Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UMLS:C0034067 (emphysema)
11,506 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

FK706, sodium 2-[4-[[(S)-1-[[(S)-2-[[(RS)-3, 3, 3-trifluoro-1-isopropyl-2-oxopropyl]aminocarbonyl]pyrrolidin -1-yl]carbonyl]-2-methylpropyl] aminocarbonyl] benzoylamino] acetate, C26H32F3N4NaO7, is a synthetic water-soluble inhibitor of human neutrophil elastase. This compound demonstrated a competitive and slow-binding inhibition of human neutrophil elastase with a Ki of 4.2 nM. In studies using synthetic substrates, FK706 inhibited human neutrophil elastase activity and porcine pancreatic elastase activity with respective IC50 values of 83 and 100 nM. FK706, however, inhibited more weakly, (IC50 values > 340 microM) other serine proteinases such as human pancreatic alpha-chymotrypsin, human pancreatic trypsin and human leukocyte cathepsin G. FK706 also effectively inhibited the hydrolysis of bovine neck ligament elastin (2 mg/ml final concentration) by human neutrophil elastase (4 microg/ml final concentration) with an IC50 value of 230 nM. FK706 protected animals against human neutrophil elastase (50 microg/animal)-induced lung hemorrhage with ED50 values of 2.4 microg/animal by intratracheal administration and 36.5 mg/kg by intravenous administration, respectively. Subcutaneous administration of FK706 significantly suppressed human neutrophil elastase (20 microg/paw)-induced paw edema in mice in a dose-dependent manner (47% inhibition at a dose of 100 mg/kg). These results suggest that FK706 would be a useful tool for investigating the role of human neutrophil elastase in inflammatory disorders associated with an excess of elastase, such as pulmonary emphysema, adult respiratory distress syndrome, septic shock, cystic fibrosis, chronic bronchitis and rheumatoid arthritis.
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PMID:Biochemical and pharmacological characterization of FK706, a novel elastase inhibitor. 938 82

Objective to review the experience of the lung transplantation unit at Hospital La Fe (Valencia). Between February 1990 and March 1996 we performed 40 lung transplants. The following causes were most common: cystic fibrosis (9 cases), emphysema (8), pulmonary fibrosis (8) and bronchiectasis (7). Types of intervention were 27 double lung transplants (25 sequential and 9 blocked), 9 single lung transplants, and 4 heart-lung transplants. We then reviewed the 36 single and double lung transplants. The main exclusion criteria were age over 65 years, malignant disease, kidney or liver disease, severe or non reversible central nervous system disease, and drug addiction. Prior surgery, mechanical ventilation and the presence of Aspergillus were considered lower-order contraindications. Mean patient age was 37.7 years (14-59). Six patients were colonized by Aspergillus before transplantation. Five had undergone earlier surgery and two were mechanically ventilated before the transplant. The most common complication was respiratory infection, which was present in 6 of the 7 patients who died. Other complications in order of frequency were dehiscence and/or bronchial stenosis, corticoid myopathy and postoperative bleeding. The actuarial survival rate of single and double lung transplants was 67.85 after 3 years, and 87.5% in patients with cystic fibrosis. Lung transplantation is a well-established procedure that is gradually being extended to treat more conditions. The main obstacle is the scarcity of donors. The main challenge at present is bronchiolitis obliterans.
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PMID:[1990-1996: the experience of the La Fe Lung Transplant Group (Valencia)]. 942 59

alpha 1-Antitrypsin (AAT) deficiency, also known as alpha 1-antiprotease inhibitor deficiency, is a disease caused by genetically determined AAT deficiency. It occurs as a result of inheritance of two protease inhibitor (PI) deficiency alleles from the AAT gene locus (designated PI) on chromosomal segment 14q32.1. The most common deficiency allele is PI*Z and a large majority of individuals with severe AAT deficiency are PI type ZZ. The disease occurs predominantly in white persons of European origin and its frequency in Europe and North America is comparable to that of cystic fibrosis (1 in 2000 to 1 in 7000.) Persons with AAT deficiency may have no clinical manifestations. Chronic obstructive pulmonary disease (COPD) with a high frequency of panacinar emphysema is the most prevalent clinical disorder associated with AAT deficiency and the most frequent cause of disability and death. Tobacco smoking is the major risk factor for developing COPD, which generally begins by the third decade of life, much earlier than "usual" COPD that occurs in AAT-replete individuals. Liver disease, the second most frequent clinical manifestation of AAT deficiency, typically presents as cholestasis in infancy but is usually not severe and generally remits by adolescence. Chronic liver disease develops infrequently, although AAT deficiency is the commonest cause of chronic liver disease in childhood. Cirrhosis and carcinoma of the liver affect at least 25% of AAT-deficient adults over the age of 50 years. AAT deficiency appears to be widely underdiagnosed and based on predicted gene frequencies even in the most intensely studied populations, only a small proportion of those predicted to have AAT deficiency have been diagnosed. Human AAT is available in limited quantity for augmentation therapy. This Memorandum summarizes the discussions and recommendations made by participants at a WHO meeting held in Geneva on 18-20 March 1996 to review existing knowledge about this highly prevalent genetic disorder, develop a strategy for enhancing awareness of it among health-care-givers and the general public, and explore new case-finding and disease-prevention strategies.
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PMID:Alpha 1-antitrypsin deficiency: memorandum from a WHO meeting. 944 74

The prevalence of lung diseases and its associated sociomedical losses remain to be intolerable. The advantages of Russia's existing outpatient pneumonia treatment are shown. Experimental and clinical data on the polyetiology of acute respiratory distress syndrome and positive experience with extracorporeal detoxification, various efferent treatments and auxiliary membrane oxygenation of blood are given. The current approaches to interpreting, treating, and preventing chronic pulmonary obstructive diseases, bronchial asthma, emphysema, interstitial (disseminated) lung diseases and mucoviscidosis are discussed.
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PMID:[Clinical and experimental aspects of pulmonology]. 951 40

In order to determine the presence and distribution of Haemophilus influenzae in lung tissue sections, we obtained lung explants from 49 lung transplant recipients with cystic fibrosis (CF) (n = 16), chronic obstructive pulmonary disease (COPD) including emphysema (n = 16), bronchiectasis (n = 5), pulmonary hypertension (n = 9), Langerhans cell histiocytosis (n = 1), and idiopathic pulmonary fibrosis (n = 2). Analysis was done by selective culturing, immunoperoxidase (IP) staining, and by polymerase chain reaction (PCR). H. influenzae was cultured from specimens of the lung explants from one CF and one COPD patient. IP staining of tissue sections was positive in 24 patients (10 CF patients, eight COPD patients, two bronchiectasis patients, and four patients with noninfectious pulmonary diseases). IP-positive tissue sections were PCR-positive, and IP-negative sections were PCR-negative. H. influenzae was more frequently detected in tissue sections of lung explants from CF and COPD patients than from patients with bronchiectasis or noninfectious pulmonary diseases. H. influenzae was diffusely present in the epithelium, the submucosa of the bronchi, the bronchioles, the interstitium, and the alveolar epithelium. H. influenzae was localized extracellularly alone and in bacterial clusters, and was also associated with macrophages in CF patients. The results of this study demonstrate that H. influenzae is often present in the lungs of patients with end-stage pulmonary disease, especially CF and COPD patients. H. influenzae is diffusely present in the respiratory epithelium and subepithelial layers of the lungs of these patients.
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PMID:Haemophilus influenzae in lung explants of patients with end-stage pulmonary disease. 951 16

The social rehabilitation of lung transplant recipients becomes increasingly important as the results of lung transplantation improve. Although return-to-work (RTW) rates have been published for recipients of other organ transplants, no such data are available after lung transplantation. The purpose of this study was to determine what factors influence RTW after lung transplantation. Of 99 lung transplant recipients (43 single, 56 bilateral) surveyed from Denver, Colorado, (n = 49) and Toronto, Ontario, Canada (n = 50), 22% (n = 22) were employed, 38% (n = 38) were unemployed but medically able to work, 29% (n = 29) were medically disabled, and 10% (n = 10) had retired. The RTW rate for those medically able to work was 37% (22/60), and it was identical at each center (n = 11). Only Canadian lung transplant recipients (36%, 4/11) secured new jobs, whereas all Colorado lung transplant recipients returned to their previous employment (100%, 11/11). A stepwise discriminant analysis revealed that (1) pretransplantation employment, (2) a diagnosis of emphysema, cystic fibrosis, or primary pulmonary hypertension, (3) a self-report of being physically able to work, (4) greater functional improvement as measured by post-lung transplantation percent predicted forced vital capacity, and (5) post-lung transplantation 6-minute walk > 550 m positively influenced RTW. This analysis accurately profiled 82% of the employed and 76% of the unemployed recipients for an overall effectiveness of 79%. The findings of this study are that (1) a 37% employment rate for those physically able was comparable to other types of organ transplant recipients, (2) employment was not determined by the type of lung transplantation procedure (single or bilateral), and (3) social factors remain employment barriers for some recipients, but their absence did not guarantee a better employment rate.
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PMID:Return to work after lung transplantation. 958 89

Cystic fibrosis (CF) is an inherited disorder associated with severe inflammation and repeated bacterial infection and colonization in the lung. Airway epithelium is involved in defence against bacteria, but this system may be defective in CF. Pro-inflammatory cytokines can stimulate the expression of inducible nitric oxide synthase (iNOS), an enzyme generating nitric oxide, which functions as an important mediator in host defence mechanisms. To understand better the poor resistance to infections in the CF lung, the expression of the iNOS gene was investigated in explanted lungs from patients with cystic fibrosis (n = 13), bronchiectasis (n = 3), emphysema (n = 14), and in normal lungs (n = 8). In addition, bronchial epithelial cell lines were examined to study iNOS gene expression in vitro. Strong immunoreactivity for iNOS was seen in inflammatory cells and bronchial epithelium in all the diseased lungs, except for bronchial epithelium in CF. Quantitative analysis showed a significant reduction in the area of epithelium immunostained in CF [CF 6.8 +/- 1.6 (% +/- SEM); emphysema 18.2 +/- 2.8; normal 9.6 +/- 0.8, P < 0.01], regardless of steroid treatment. These results were supported by in situ hybridization of iNOS mRNA, which showed a pattern of gene expression in CF, emphysema, and normal lung which paralleled that of protein immunoreactivity. Stimulation with cytokines (IL-1 beta, TNF-alpha, and IFN-gamma) increased the expression of iNOS mRNA detected by reverse transcriptase-polymerase chain reaction (RT-PCR) in cultures of normal (16HBE14o-), but not CF (CFBE41o-, with delta F508 CFTR mutation) epithelial cells. Expression of iNOS in inflammatory cells suggests that the gene is normal in CF. Absence of iNOS from bronchial epithelium may be due to low expression of the gene resulting from abnormalities in the signalling system that normally causes induction, such as cytokine receptors, second messengers or transcription factors. The resulting deficiency of the nitric oxide defence system may be relevant to the susceptibility of CF patients to pulmonary bacterial colonization.
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PMID:Lack of inducible nitric oxide synthase in bronchial epithelium: a possible mechanism of susceptibility to infection in cystic fibrosis. 961 86

Neutrophils release elastase, which is known secondarily to cause tissue damage. However, it is rapidly inactivated by the endogenous alpha1-proteinase inhibitor (alpha1Pi). Nevertheless, under pathological conditions, alpha1i is inactivated by oxidants released from neutrophils, resulting in an excess of elastase at the site of inflammation. This elastase/alpha1Pi imbalance has been implicated as a pathogenic factor in cystic fibrosis, acute respiratory distress syndrome, and emphysema. Elastase inhibitors, which do not interfere with the microbicidal activity of neutrophils and are resistant to neutrophil-released oxidants, would undoubtedly represent an important advance in the management of neutrophil-mediated tissue injury. We report that a new family of elastase inhibitors ICI200355 and ZD0892 was found to be resistant toward superoxide, hypochlorous acid, hydrogen peroxide, hydroxyl radical, and peroxynitrite mediated degradation as well as having no effect on the formation of these oxidants by activated neutrophils. More importantly, we found that these inhibitors did not interfere with the ability of human neutrophils to phagocytose and to kill Staphylococcus aureus. In conclusion, a new potent class of elastase inhibitors, while blocking the effects of neutrophil elastase, was found not to impede various physiological functions of human neutrophils, in particular the ability of these phagocytic cells to phagocytose and kill bacteria.
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PMID:Effect of trifluoromethyl ketone-based elastase inhibitors on neutrophil function in vitro. 973 58

1. The number of heart transplant operations performed in the United States has decreased by 16 procedures between 1995 (2,360) and 1996 (2,344). Following a period of rapid growth from 1990 (203) through 1995 (871), there was a decrease of 71 lung transplant procedures between 1995 (871) and 1996 (800). 2. The most frequently reported indication for heart transplantation in the US was coronary artery disease (44.88%). For other thoracic transplants, the most frequently reported indications included cystic fibrosis (31.85%) for double lung, emphysema/COPD (55.88%) for single lung and congenital heart disease (48.72%) for heart-lung transplants. The most frequently reported diagnoses for thoracic transplantation outside the US included cardiomyopathy (47.4%) for heart, cystic fibrosis (33.0%) for double lung, idiopathic pulmonary fibrosis (29.1%) for single lung and primary pulmonary hypertension (23.4%) for heart-lung transplants. 3. US heart transplant recipients were predominantly male (77.6%), older than age 50 (55.4%) and white (82.3%). In contrast, US lung transplant recipients were predominantly female (52.1%), aged 35-64 (73.5%) and white (89.5%). No significant variance from the US recipient demographic profile was noted for non-US recipients in this analysis. 4. The mean donor age for heart and lung transplants has risen slightly with an increase in mean age of 3.12 years for heart donors and 4.72 years for lung donors from 1987-1997. 5. The one-year survival rate for thoracic transplants performed in the US was 84.8% for heart, 70.1% for lung and 73.4% for heart-lung in 1996. Five-year survival for US thoracic transplants was 66.5% for heart and 43.2% for lung transplants performed in 1992. 6. There was little change in heart transplant survival based on transplant era (1987-89, 1990-92 and 1993-95). Lung recipients transplanted in the 1993-95 era showed a 16% increase in survival compared with those transplanted in the 1987-89 era at the 48-month time point. 7. The most important risk factor for US heart recipients at one month, one year, and conditionally at 5 years after transplantation was receipt of a previous heart transplant. Other substantial long-term risk factors included donor age and non-white, non-black recipient. 8. The most important risk factors for mortality in US lung recipients were the order of the transplant (primary or repeat) and the patient's medical condition at time of transplant. Diagnosis, recipient age and recipient race were highly influential risk factors for conditional 5-year mortality. 9. For heart and lung recipients, the major cause of hospitalization during the first 2 years after transplantation was infection.
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PMID:Worldwide thoracic organ transplantation: a report from the UNOS/ISHLT International Registry for thoracic organ transplantation. 991 89

In order to determine the possible role of the cystic fibrosis transmembrane regulator (CFTR) gene in pulmonary diseases not due to cystic fibrosis, a complete screening of the CFTR gene was performed in 120 Italian patients with disseminated bronchiectasis of unknown cause (DBE), chronic bronchitis (CB), pulmonary emphysema (E), lung cancer (LC), sarcoidosis (S) and other forms of pulmonary disease. The 27 exons of the CFTR gene and their intronic flanking regions were analyzed by denaturing gradient gel electrophoresis and automatic sequencing. Mutations were detected in 11/23 DBE (P = 0.009), 7/25 E, 5/27 CB, 5/26 LC, 5/8 S (P = 0.013), 1/4 tuberculosis, and 1/5 pneumonia patients, and in 5/33 controls. Moreover, the IVS8-5T allele was detected in 6/25 E patients (P = 0.038). Four new mutations were identified: D651N, 2377C/T, E826K, and P1072L. These results confirm the involvement of the CFTR gene in disseminated bronchiectasis of unknown origin, and suggest a possible role for CFTR gene mutations in sarcoidosis, and for the 5T allele in pulmonary emphysema.
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PMID:Complete mutational screening of the CFTR gene in 120 patients with pulmonary disease. 992 9


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