Although these conditions are rare, a proportion of patients with interstitial lung diseases (ILDs) may develop a progressive-fibrosing phenotype. Progressive fibrosis is associated with worsening ...respiratory symptoms, lung function decline, limited response to immunomodulatory therapies, decreased quality of life and, potentially, early death. Idiopathic pulmonary fibrosis may be regarded as a model for other progressive-fibrosing ILDs. Here we focus on other ILDs that may present a progressive-fibrosing phenotype, namely idiopathic nonspecific interstitial pneumonia, unclassifiable idiopathic interstitial pneumonia, connective tissue disease-associated ILDs (
rheumatoid arthritis-related ILD), fibrotic chronic hypersensitivity pneumonitis, fibrotic chronic sarcoidosis and ILDs related to other occupational exposures. Differential diagnosis of these ILDs can be challenging, and requires detailed consideration of clinical, radiological and histopathological features. Accurate and early diagnosis is crucial to ensure that patients are treated optimally.
The connection between aging‐related immune dysfunction and the lung manifestations of aging is poorly understood. A detailed characterization of the aging IL10‐deficient murine lung, a model of ...accelerated aging and frailty, reconciles features of both immunosenescence and lung aging in a coherent model. Airspace enlargement developed in the middle‐aged (12 months old) and aged (20–22 months old) IL10‐deficient lung punctuated by an expansion of macrophages and alveolar cell apoptosis. Compared to wild‐type (WT) controls, the IL10‐deficient lungs from young (4‐month‐old) mice showed increased oxidative stress which was enhanced in both genotypes by aging. Active caspase 3 staining was increased in the alveolar epithelial cells of aged WT and mutant lungs but was greater in the IL10‐deficient milieu. Lung macrophages were increased in the aged IL10‐deficient lungs with exuberant expression of MMP12. IL10 treatment of naïve and M2‐polarized bone marrow‐derived WT macrophages reduced MMP12 expression. Conditioned media studies demonstrated the secretome of aged mutant macrophages harbors reduced AECII prosurvival factors, specifically keratinocyte growth factor (KGF) and hepatocyte growth factor (HGF), promotes cell death, and reduces survival of primary alveolar epithelial cells. Compared to WT controls, aged IL10‐deficient mice have increased parenchymal lymphoid collections comprised of a reduced number of apoptotic cells and B cells. We establish that IL10 is a key modulator of airspace homeostasis and lymphoid morphogenesis in the aging lung enabling macrophage‐mediated alveolar epithelial cell survival and B‐cell survival within tertiary lymphoid structures.
The loss of IL10 causes airspace enlargement and expansion of lymphoid aggregates in the aged murine lung. Enhanced alveolar epithelial cell death from reduced macrophage‐secreted prosurvival factors and increased MMP12 production contributes to the airspace phenotype. The expansion of altered lymphoid aggregates in the aged mutant lung features reduced cell apoptosis and reduced B‐cell content. IL10 is a key modulator of airspace homeostasis and lymphoid morphogenesis in the lung.
Chronic obstructive pulmonary disease (COPD) is a prevalent smoking-related disease for which no disease-altering therapies currently exist. As dysregulated TGF-β signaling associates with lung ...pathology in patients with COPD and in animal models of lung injury induced by chronic exposure to cigarette smoke (CS), we postulated that inhibiting TGF-β signaling would protect against CS-induced lung injury. We first confirmed that TGF-β signaling was induced in the lungs of mice chronically exposed to CS as well as in COPD patient samples. Importantly, key pathological features of smoking-associated lung disease in patients, e.g., alveolar injury with overt emphysema and airway epithelial hyperplasia with fibrosis, accompanied CS-induced alveolar cell apoptosis caused by enhanced TGF-β signaling in CS-exposed mice. Systemic administration of a TGF-β-specific neutralizing antibody normalized TGF-β signaling and alveolar cell death, conferring improved lung architecture and lung mechanics in CS-exposed mice. Use of losartan, an angiotensin receptor type 1 blocker used widely in the clinic and known to antagonize TGF-β signaling, also improved oxidative stress, inflammation, metalloprotease activation and elastin remodeling. These data support our hypothesis that inhibition of TGF-β signaling through angiotensin receptor blockade can attenuate CS-induced lung injury in an established murine model. More importantly, our findings provide a preclinical platform for the development of other TGF-β-targeted therapies for patients with COPD.
Bronchopulmonary dysplasia (BPD), a common chronic respiratory disease that occurs after premature birth, is believed to be secondary to oxidative damage from hyperoxia and inflammation, which leads ...to impaired alveolar formation and chronic lung dysfunction. We hypothesized that extracellular superoxide dismutase (SOD)3, an antioxidant uniquely targeted to the extracellular matrix (ECM) and alveolar fluid, might have a different response (down-regulation) to hyperoxic injury and recovery in room air (RA), thereby contributing to the persistent airspace injury and inflammation. We used a murine BPD model using postnatal hyperoxia (O2) (4 or 5 d) followed by short-term recovery (14 d) in RA, which mimics the durable effects after injury during alveolar development. This was associated with significantly increased mRNA expression for antioxidant genes mediated by nuclear factor erythroid 2-related factor (Nrf2) in the O2 (n = 4) versus RA group (n = 5). SOD3, an Nrf2-independent antioxidant, was significantly reduced in the O2-exposed mice compared with RA. Immunohistochemistry revealed decreased and disrupted SOD3 deposition in the alveolar ECM of O2-exposed mice. Furthermore, this distinct hyperoxic antioxidant and injury profile was reproducible in murine lung epithelial 12 cells exposed to O2. Overexpression of SOD3 rescued the injury measures in the O2-exposed cells. We establish that reduced SOD3 expression correlates with alveolar injury measures in the recovered neonatal hyperoxic lung, and SOD3 overexpression attenuates hyperoxic injury in an alveolar epithelial cell line. Such findings suggest a candidate mechanism for the pathogenesis of BPD that may lead to targeted interventions.
Respiratory dysfunction is a major contributor to morbidity and mortality in aged populations. The susceptibility to pulmonary insults is attributed to "low pulmonary reserve", ostensibly reflecting ...a combination of age-related musculoskeletal, immunologic and intrinsic pulmonary dysfunction.
Using a murine model of the aging lung, senescent DBA/2 mice, we correlated a longitudinal survey of airspace size and injury measures with a transcriptome from the aging lung at 2, 4, 8, 12, 16 and 20 months of age. Morphometric analysis demonstrated a nonlinear pattern of airspace caliber enlargement with a critical transition occurring between 8 and 12 months of age marked by an initial increase in oxidative stress, cell death and elastase activation which is soon followed by inflammatory cell infiltration, immune complex deposition and the onset of airspace enlargement. The temporally correlative transcriptome showed exuberant induction of immunoglobulin genes coincident with airspace enlargement. Immunohistochemistry, ELISA analysis and flow cytometry demonstrated increased immunoglobulin deposition in the lung associated with a contemporaneous increase in activated B-cells expressing high levels of TLR4 (toll receptor 4) and CD86 and macrophages during midlife. These midlife changes culminate in progressive airspace enlargement during late life stages.
Our findings establish that a tissue-specific aging program is evident during a presenescent interval which involves early oxidative stress, cell death and elastase activation, followed by B lymphocyte and macrophage expansion/activation. This sequence heralds the progression to overt airspace enlargement in the aged lung. These signature events, during middle age, indicate that early stages of the aging immune system may have important correlates in the maintenance of tissue morphology. We further show that time-course analyses of aging models, when informed by structural surveys, can reveal nonintuitive signatures of organ-specific aging pathology.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
PC-SPES, a proprietary mixture composed of eight different herbs, is used worldwide as an alternative treatment by prostate cancer patients. It has been suggested that the clinical and in vitro ...antitumor activity exhibited by PC-SPES may be due to estrogenic activity, which in turn may be mediated by the presence of undeclared prescription drug contaminants. Here, we evaluated the in vivo effects of two different commercial lots of PC-SPES in male and female rats. Our high-pressure liquid chromatography analysis coupled with gas chromatography/mass spectrometry analysis by an independent laboratory suggested that PC-SPES lot 5430125 was contaminated with diethylstilbestrol (DES), whereas lot 5431249 was not. Treatment of male rats with PC-SPES lot 5430125 or DES alone reduced the weight of androgen target organs and decreased circulating levels of sex steroids and luteinizing hormone, whereas lot 5431249 was without effect. In addition, lot 5430125 and DES, but not lot 5431249 increased uterine weight in female rats. These results suggest that the inhibitory effects on androgen targets are mediated through suppression of the hypothalamic-pituitary axis and this suppression is probably due to DES contamination. We assessed the effects of both lots of PC-SPES and DES on hepatic cytochrome P450 expression and activity. Both lots of PC-SPES and DES reduced CYP3A activity and protein levels. Because the response of CYP3A to PC-SPES was not dependent on whether it contained DES, a phytochemical component of PC-SPES is most likely responsible for this effect. Inhibition of CYP3A has important implications for potential herbal-drug interactions.
Lung resection provides the best chance of cure for individuals with early-stage non-small-cell lung cancer. Lung resection will lead to a decrease in lung function. The population that develops lung ...cancer often has concomitant lung disease and a reduced ability to tolerate further losses in lung function. The goal of the preoperative pulmonary assessment of individuals with resectable lung cancer is to identify those individuals whose short- and long-term morbidity and mortality would be unacceptably high if surgical resection were to occur. Pulmonary function measures such as the forced expiratory volume in 1 second (FEV1) and the diffusing capacity for carbon monoxide (DLCO) are useful predictors of postoperative outcome. When lung function in not normal, the prediction of postoperative lung function from preoperative results, and the assessment of exercise capacity, can help to clarify the risks. Testing algorithms and published guidelines help to direct the order of testing. Interventions that allow us to consider resection outside of the guidelines, or to maximize the potential to tolerate lung resection, help us to offer potentially curative treatment to as many as possible. Knowledge of alternative treatment options will help to guide those deemed unfit for resection.
Department of Cardiothoracic Surgery, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, New York, USA
*Corresponding author. Address: 15 Charles Plaza, #1703, Baltimore, MD ...21201, USA. Tel./fax: +1-410-347-0836. E-mail address : lnwakanma{at}aol.com (L. Nwakanma).
Objective: Optimal management of patients with combined coronary and carotid artery disease remains controversial. This study analyzed the outcomes between simultaneous carotid endarterectomy (CEA) and coronary artery bypass grafting (CABG) vs. isolated CABG. Methods: We reviewed the early and late follow-up data of 412 patients who underwent either combined CEA/CABG vs. CABG alone between August 1999 and October 2003. All patients undergoing CEA had at least 80% stenosis of one carotid artery. Data were obtained for pre-, intra-, and early postoperative variables. Late follow-up data (range 1.1 to 69.5 months postoperative, mean 42.4 months, median 42.7 months) included myocardial infarctions (MI), stroke and death. Differences between the two groups were investigated. Univariate and multivariate analysis were carried out to identify predictors of death, MI, and stroke in the entire group. Results: There were 27 patients (6.6%) in the CEA/CABG group and 385 patients in the CABG alone group. There was one patient (3.7%) in the CEA/CABG group who had a perioperative stroke versus six (1.6%) in the CABG group ( P =0.38). There were no documented postoperative myocardial infarctions (MI) by EKG and CK-MB criteria in both groups. There were no deaths in the CEA/CABG group versus three in the CABG group ( P =1.00). Within the follow-up period, strokes developed in 2 (7.4%) CEA/CABG patients and in 7 (2.3%) CABG patients ( P =0.16). Three CEA/CABG patients (11.1%) developed MI versus 19 (6.1%) patients in the CABG group ( P =0.40). There were 4 (14.8%) deaths in the CEA/CABG group versus 51 (13.4%) in the CABG group ( P =0.77). Freedom from death, stroke, and myocardial infarction was not statistically different between the groups at 60 months (all P >0.05). Conclusions: The addition of CEA to CABG did not increase short- and long-term morbidity and mortality compared to isolated CABG in our group of patients. Combined CEA/CABG can be performed safely in this high-risk group of patients. Prospective randomized study is needed to further substantiate these findings.
Key Words: Coronary artery bypass; Carotid endarterectomy; Combined coronary artery bypass and carotid endarterectomy; Carotid stenosis; Stroke
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