Administration of S. persica at 200 mg/kg improved significantly (p < 0.05) the parameters related to libido. The decoction also reversed the changes in the levels of tested hormones in serum.Interpretation and ConclusionThe findings indicate that a 200 mg/kg S. persica decoction can protect libido in chronic cigarette smoke-exposed rats. The activity may be due to the presence of several phytoconstituents such as alkaloid, flavonoids and phytosterols that might produce vasodilatory effect in sex organs and enhance the synthesis of endogenous testosterone to improve libido characteristics weakened by chronic cigarette smoke exposure.

The effect of acute and chronic nicotine consumption on intra-cortical inhibition and facilitation: A transcranial magnetic stimulation study

ObjectiveThe aim of the present study was to explore the impact of acute and chronic nicotine consumption on measures of intracortical inhibition and facilitation. MethodsThis study involved 50 chronic heavy cigarette smokers and 40 healthy subjects matched for age, sex and educational level, with no history of chronic nicotine intake. Intracortical inhibition and facilitation were assessed using transcranial magnetic stimulation (TMS) measures of motor threshold (MT), short- and long-interval intra-cortical inhibition (SICI, LICI), cortical silent period (CSP) and intra-cortical facilitation (ICF). Basal serum levels of cotinine were measured in the healthy group and at ½ and 2 h after smoking a single cigarette in the chronic smokers. ResultsThere was enhanced SICI and reduced ICF in smokers (independent of time after smoking) compared with non-smokers. The former suggests a chronic effect of increased nicotine levels on GABA-A neurotransmission whereas the latter suggests an additional effect on glutamatergic transmission. There were no significant differences between smokers and non-smokers in other TMS parameters. There was a significant negative correlation between cotinine levels at ½ h after smoking and SICI at 3 ms ISI (P < 0.001). There were no significant differences in any of the neurophysiological measures between smokers at ½ h versus 2 h after smoking a single cigarette. ConclusionChronic nicotine consumption enhances SICI, and reduces ICF, supporting the hypothesis that nicotine acts as a neuromodulator of GABA-A and glutamate neurotransmission.

First Report of Red Blood Cell Lifespan in a Marine Mammal: An Insight Into Endogenous Carbon Monoxide (CO) Production

Deep-diving marine mammals are known to have high concentrations of hemoglobin (Hb), experience hypoxemia from extended breath-holds, and ischemia-reperfusion events in tissues from the physiological dive response. However, certain deep-diving seals (e.g., elephant and Weddell seals) are known to have levels of carbon monoxide (CO) in their blood that are similar to those seen in chronic cigarette smokers (>10% carboxyhemoglobin; COHb). The source of the high CO in the seals is currently unknown. The gas is naturally produced in humans and lab animals as a byproduct of heme degradation, by heme oxygenase enzymes. Therefore, CO production is tightly correlated with red blood cell (RBC) lifespan and associated Hb degradation, as shown by higher COHb (average 1.9%, maximum 9.7%) in patients with shortened RBC lifespans due to hemolytic anemia. Although normally considered a toxic gas, low levels of CO are naturally produced in most mammals (≤ 1% COHb in healthy humans), and exposure to moderate concentrations of exogenous CO has shown to elicit cytoprotective effects (e.g., anti-inflammation) in tissues exposed to hypoxia or ischemia-reperfusion events. Therefore, there is a desire to ascertain the mechanisms behind the regulation of elevated CO in marine mammals. Similar to humans, the production of high concentrations of CO in marine mammals is hypothesized to be directly related to their RBC lifespan. The RBC lifespan has been determined in a variety of terrestrial vertebrates, but never reported for any marine mammal species. In terrestrial mammals, there is an allometric relationship with larger animals having longer RBC lifespans (RBC lifespan (days) = (body mass (kg)0.132) (68) + 49). This study reports the first measurements of RBC lifespan in a marine mammal, the shallow-diving bottlenose dolphin (mass = 216 ± 23 kg, Hb = 14 g/dl). We hypothesize that the bottlenose dolphin would have a RBC lifespan that is similar to healthy humans (~120 days). Our results show the RBC lifespan of the bottlenose dolphin is 165.7 ± 18.4 days. Like humans, bottlenose dolphins also had low levels of CO in their blood (1.6 ± 0.5 % COHb) and exhaled breath (2.4 ± 1.0 ppm). Ongoing measurements in larger, deeper-diving mammals (e.g., beluga whales, 747 ± 244 kg, Hb = 21 g/dl), will further reveal the impact of heme stores and body mass on RBC lifespan and endogenous CO production in mammals.

Cigarette Smoking and Longitudinal Associations With Blood Pressure: The CARDIA Study.

BackgroundThe associations of chronic cigarette smoking with blood pressure (BP) remain mixed. It is unclear whether a lack of examination of racial differences contributed to the mixed findings in previous studies. Black smokers metabolize nicotine at a slower rate than White smokers and racial discrimination contributes to nicotine dependence and higher BP among Black smokers.Methods and ResultsWe studied the association between cigarette smoking and longitudinal (30‐year) changes in systolic BP, diastolic BP, and pulse pressure (PP) in 4786 Black and White individuals from the CARDIA (Coronary Artery Risk Development in Young Adults) study using repeated‐measures regression models. Neither systolic BP, nor diastolic BP differed between Black consistent smokers compared with Black never smokers, although Black consistent smokers had higher PP than Black never smokers (β=1.01 mm Hg, P=0.028). White consistent smokers had similar systolic BP, but lower diastolic BP (β=−2.27 mm Hg, P<0.001) and higher PP (β=1.59 mm Hg, P<0.001) compared with White never smokers. There were no differences in systolic BP, diastolic BP, or PP between Black or White long‐term former smokers compared with never smokers (all P>0.05).ConclusionsAlthough the associations of cigarette smoking with alterations in BP are small, the greater PP observed in consistent smokers may contribute in part to the higher cardiovascular disease risk observed in this group because PP is a strong predictor of cardiovascular disease risk after middle age.

Macrophages Inhibit Ciliary Protein Levels by Secreting BMP-2 Leading to Airway Epithelial Remodeling Under Cigarette Smoke Exposure.

Chronic obstructive pulmonary disease (COPD) is a chronic respiratory disease with high morbidity and mortality worldwide. So far, smoking is still its leading cause. The characteristics of COPD are emphysema and airway remodeling, as well as chronic inflammation, which were predominated by macrophages. Some studies have reported that macrophages were involved in emphysema and chronic inflammation, but whether there is a link between airway remodeling and macrophages remains unclear. In this study, we found that both acute and chronic cigarette smoke exposure led to an increase of macrophages in the lung and a decrease of ciliated cells in the airway epithelium of a mouse model. The results of in vitro experiments showed that the ciliary protein (β-tubulin-IV) levels of BEAS-2B cells could be inhibited when co-cultured with human macrophage line THP-1, and the inhibitory effect was augmented with the stimulation of cigarette smoke extract (CSE). Based on the results of transcriptome sequencing, we focused on the protein, bone morphogenetic protein-2 (BMP-2), secreted by the macrophage, which might mediate this inhibitory effect. Further studies confirmed that BMP-2 protein inhibited β-tubulin-IV protein levels of BEAS-2B cells under the stimulation of CSE. Coincidentally, this inhibitory effect could be nearly blocked by the BMP receptor inhibitor, LDN, or could be interfered with BMP-2 siRNA. This study suggests that activation and infiltration of macrophages in the lung induced by smoke exposure lead to a high expression of BMP-2, which in turn inhibits the ciliary protein levels of the bronchial epithelial cells, contributing to the remodeling of airway epithelium, and aggravates the development of COPD.