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)

Inhibitors of human leukocyte elastase (HLE) may exert potent therapeutic effects on pulmonary emphysema, adult respiratory distress syndrome and other diseases involving tissue degradation. 7-(4-Chlorophenylsulfonyl-L-glutanyl)amino-5-methyl-2-isopro pylamino-4H-3,1- benzoxazin-4-one (TEI-5624) and 7-(4-chlorophenylsulfonyl-L-lysyl)amino-5-methyl-2- isopropylamino-4H-3,1-benzoxazin-4-one (TEI-6344), two derivatives of 5-methyl-4H-3,1-benzoxazin-4-one, showed strong and highly specific inhibition of human sputum elastase (HSE), which is equivalent to HLE, with Ki values of 6.91 and 16.3 nM, respectively. The selectivity of TEI-5624 for HSE vs. several proteinases ranged from 300-fold to 45,000-fold in favor of HSE. TEI-5624 and TEI-6344 also efficiently prevented degradation of insoluble elastin by stimulated polymorphonuclear leukocytes. The elastase inhibitory capacity of these compounds was not affected by treatment with stimulated polymorphonuclear leukocytes or Pseudomonas aeruginosa-origin elastase. When administered intratracheally to hamsters. TEI-5624 and TEI-6344 were eliminated from the lung with half-times of 85 and 240 min, respectively. In acute injury induced by intratracheal administration of HSE in hamsters, these compounds significantly suppressed pulmonary hemorrhage when administered intratracheally (1 mg/kg) either 30 or 240 min before challenge with HSE (1 mg/kg). HSE-induced emphysema in hamsters was also prevented by TEI-5624 (1 mg/kg) administered intratracheally 7 hr after HSE administration (1 mg/kg). These results suggest that TEI-5624 and TEI-6344 may be useful therapeutic agents for the treatment of HLE-mediated diseases.
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PMID:5-Methyl-4H-3,1-benzoxazin-4-one derivatives: specific inhibitors of human leukocyte elastase. 849 3

In summary, the chest radiograph has only moderate accuracy in visualizing opacification caused by cardiopulmonary abnormalities and may be quite nonspecific as to etiology, whereas it has high diagnostic accuracy for detecting malpositioning of tubes and lines. While focal parenchymal abnormalities are usually visualized on chest radiographs, identification of concomitant abnormalities when ARDS or PE already exist is more difficult. Atelectasis, aspiration, pneumonia, pulmonary hemorrhage, pulmonary thromboembolism, atypical cardiogenic edema, asymmetric ARDS, and neoplasms may be indistinguishable. Repeat chest radiographs and different views may be helpful, as the progression and time course of various etiologies can be quite different. On the other hand, Winer-Muram et al found that review of prior radiographs and clinical data did not improve the diagnostic accuracy for either ARDS or pneumonia. Pleural effusions may even be difficult to distinguish from parenchymal processes, particularly when the patient is in the supine position. Additional views with the patient in a different position--semi-erect, decubitus, or cross-table lateral--may be of assistance. In most cases, pneumothorax is readily detected. Additional studies such as the decubitus view occasionally may be necessary for further evaluation when there is uncertainty about the findings. Subcutaneous air is readily visualized radiographically. Pneumomediastinum and interstitial pulmonary emphysema may be more difficult to see. It is well known that CT allows visualization of much smaller abnormal air collections than radiography. Despite this lack of sensitivity and specificity of chest films, studies have shown that up to 65% of daily films in the ICU reveal significant and/or unsuspected abnormalities that may change the patient's diagnosis or management. Based on these results, the consensus opinion of the ACR Expert Panel found that daily chest radiographs are indicated on patients with acute cardiopulmonary problems and those receiving mechanical ventilation. Patients who require cardiac monitoring but are otherwise stable require only an initial admission film. Additional radiographs are indicated only when a new device is placed or when there is a specific question regarding cardiopulmonary status. It is also noteworthy that despite the chest film being the most commonly ordered radiologic examination for inpatients, there are no comprehensive studies evaluating its cost-effectiveness. Although several studies have done a very limited cost accounting of the potential savings by eliminating routine films in the evaluation of specific subsets of patients, overall impact on patient outcome has not been investigated. Thus, a true assessment of cost-effectiveness has yet to be determined.
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PMID:Accuracy and efficacy of chest radiography in the intensive care unit. 853 51

Mechanical ventilation may have adverse effects on the lung. The appearance of extra-alveolar air, either as a pneumothorax or as subcutaneous emphysema along with other manifestations, is a complication of barotrauma which has been known for a long time. Recent experimental studies have clearly shown that mechanical ventilation can also lead to alterations in the blood gas barrier. Mechanical ventilation with high inflation pressure and elevated tidal volumes induces pulmonary oedema; the genesis of which results principally from anomalies of alveolar capillary permeability. These anomalies are made as a result of pulmonary distension and not as a result of elevated pressures in the airways, thus justifying the term "volume traumatism". The existence of previous acute pulmonary injury considerably worsens the deleterious pulmonary effect of mechanical ventilation. Although the direct clinical implications of these experimental studies are difficult to confirm, these latter have nevertheless lead to profound changes in ventilatory strategy during the course of acute pulmonary disease such as the adult respiratory distress syndrome.
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PMID:[Deleterious effects of mechanical ventilation on the lower lung]. 867 49

Accumulating evidence suggests that oxidative stress plays a central role in the pathogenesis of many pulmonary diseases including adult respiratory distress syndrome, emphysema, asthma, bronchopulmonary dysplasia, and interstitial pulmonary fibrosis. The morbidity and mortality of these diseases remain high even with optimal medical management. In our attempts to devise new therapies for these disorders, it is crucial to improve our understanding of the basic mechanism(s) of oxidant-induced lung injury. A major line of investigation seeks to characterize the cellular and molecular responses of the lung to oxidant insults. Much progress has been made in our understanding of the role of the "classic" antioxidant enzymes (e.g., superoxide dismutase, catalase, glutathione peroxidase) in mediating the lung's resistance against oxidant lung injury. However, it is becoming clear that other oxidant-induced gene products may also play vital roles in the lung's adaptive and/or protective response to oxidative stress. One such stress-response protein is heme oxygenase-1, HO-1. Since the identification of HO-1 in 1968, many of the studies involving this enzyme were understandably focused on the regulation and function of HO-1 in heme metabolism. This emphasis is self-evident as HO-1 catalyzes the first and rate-limiting step in heme degradation. Interestingly, however, evidence accumulated over the past 25 years demonstrates that HO-1 is induced not only by the substrate heme but also by a variety of non-heme inducers such as heavy metals, endotoxin, heat shock, inflammatory cytokines, and prostaglandins. The chemical diversity of HO-1 inducers led to the speculation that HO-1, besides its role in heme degradation, may also play a vital function in maintaining cellular homeostasis. Further support for this hypothesis was provided by Tyrrell and colleagues who showed in 1989 that HO-1 is also highly induced by a variety of agents causing oxidative stress. Subsequently, many investigators have focused their attention on the function and regulation of HO-1 in various in vitro and in vivo models of oxidant-mediated cellular and tissue injury. The magnitude of HO-1 induction after oxidative stress and the wide distribution of this enzyme in systemic tissues coupled with the intriguing biological activities of the catalytic byproducts, carbon monoxide, iron, and bilirubin, makes HO-1 a highly attractive and interesting candidate stress-response protein which may play key role(s) in mediating protection against oxidant-mediated lung injury. This review will focus on the current understanding of the physiological significance of HO-1 induction and the molecular regulation of HO-1 gene expression in response to oxidative stress. We hope that this discussion will stimulate interest and investigations into a field which is still largely uncharted in the pulmonary research community.
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PMID:Heme oxygenase-1: function, regulation, and implication of a novel stress-inducible protein in oxidant-induced lung injury. 867 27

With a limited number of beds for patients undergoing medical and surgical treatment for respiratory diseases, we set aside 6 of 45 beds on one floor to be used as a respiratory care unit. During the past 5 years, 1820 patients (1225 medical and 595 surgical) were admitted to the respiratory care unit; they were treated for an average of 5.02 days. Of the patients being treated medically, 451 received mechanical ventilatory support. The majority of those patients had acute exacerbations of chronic respiratory failure due to emphysema or to sequelae of pulmonary tuberculosis. Acute respiratory distress associated with asthma or with pneumonia were also relatively common, as was the adult respiratory distress syndrome. A total of 119 patients on home oxygen therapy are being seen as out-patients, and the respiratory care unit was found to be quite useful whenever they needed intensive management. Only 148 (8.1%) of the patients admitted to the respiratory care unit died before discharge, and the ratio of cost to performance was good. The respiratory care unit was most effective in allowing for continuity of care from the onset of respiratory distress, and including exacerbations, surgical interventions, postoperative management, and out-patient care.
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PMID:[Evaluation of a respiratory care unit on a 45-bed hospital ward]. 875 97

Computed tomography (CT) has played an important role in improving our knowledge of the pathophysiology of the adult respiratory distress syndrome (ARDS), and in determining the morphological and functional relationships of different manoeuvres commonly used in the therapeutic management of this syndrome (changes in body position, application of positive end-expiratory pressure (PEEP) and mechanical ventilation). During the early phase of the disease, the ARDS lung is characterized by a homogenous alteration of the vascular permeability. Thus, oedema accumulates evenly in all lung regions with a nongravitational distribution (homogenous lung). The increased lung weight, due to increased oedema, causes a collapse of the lung regions along the vertical axis, through the transmission of hydrostatic forces (compression atelectasis). Thus, the lesions appear mainly in the dependent lung regions (dishomogeneous lung). During inspiration, at plateau pressure, the pulmonary units reopen and, if the PEEP applied is adequate, they stay open during the following expiration. Adequate PEEP is equal to or higher than the hydrostatic forces compressing that unit. Prone position is another manoeuvre which allows previously collapsed lung regions to reopen and, conversely, compresses previously aerated regions, reversing the distribution of gravitational forces. During late ARDS, there is less compression atelectasis and the lung undergoes structural changes, due to the reduced amount of oedema. This is usually associated with CO2 retention and the development of emphysema-like lesions. In conclusion, computed tomography is not only a research tool, but a useful technique which allows a better understanding of the progressive change in strategy needed to ventilate the adult respiratory distress syndrome lung at different stages of the disease.
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PMID:Computed tomography in adult respiratory distress syndrome: what has it taught us? 879 69

Secretory leukoprotease inhibitor (SLPI) is a low molecular weight serine proteinase inhibitor, notably of neutrophil elastase (NE), which is synthesised and secreted by the pulmonary epithelium. SLPI plays an important role in limiting NE-induced pulmonary inflammation and, significantly, it also possesses anti-HIV activity. SLPI is a significant component of the anti-NE shield in the lung which has different reactivity from, and is therefore complementary to, the anti-NE action of alpha 1-proteinase inhibitor (alpha 1-PI). Inhaled recombinant SLPI (rSLPI) could prove beneficial in partnership with alpha 1-PI in the treatment of a number of inflammatory lung disorders including emphysema, chronic bronchitis, cystic fibrosis, and adult respiratory distress syndrome.
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PMID:Secretory leukoprotease inhibitor: partnering alpha 1-proteinase inhibitor to combat pulmonary inflammation. 899 29

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

FR134043, disodium(Z,1S,15S,8S,24S,27R,29S,34S,37R)-29-ben zyl-21-ethylidene-27-hydroxy-15-isobutyrylamino-34-isopropyl-31,37 -dimethyl-10,16,19,22,30,32,35,38-octaoxo-36-oxa-9,11,17,20,23,28, 31,33-octaazatetracyclo[16.13.6.1(24),(28).0(3),(8)]octatricont a-3,5,7-trien-5,6-diyl disulfate, is a water-soluble inhibitor of human neutrophil elastase with a molecular mass of 1166.15 Da. FR134043 demonstrated a characteristic competitive inhibition of human neutrophil elastase with a Ki of 8 nM. In studies using synthetic substrates, FR134043 inhibited both neutrophil elastase activity and porcine pancreatic elastase activity with IC50 values of 35 nM and 49 nM respectively. FR134043 also inhibited hydrolysis of bovine neck ligament elastin by human neutrophil elastase with an IC50 value of 210 nM. In in vivo experiments, FR134043 protected animals against human neutrophil elastase (50 microg/animal)-induced lung hemorrhage in hamsters with an ED50 value of 3.1 microg/animal for intratracheal administration and 5.0 mg/kg for intravenous administration. Subcutaneous treatment with FR134043 significantly suppressed human neutrophil elastase (20 microg/paw)-induced paw edema in mice with an ED50 value of 3.3 mg/kg when evaluated 4 h after elastase injection. The potency of FR134043 given intratracheally to protect against porcine pancreatic elastase (100 microg/animal)-induced emphysema in hamsters was relatively low (Quasi-static lung compliance; ED50 = 1590 microg/animal) compared to that in acute animal models. FR134043 (10 mg/kg per h i.v. infusion) significantly improved lipopolysaccharide (0.25 mg/kg per h i.v. infusion)-induced thrombocytopenia and some coagulation parameters in rats. These results suggest that systemic administration of FR134043 would be advantageous over intratracheal administration of FR134043 for the treatment of adult respiratory distress syndrome, septic shock and pulmonary emphysema and other pathophysiologic conditions in which elastases are thought to be involved.
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PMID:Biochemical and pharmacological characterization of FR134043, a novel elastase inhibitor. 959 30

We report the case of a 42 years old, non-immunocompromised native Austrian living in Vienna. He presented at home with severe dyspnea and had to be intubated immediately. Shortly after hospital admission, he developed severe adult respiratory distress syndrome (ARDS) and septic shock with massive, bilobar patchy to confluent infiltrations and a need for norepinephrine. A CT-scan revealed severe loss of functional lung tissue with areas of consolidation and multiple communicating cystic spaces. Air leaking into the mediastinum through fistulas produced pneumomediastinum, pneumoperitoneum, and a massive soft tissue emphysema. Bronchoalveolar lavage performed within the first 24 hours of admission revealed + of acid-fast bacilli. Even though appropriate tuberculostatic medication was started immediately, the patient succumbed the next day to ARDS due to massive tuberculous pneumonia and miliary disease (Sepsis tuberculosis gravissima).
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PMID:Fulminant lethal tuberculous pneumonia (Sepsis tuberculosis gravissima) with ARDS in a non-immunocompromised western European middle-aged man. 1019 49


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