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)

The present investigation was designed to characterize the biochemical and connective tissue components and to correlate the significance of morphological and biochemical perturbations in cyclophosphamide (CP)-induced lung fibrosis in rats. Lung fibrosis was induced in male Wistar rats by intraperitoneal injection of 20 mg/100 g body weight of CP, and their pneumotoxic derangements were characterized during an early destructive phase followed by a proliferative and synthetic phase. Serum angiotensin-converting enzyme (ACE) activity was higher in CP-treated rats at days 2, 3, 5, 7, and 11, but there was a significant decrease in lung ACE activity during the same time period. Elevated levels of beta-glucuronidase activity were observed in the lung lavage fluid of CP-administered rats days 2, 3, 5, and 7. Lung myeloperoxidase activity was higher in CP rats. Of significance was the presence of collagenase and collagenolytic cathepsin in the lavage fluid of CP rats, when compared with the barely detectable levels in controls. A similar increase in these enzyme activities was also noticed in the lung tissue of CP rats during the same experimental period. Lavage fluid hydroxyproline content was higher in CP rats when compared with controls. Similarly, lung protein and DNA levels were elevated significantly after treatment with CP. The pulmonary histamine and serotonin contents were significantly higher in CP rats. The incorporation of [3H]thymidine into lung total DNA, [3H]proline into lung hydroxyproline, and [35S]sulphate into lung glycosaminoglycan, measured as indicators of lung DNA, collagen, and glycosaminoglycan synthesis, respectively, was also higher in CP groups. Increased levels of hydroxyproline, elastin, hexosamine, total hexose, fucose, sialic acid, and uronic acid in the lungs of rats 14, 28, and 42 days after CP insult were characterized as biomarkers of CP-induced interstitial changes. These findings indicate that CP-induced lung fibrosis results in alterations not only in collagen synthesis and accumulation, but also in glycosaminoglycan and glycoprotein content.
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PMID:Biochemical and connective tissue changes in cyclophosphamide-induced lung fibrosis in rats. 977 51

Guinea pigs infected with M. tuberculosis were studied for parameters relating to fibrosis following infection. The infected animals were followed up to a period of 44 wk and the changes that occurred in the lung, liver and spleen were studied. Corresponding tissues from animals injected with bleomycin, an anti-mitotic drug which has the ability to produce pulmonary fibrosis, served as positive controls. Tissue collagen, elastin and hexosamines were estimated biochemically. The presence of granuloma and stainable collagen in paraffin sections of these tissues was also studied. Establishment of the infection was assessed bacteriologically by culturing the viable organisms from the spleen. It was observed that a self-limiting infection was established in the guinea pigs and none of the animals died of the infection. In the infected animals, collagen, elastin and hexosamines showed an initial decrease followed by an increase. While the elastin and the hexosamine levels returned to the basal levels in all the three organs, collagen levels increased in the lung and were comparable to those of the bleomycin control. Collagen stainable by Van Gieson's method was found to be increased in the lung from the 4th wk onwards. The present report indicates the potential of adopting this system for studying mechanisms of fibrogenesis in tuberculous infection.
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PMID:Biochemical & histochemical changes relating to fibrosis following infection with Mycobacterium tuberculosis in the guinea pig. 1061 10

Elastin is a chief component of lung interstitium, and it is central to lung morphology and function. Efforts to understand the pathogenesis of pulmonary fibrosis have focused primarily upon collagen turnover in the lung; few studies have focused on elastin. In this study, we examined steady-state elastin mRNA levels after lung injury in the mouse induced by (1) butylated hydroxytoluene (BHT) which causes acute lung injury with recovery, (2) BHT + 70% O2 (fibrosis), or (3) 70% O2. Total lung elastin mRNA increased 70-80-fold on d10-14 after BHT/O2, but was unchanged after BHT or O2 alone. In situ hybridization studies localized elastin mRNA to cells in the muscularis of conducting airways and to scattered interstitial cells in fibrotic foci. Elastic fiber morphology was markedly distorted after BHT/O2. Thus, marked upregulation of elastin gene expression is correlated with the histopathology of fibrotic lung disease.
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PMID:Elastin gene expression is upregulated during pulmonary fibrosis. 1076 39

Increased expression of matrix metalloproteinases, particularly gelatinase B (MMP-9), has been described in the lungs in pulmonary fibrosis. Intratracheal bleomycin is often used experimentally to produce lesions resembling human fibrosing alveolitis. To assess the role of gelatinase B in bleomycin-induced fibrosing alveolitis, we instilled bleomycin intratracheally into gelatinase B-deficient mice and gelatinase B+/+ littermates. Twenty-one days after bleomycin the two groups of mice were indistinguishable in terms of pulmonary histology and total lung collagen and elastin. However, the lungs of gelatinase B-deficient mice showed minimal alveolar bronchiolization, whereas bronchiolization was prominent in the lungs of gelatinase B+/+ mice. Gelatinase B was identified immunohistochemically in terminal bronchiolar cells and bronchiolized cells 7 and 14 days after bleomycin in gelatinase B+/+ mice, and whole lung gelatinase B mRNA was increased at the same times. Many bronchiolized cells displayed Clara cell features by electron microscopy. Some bronchiolized cells stained with antibody to helix transcription factor 4, a factor associated with the ciliated cell phenotype. Thus, fibrosing alveolitis develops after intratracheal bleomycin irrespective of gelatinase B. However, gelatinase B is required for alveolar bronchiolization, perhaps by facilitating migration of Clara cells and other bronchiolar cells into the regions of alveolar injury.
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PMID:Gelatinase B is required for alveolar bronchiolization after intratracheal bleomycin. 1093 55

This paper maintains that negative intrapleural pressure is a prerequisite for the appearance of emphysema, either simply by the enlargement of the air space in combination with elastolytic enzymatic factors, or, frequently, by its contribution to the breakdown of collagen and elastin fibers through the increase in intrapulmonary pressures. Hence the factors that make the intrapleural pressure more negative play an indirect part in causing emphysema. Thus the development of collagen fibers, whatever its cause, gives rise to a reduction in the lung compliance which may produce more negative intrapleural pressure and, in consequence, an increase in the intrapulmonary pressures. The development of collagen fibers also contributes to the unequal distribution of these pressures in various regions, including the microenvironment of the lung, resulting in the breakdown of fibers in some areas due to the powerful forces that develop in them. It is by this mechanism that the development of collagen fibers contributes to the development of emphysema in areas that have suffered damage, in combination with enzymatic factors or even without them. Moreover, the intensified functioning of the respiratory muscles which may result from a reduction in the functional capacity of the lung parenchyma may also contribute indirectly to the pathogenesis of emphysema through the more negative intrapleural pressure. A chest radiogram cannot distinguish what is occurring in the microenvironment of the lung; it can, however, follow from a distance the overall changes throughout the subjects' lives. The present work is the product of such a follow-up. Chest radiograms show that very often the pulmonary fibrosis may be combined with emphysema or may precede the emphysema. The more negative the intrapleural pressure becomes, the greater its role in the production of emphysema. It is claimed that the form of the emphysema depends on the conditions created in the lung microenvironment and that negative intrapleural pressure plays a greater or lesser role in all forms of emphysema, including panacinar emphysema.
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PMID:The contribution of intrapleural pressures to the pathogenesis of emphysema. 1560 59

As many metalloproteinases (MMPs), macrophage elastase (MMP-12) is able to degrade extracellular matrix components such as elastin and is involved in tissue remodeling processes. Studies using animal models of acute and chronic pulmonary inflammatory diseases, such as pulmonary fibrosis and chronic obstructive pulmonary disease (COPD), have given evidences that MMP-12 is an important mediator of the pathogenesis of these diseases. However, as very few data regarding the direct involvement of MMP-12 in inflammatory process in the airways were available, we have instilled a recombinant form of human MMP-12 (rhMMP-12) in mouse airways. Hence, we have demonstrated that this instillation induced a severe inflammatory cell recruitment characterized by an early accumulation of neutrophils correlated with an increase in proinflammatory cytokines and in gelatinases and then by a relatively stable recruitment of macrophages in the lungs over a period of ten days. Another recent study suggests that resident alveolar macrophages and recruited neutrophils are not involved in the delayed macrophage recruitment. However, epithelial cells could be one of the main targets of rhMMP-12 in our model. We have also reported that a corticoid, dexamethasone, phosphodiesterase 4 inhibitor, rolipram and a non-selective MMP inhibitor, marimastat could reverse some of these inflammatory events. These data indicate that our rhMMP-12 model could mimic some of the inflammatory features observed in COPD patients and could be used for the pharmacological evaluation of new anti-inflammatory treatment. In this review, data demonstrating the involvement of MMP-12 in the pathogenesis of pulmonary fibrosis and COPD as well as our data showing a pro-inflammatory role for MMP-12 in mouse airways will be summarized.
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PMID:Macrophage elastase (MMP-12): a pro-inflammatory mediator? 1596 17

Matrix metalloproteinases (MMPs) are a major group of proteases known to regulate extracellular matrix (ECM) turnover and so they have been suggested to be important in the process of lung disease associated with tissue remodeling. This has led to the concept that modulation of airway remodeling including excessive proteolysis damage to the tissue may be of interest for future treatment. Within the MMP family, macrophage elastase (MMP-12) is able to degrade ECM components such as elastin and is involved in tissue remodeling processes in chronic obstructive pulmonary disease including emphysema. Pulmonary fibrosis has an aggressive course and is usually fatal within an average of 3 to 6 years after the onset of symptoms. Pulmonary fibrosis is associated with deposition of ECM components in the lung interstitium. The excessive airway remodeling as a result of an imbalance in the equilibrium of the normal processes of synthesis and degradation of ECM components could justify anti-protease treatments. Indeed, the correlation of the differences in hydroxyproline levels in the lungs of bleomycin-treated mice strongly suggests that a reduced molar pro-MMP-9/TIMP-1 ratio in bronchoalveolar lavage fluid is associated with collagen deposition, beginning as early as the inflammatory events at day 1 after bleomycin administration. Finally, these observations emphasize that effective treatment of these disorders must be started early during the natural history of the disease, prior to the development of extensive lung destruction and fibrosis.
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PMID:Role of matrix metalloproteinases in the development of airway inflammation and remodeling. 1617 45

Fundamental physical properties, such as the intrinsic recoil of the lung, are governed by the extracellular matrix. The prototypical roles of the matrix proteins, collagen and elastin, in pulmonary fibrosis and emphysema have long been recognized, and much research effort has been devoted to understanding mechanisms of extracellular matrix synthesis and turnover in the lung. Yet, despite extensive knowledge of the biochemical properties of collagen and elastin, none of the present clinical strategies for treating COPD directly target the extracellular matrix. From a matrix perspective, therapeutic interventions that limit elastic fiber destruction and/or restore function to damaged alveolar units merit particular consideration as clinical strategies for treating the emphysema component of COPD. Effective treatment of the bronchiolar component of COPD requires a better understanding of the relationship between airway fibrosis and airflow obstruction. Translating basic knowledge of extracellular matrix biology into the clinical venue will be essential in the development of new approaches to COPD treatment.
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PMID:Treatment of COPD: a matrix perspective. 1848 34

Platelet-derived growth factor-A and its receptor, platelet-derived growth factor receptor-alpha (PDGF-Ralpha), are required for formation of the secondary pulmonary alveolar septa in mice. However, it remains unclear how these molecules direct the secondary septation process. We have examined the abundance, location, and the accumulation of alpha-smooth muscle actin (alphaSMA), neutral lipid droplets, and elastin in the proximity of PDGF-Ralpha-expressing alveolar cells during postnatal days 4 through 12 in the mouse. PDGF-Ralpha-expressing cells preferentially have characteristics of myofibroblasts and were more likely to contain alphaSMA than are alveolar cells that do not express PDGF-Ralpha. PDGF-Ralpha expressing cells were preferentially located in the alveolar entry ring (AER) where alphaSMA and elastic fibers accumulate. In contrast, PDGF-Ralpha expression inversely correlated with neutral lipid accumulation, which was more prominent at the alveolar base, distant from the AER. PDGF-Ralpha-expressing alveolar cells accumulate in the AER where they may promote mechanical stability during respiration. In addition to defining how alveolar septa form, these findings may have implications for the treatment of diseases which involve alveolar effacement such as emphysema and pulmonary fibrosis.
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PMID:Platelet-derived growth factor receptor-alpha-expressing cells localize to the alveolar entry ring and have characteristics of myofibroblasts during pulmonary alveolar septal formation. 1883 69

Acute respiratory distress syndrome (ARDS), the most severe manifestation of acute lung injury (ALI), is described as a stereotyped response to lung injury with a transition from alveolar capillary damage to a fibroproliferative phase. Most ARDS patients survive the acute initial phase of lung injury and progress to either reparation of the lesion or evolution of the syndrome. Despite advances in the management of ARDS, mortality remains high (40%) and autopsies show extended pulmonary fibrosis in 55% of patients, suggesting the importance of deregulated repair in the morbidity and mortality of these patients. Factors influencing progression to fibroproliferative ARDS versus resolution and reconstitution of the normal pulmonary parenchymal architecture are poorly understood. Abnormal repair and remodeling may be profoundly affected by both environmental and genetic factors. In this line, mechanical ventilation may affect the macromolecules that constitute the extracellular matrix (collagen, elastin, fibronectin, laminin, proteoglycan and glycosaminoglycans), suffer changes and impact the biomechanical behavior of lung parenchyma. Furthermore, evidence suggests that acute inflammation and fibrosis may be partially independent and/or interacting processes that are autonomously regulated, and thus amenable to individual and specific therapies. In this review, we explore recent advances in the field of fibroproliferative ARDS/ALI, with special emphasis on 1) the physiological properties of the extracellular matrix, 2) the mechanisms of remodeling, 3) the impact of mechanical ventilation on lung fibrotic response, and (4) therapeutic interventions in the remodeling process.
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PMID:Lung parenchyma remodeling in acute respiratory distress syndrome. 1994 Aug 26


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