After deployment to Southwest Asia, some soldiers develop persistent respiratory symptoms, including exercise intolerance and exertional dyspnea. We identified 50 soldiers with a history of deployment to Southwest Asia who presented with unexplained dyspnea and underwent an unrevealing clinical evaluation followed by surgical lung biopsy. Lung tissue specimens from 17 age-matched, nonsmoking subjects were used as controls. Quantitative histomorphometry was performed for evaluation of inflammation and pathologic remodeling of small airways, pulmonary vasculature, alveolar tissue and visceral pleura. Compared with control subjects, lung biopsies from affected soldiers revealed a variety of pathologic changes involving their distal lungs, particularly related to bronchovascular bundles. Bronchioles from soldiers had increased thickness of the lamina propria, smooth muscle hypertrophy, and increased collagen content. In adjacent arteries, smooth muscle hypertrophy and adventitial thickening resulted in increased wall-to-lumen ratio in affected soldiers. Infiltration of CD4 and CD8 T lymphocytes was noted within airway walls, along with increased formation of lymphoid follicles. In alveolar parenchyma, collagen and elastin content were increased and capillary density was reduced in interalveolar septa from soldiers compared to control subjects. In addition, pleural involvement with inflammation and/or fibrosis was present in the majority (92%) of soldiers. Clinical follow-up of 29 soldiers (ranging from 1 to 15 y) showed persistence of exertional dyspnea in all individuals and a decline in total lung capacity. Susceptible soldiers develop a postdeployment respiratory syndrome that includes exertional dyspnea and complex pathologic changes affecting small airways, pulmonary vasculature, alveolar tissue, and visceral pleura.
Background The liver fluke, Opisthorchis felineus, is widely distributed throughout Europe and large parts of the Russian Federation. In Western Siberia, information about opisthorchiasis is lacking although infection may lead to severe liver and bile duct diseases. We aimed to assess the current prevalence of O. felineus infection along with associated risk factors and morbidity in rural Western Siberia. Methods We conducted a community-based, cross-sectional study in the rural Shegarskiy district, Tomsk Oblast, Russian Federation. All household members (� 7 years) present on the survey day were enrolled (n = 600). Two stool samples per person were examined for helminth eggs, using PARASEP (DiaSys Ltd, UK). The number of eggs per gram (EPG) of feces was recorded. Each study participant was interviewed to determine risk factors, using a pretested questionnaire. An abdominal ultrasonography examination of liver and bile ducts was performed with a mobile, high resolution ultrasound device. In total, 488 persons completed assessments (two stool samples, completed questionnaires); of those, 436 individuals had an ultrasonography (US) examination. Results We observed a prevalence of O. felineus infection of 60.2%. Significant risk factors for infection were the consumption of river fish (odds ratio from adjusted analysis [aOR] 2.4, 95% CI
Emerging evidence indicates that early life events can increase the risk for developing chronic obstructive pulmonary disease (COPD). Using an inducible transgenic mouse model for NF-κB activation in the airway epithelium, we found that a brief period of inflammation during the saccular stage [postnatal day (PN)3-PN5] but not alveolar stage (PN10-PN12) of lung development disrupts elastic fiber assembly, resulting in permanent reduction in lung function and development of a COPD-like lung phenotype that progresses through 24 months of age. Neutrophil depletion prevented disruption of elastic fiber assembly and restored normal lung development. Mechanistic studies uncovered a role for neutrophil elastase (NE) in downregulating expression of critical elastic fiber assembly components, particularly fibulin-5 and elastin. Further, both purified human NE and NE-containing exosomes from tracheal aspirates of premature infants with lung inflammation down-regulated elastin and fibulin-5 expression by saccular stage mouse lung fibroblasts. Together, our studies define a critical developmental window for assembling the elastin scaffold in the distal lung, which is required to support lung structure and function throughout the lifespan. While neutrophils play a wellrecognized role in COPD development in adults, neutrophilic inflammation may also contribute to early life predisposition to COPD.
Although activation of adaptive immunity is a common pathological feature of chronic obstructive pulmonary disease (COPD), particularly during later stages of the disease, the underlying mechanisms are poorly understood. In small airways of COPD patients, we found that localized disruption of the secretory immunoglobulin A (SIgA)-containing mucosal immunobarrier correlated with lymphocyte accumulation in airway walls and development of tertiary lymphoid structures (TLS) around small airways. In SIgA-deficient mice, we observed bacterial invasion into the airway epithelial barrier with lymphocytic infiltration and TLS formation, which correlated with the progression of COPD-like pathology with advanced age. Depletion of either CD4+ or CD8+ T lymphocytes reduced the severity of emphysema in SIgA-deficient mice, indicating that adaptive immune activation contributes to progressive lung destruction. Further studies revealed that lymphocyte infiltration into the lungs of SIgA-deficient mice was dependent on monocyte-derived dendritic cells (moDCs), which were recruited through a CCR2-dependent mechanism in response to airway bacteria. Consistent with these results, we found that moDCs were increased in lungs of COPD patients, along with CD4+ and CD8+ effector memory T cells. Together, these data indicate that endogenous bacteria in SIgA-deficient airways orchestrate a persistent and pathologic T lymphocyte response through monocyte recruitment and moDC differentiation.
Growth arrest-specific 6 (Gas6) has been implicated in carcinogenesis through activation of its receptors, particularly MerTK. To investigate whether Gas6 plays a role in resistance to NF-κB inhibitors, which have not proven to be effective agents for lung cancer therapy, we studied lung cancer models induced by urethane injection or expression of mutant Kras (KrasG12D). We found that Gas6 is primarily produced by macrophages during tumorigenesis and that Gas6 is negatively regulated by NF-κB. Since Gas6 is a vitamin K dependent protein, we used low-dose warfarin to block Gas6 production and showed that this treatment inhibited tumorigenesis in both the urethane and KrasG12D models, most prominently in mice with targeted deletion of IKKβ in myeloid cells (IKKβΔMye mice). In addition, MerTK deficient mice had reduced urethane-induced tumorigenesis. Inhibition of the Gas6-MerTK pathway in all these models reduced macrophages and neutrophils in the lungs of tumor-bearing mice. Analysis of mouse lung tumors revealed MerTK staining on tumor cells and in vitro studies showed that Gas6 increased proliferation of human lung cancer cell lines. To assess the therapeutic potential for combination treatment targeting NF-κB and Gas6-MerTK, we injected Lewis Lung Carcinoma cells subcutaneously and treated mice with Bay 11-70852 (NF-κB inhibitor) and/or Foretinib (MerTK inhibitor). While individual treatments were ineffective, combination therapy markedly reduced tumor growth, blocked tumor cell proliferation, reduced tumor-associated macrophages, and increased CD4+ T cells. Together, our studies unmask a role for Gas6-MerTK signaling in lung carcinogenesis and indicate that up-regulation of Gas6 production in macrophages could be a major mechanism of resistance to NF-κB inhibitors.
Popov S.V.urpose. . The aim of the research was to study the possibility of using the myocardium SPECT with 99mTc-MIBI and myocardium scintigraphy with 123I-metaiodobenzylguanidine (123I-MIBG) in order to optimize the location choice of the cardioverter defibrillator (ICD) defibrillating electrode (DE) in patients with coronary artery diseases (CAD).Materials and methods. The study included 80 patients (men -68, women -12, aged 65.0 ± 7.3 years) with CAD, who had indications for ICD implantation. Patients were divided into 3 groups. The first group consisted of 26 patients who underwent SPECT with 99mTc-MIBI at rest, and the implantation of DE of ICD was performed taking into account the scintigraphic results.The second group consisted of 27 patients who underwent myocardial scintigraphy with 123I-MIBG and ICD implantation was performed taking into account the results of this study. The third group included 27 patients to whom DE was implanted only on the basis of generally accepted electrophysiological criteria. The groups were compared by electrophysiological indices of the efficiency of the DE implantation at the 1st, 7th and 31st days after the operation.Results. Significant differences were found for the majority of electrophysiological indices on the 1st, 7th and 31st days after the operation between 1 and 3 groups. In addition, in the first group, the degree of perfusion impairment in the septal segment (scores) in patients to whom the DE was implanted into the apical position was closely correlated with the threshold of electrical stimulation (PES) on the 1st (p<0.05, R = 0.725), the 7th (p <0.05, R = 0.805) and the 31st day (p <0.05, R = 0.922). In the same group, in patients to whom DE was implanted into a septal position, the degree of perfusion defects in the apical segment correlated with PES at the 7th ( p <0.05, R = 0.660) and 31st (for p <0.05 R = 0,843) day.There were no significant differences in the majority of the electrophysiological indices on the 1st, 7th and 31st days after the operation between the 2nd and 3rd groups. In patients to whom the DE was implanted into the apical position, the score of the 123I-MIBG accumulation defects in the septal segment correlated only with the index of the ventricular signal amplitude on the first day (p <0.05, R = 0.523). However, in the same group, in patients to whom the DE was implanted into the septal position, no significant correlations between electrophysiological indices and the score of 123I-MIBG accumulation defects were found.Conclusion. Myocardial SPECT with 99mTc-MIBI with detailed evaluation of perfusion defects in the apical and septal segments of the heart ventricles allows optimizing the choice of the site of DE implantation in patients with CAD. The use of the 123I-MIBG scintigraphy for choosing the place of DE implantation did not result at significant improvement of electrophysiological parameters in the examined category of patients.Keywords: myocardium scintigraphy, 99mТс-MIBI, ¹²³I-MIBG, defibrillating electrode, ICD.Corresponding...
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