Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0034069 (pulmonary fibrosis)
 7,050 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Adult respiratory distress syndrome (ARDS) remains a highly lethal complication of autodestructive inflammation. This syndrome originally referred to a single organ failure but is now considered a component, usually the first, of the multisystem organ failure syndrome (MOFS). Cytokines, neutrophils, and endothelial adherence molecules initiate the disease process, with cell injury caused by oxidants and proteases released from inflammatory cells. ARDS, if progressive, will result in pulmonary fibrosis. Improved ventilatory support techniques have not been shown to decrease mortality. Pharmacologic manipulation of the inflammatory response is a more promising method of controlling the disease process.
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PMID:The modern version of adult respiratory distress syndrome. 759 56

The role of pulmonary fibroblasts (PFBs) in early adult respiratory distress syndrome is poorly understood. To investigate PFB cellular function in acute lung injury, New Zealand rabbits (2 to 3 kg) were given either three daily doses of phorbol myristate acetate (PMA; 65 micrograms/kg, IV), a potent stimulator of oxygen radical formation, or saline (control). On day 4, the lungs were harvested, subjected to enzymatic digestion, and PFBs isolated via serial subculture. Proliferation was assessed via 6-hour pulsed [3H]thymidine incorporation and by creating 5-day growth curves. Confluent PFB cultures were assessed for collagen production and total protein production, as well as interleukin (IL)-1 alpha secretion. Qualitative comparisons using transmission electron micrography were also made. There were no differences between PFBs harvested from control versus PMA-treated animals in terms of growth rates, total protein, and IL-1 alpha production. However, there was a significant difference in collagen production, with the PMA-treated animals' PFBs producing 35% more collagen than controls. Transmission electron micrography revealed PMA fibroblasts to be smaller (two to three times), have more dark staining granules, and have hypertrophied smooth endoplasmic reticulum--all consistent with increased metabolic activity. This suggests that pulmonary fibrosis, a late development in adult respiratory distress syndrome, may be triggered during the acute phase of lung injury. The increase in collagen synthesis is not related to PFB proliferation or the secretion of IL-1 alpha.
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PMID:Pulmonary fibroblast function in an acute lung injury model. 763 11

A progressive pulmonary disease resulting in severe respiratory failure and death in an average of 3 weeks was diagnosed in 11 young Dalmatian dogs. The dogs were from 4 litters, all genetically related by a common ancestor. The initial clinical signs were tachypnea and noisy respiration. Respiratory distress developed shortly before death and was characterized by strenuous and rapid respirations, along with cyanosis and vomiting. On blood gas analysis, there were severe arterial hypoxemia, hypercapnia, and marked alveolar-arterial oxygen difference. Radiographically, a diffuse pattern of alveolar, interstitial, and peribronchial densities was observed in the lungs. Most dogs developed pneumomediastinum and gastroesophageal intussusception in the terminal phase of the disease. There was no response to treatment with antibiotics, corticosteroids, diuretics, or oxygen. At necropsy, the lungs were wet, heavy, and relatively airless. Absence of 1 kidney in 2 dogs and severe internal hydrocephalus in 2 dogs were additional necropsy findings. Pulmonary histopathology included metaplasia and atypia of the alveolar and bronchiolar epithelium, a nonpurulent inflammatory reaction characterized mainly by mononuclear cells and macrophages, eosinophilic hyaline membrane formation, and focal pulmonary fibrosis. The histological manifestations were typical of acute lung injury. Clinically, the findings were consistent with adult respiratory distress syndrome (ARDS), except for the relatively long course. No known risk factors for ARDS, such as trauma, toxin exposure, infection, or endotoxemia could be identified. The relationship of the other abnormalities (ie, renal aplasia, hydrocephalus) to the pulmonary disease also remains obscure. An inherited defect is suspected, because segregation analysis of the 4 litters suggests autosomal recessive inheritance.
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PMID:Lung injury leading to respiratory distress syndrome in young Dalmatian dogs. 767 17

Amiodarone is an effective antidysrhythmic agent, restricted in use by the development of pulmonary toxicity. Several in vivo animal models have been used to study amiodarone-induced pulmonary toxicity. Intratracheal administration of amiodarone to the hamster has been used as a model for the critical amiodarone-induced pulmonary fibrosis (AIPF). In order to investigate the cellular mechanism of human AIPF, which occurs following oral or intravenous administration, an animal model of AIPF resulting from systemic administration of the drug would appear to be preferable. We have evaluated pulmonary toxicity following repeated intraperitoneal amiodarone administration to the hamster. Intraperitoneal treatment of hamsters for 1, 4, or 7 weeks with amiodarone (100 mg/kg/day) did not lead to pulmonary toxicity based on wet lung weight, hydroxyproline content, or histological examination. Furthermore, when comparing 1- and 7-week treatment groups, there was no pulmonary accumulation of either amiodarone or desethylamiodarone beyond levels found at 1 week. Therefore, failure to develop pulmonary toxicity may be due to an inability to accumulate sufficient amiodarone and/or desethylamiodarone. Intratracheal administration of amiodarone to rodents remains the only in vivo animal model for studying the mechanism(s) of AIPF.
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PMID:Resistance of the hamster to amiodarone-induced pulmonary toxicity following repeated intraperitoneal administration. 808 70

Paraquat (PQ) is a herbicide which is highly pneumotoxic by generating reactive oxygen intermediates (ROI). Pro-inflammatory cytokines, particularly IL-1 and TNF, have been implicated in some ROI-mediated pathologies, including bleomycin toxicity and ischaemia/reperfusion injury. We have studied the effect of PQ on the expression of the neutrophil chemotactic cytokine, IL-8, by human peripheral blood mononuclear cells (PBMC). While almost no IL-8 mRNA was detected in unstimulated cells, PQ (100 microM) induced high mRNA expression with a maximum at 24 h of incubation. While PQ did stimulate the appearance of IL-8 mRNA, no significant production of IL-8 protein was detected. However, PQ potentiated the production of IL-8 in the presence of 1 ng/ml of endotoxin (lipopolysaccharide, LPS). This was paralleled by an increased production of chemotactic activity for neutrophils, indicating that the IL-8 was actually bioactive. Stimulation of IL-8 mRNA by PQ was suppressed by IL-4 and by free radical scavengers (dimethylsulfoxide, mannitol). Increased IL-8 expression by PQ was also observed in the human pulmonary epithelial cell line A549 indicating that the effect of PQ was not specific for PBMC. These findings suggest that IL-8 might be involved in the pulmonary effects of PQ and that its production might be stimulated following an oxidative insult, and might clarify the pathogenetic mechanisms of adult respiratory distress syndrome (ARDS) or oxidant-induced pulmonary fibrosis.
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PMID:The pneumotoxicant paraquat induces IL-8 mRNA in human mononuclear cells and pulmonary epithelial cells. 814 10

A 58 year old man with arthralgia had been treated with antiinflammatory drugs since November, 1987. On March 1988, he was admitted to a local hospital because of jaundice. On April 18, exploratory laparotomy was done to look for the cause of continued jaundice. Macro-pathological and micropathological findings of the liver were compatible with those of intrahepatic cholestasis. On April 29, he was transferred to Kyushu University Hospital because of persistent jaundice. Physical examination showed jaundice, tachypnea and low grade fever. Laboratory examination showed elevated level of serum bilirubin, marked hypoxia and endotoxemia. Plain chest radiogram revealed ground-glass appearance in bilateral lung fields. He was diagnosed to be complicated with adult respiratory distress syndrome (ARDS). Glucocorticoid therapy and oxygen administration were started immediately. But pulmonary fibrosis developed and he died of respiratory failure. Histological findings of lung necropsy specimen were compatible with those of ARDS. These data strongly suggested that endotoxemia and reticuloendothelial dysfunction due to intrahepatic cholestasis had played important roles to develop ARDS.
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PMID:[A case of intrahepatic cholestasis following with adult respiratory distress syndrome]. 837 98

The authors reviewed the radiographic and computed tomographic (CT) appearances of abnormal air-filled spaces in the lung that develop in response to lung diseases. The major types of these lung diseases include infection, vessel-related or vascular-embolic disorders, bronchiectasis, emphysema, pulmonary fibrosis, adult respiratory distress syndrome and air-block diseases, and unusual disorders of the lung (such as Langerhans cell histiocytosis, Klippel-Trenaunay syndrome, and tracheolaryngeal papillomatosis). After studying the CT scans, conventional radiographs, and medical records of 150 patients with various abnormal air-filled spaces in their lungs and 300 lung specimens and the corresponding high-resolution CT scans, the authors concluded that mechanisms of air-space formation fall into five basic categories: (a) vascular occlusion or ischemic necrosis, (b) dilatation of the bronchi, (c) disruption of the elastic fiber network of the lung, (d) remodeling of the lung architecture and retractile fibrosis, and (e) multifactorial or unknown mechanisms.
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PMID:Abnormal air-filled spaces in the lung. 839 71

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

Bleomycin is a widely used antineoplastic drug which produces dose- and time-dependent interstitial pulmonary fibrosis in humans. The mechanism of bleomycin-induced lung injury is not well understood. However, current data show that bleomycin can generate reactive oxygen species such as superoxide and hydroxyl radicals. The antioxidant role of vitamin E in biological systems is well known. We investigated the effect of vitamin E on bleomycin-induced lung fibrosis in mice biochemically and histologically. Animals were divided into four groups: control, saline + vitamin E (S/Vit E), bleomycin + saline (Bleo/S) and bleomycin + vitamin E (Bleo/Vit E). Bleomycin was administered subcutaneously at a dose of 10 mg/kg in Bleo/S and Bleo/Vit E groups, and vitamin E was administered intraperitoneally at a dose of 15 mg/animal in S/Vit E and Bleo/Vit E groups twice weekly for 4 weeks. The control group received saline. As a marker of collagen amount or fibrosis in lung tissue, hydroxyproline and soluble protein content were measured and hydroxyproline/soluble protein ratio per gram wet lung tissue was calculated. For hydroxyproline and protein determinations, and histologic examination of lung tissue, 6 mice from the control and S/Vit E groups and 7 mice from the Bleo/S and Bleo/Vit E groups were killed at at 4, 6 and 8 weeks after administration of bleomycin. The mean hydroxyproline/soluble protein ratio of the Bleo/Vit E group was significantly lower than that of the Bleo/S group and significantly higher than those of the control and S/Vit E groups at 6 and 8 weeks (p < 0.05). Parallel with the biochemical findings, the grade of the histological lesions in the Bleo/Vit E group was lower than that in the Bleo/S group, but higher than those of the S/Vit E and control groups (p < 0.05). These results suggest that a high dose of vitamin E considerably reduces the fibrotic effect of bleomycin on lung tissue in mice.
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PMID:Vitamin E reduces bleomycin-induced lung fibrosis in mice: biochemical and morphological studies. 867 19

Procollagen-III peptide (PIIIP) has been suggested as a marker for hepatic veno-occlusive disease (VOD) after bone marrow transplantation (BMT). Using the RIA-gnost PIIIP assay, we examined frozen plasma samples from three groups of patients. The groups included (A) four patients with clinically proven VOD, (B) nine patients with remarkably uneventful post-BMT courses, and (C) patients with either early complications other than VOD or pulmonary fibrosis in their later course. In group A, PIIIP levels increased parallel to the clinical course, with maximum values of 2.7-5.5 units/ml. In group B, values did not exceed 1.4 units/ml. In group C, higher values were occasionally observed. In one patient with early relapse of a lymphoma PIIIP peaks correlated with episodes of fever and graft versus host disease (GVHD). In another patient mild VOD seems possible retrospectively. The highest levels ( > 15 units/ml) occurred in one patient with ileus. Several patients with interstitial pneumonia (IP), adult respiratory distress syndrome (ARDS), or lung fibrosis showed increases in PIIIP levels corresponding to the clinical course; most of these events occurred later than day 30 after BMT. One patient with severe GVHD of the liver showed a maximum of only 1.4 units/ml. PIIIP elevation correlated with clinical VOD and may help to differentiate it from hepatic GVHD. In the presence of other complications (pulmonary, gastrointestinal), some caution in interpreting the results may be advisable.
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PMID:Evaluation of procollagen-III peptide as a marker for veno-occlusive disease after bone marrow transplantation. 869 19


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