elastin and Pulmonary-Fibrosis

The lung is a delicately balanced and highly integrated mechanical system. Lung tissue is continuously exposed to the environment via the air we breathe, making it susceptible to damage. As a consequence, respiratory diseases present a huge burden on society and their prevalence continues to rise. Emergent function is produced not only by the sum of the function of its individual components but also by the complex feedback and interactions occurring across the biological scales - from genes to proteins, cells, tissue and whole organ - and back again. Computational modeling provides the necessary framework for pulling apart and putting back together the pieces of the body and organ systems so that we can fully understand how they function in both health and disease. In this review, we discuss models of lung tissue mechanics spanning from the protein level (the extracellular matrix) through to the level of cells, tissue and whole organ, many of which have been developed in isolation. This is a vital step in the process but to understand the emergent behavior of the lung, we must work towards integrating these component parts and accounting for feedback across the scales, such as mechanotransduction. These interactions will be key to unlocking the mechanisms occurring in disease and in seeking new pharmacological targets and improving personalized healthcare.

Topics: Collagen; Computer Simulation; Disease Progression; Elastin; Extracellular Matrix; Humans; Lung; Mechanotransduction, Cellular; Models, Biological; Proteoglycans; Pulmonary Alveoli; Pulmonary Fibrosis

Elastic fibres are present in lung structures including alveoli, alveolar ducts, airways, vasculature and pleura. The rate of lung elastin synthesis is greatest during fetal and neonatal development, and is minimal in the healthy adult. We have determined that glucocorticoids up-regulate fetal lung tropoelastin expression while concomitantly accelerating terminal airspace maturation. Because there is minimal turnover of elastin in healthy adult lung, the elastin incorporated into the lung early in development supports lung function for the normal lifespan. However, in the adult lung, in pathological circumstances such as emphysema or pulmonary fibrosis there may be reactivation of elastin expression. We have found in silica-induced pulmonary fibrosis that expression of tropoelastin is primarily increased in the walls and the septal tips of the alveolus, with modest increases in other compartments which normally express tropoelastin during development. This finding suggests that the mesenchymal cell of the alveolar wall increases tropoelastin expression during fibrotic disorders. In emphysema and fibrosis, elastin is present in abnormal-appearing, probably non-functional, elastic fibres, suggesting that the adult lung cannot recapitulate the elastic fibre assembly mechanisms operative during normal lung growth.

Topics: Adult; Animals; Elastin; Fetus; Humans; Lung; Pulmonary Emphysema; Pulmonary Fibrosis

Various elastases classes normally reside in alveolar structure and are liable to degrade the elastin as well as the other macromolecular components of pulmonary extracellular matrix (collagen, proteoglycans, fibronectin...), during lung injury. The most are the polymorphonuclear or monocyte serine elastase and the macrophage metallo and cysteine elastases. Metalloelastase may also arise from pathogenic bacteria as Pseudomonas aeruginosa. In another part proteases elastase-type from fibroblasts, endothelial cells or alveolar macrophages might to be involved into the remodelling of lung connective tissue or pulmonary cells differentiation and activation. The regulation of elastolytic activities, is supported both by activators (as plasminogen activator...) and inhibitors (alpha 1 Pi, 2M, BrI, TIMP, bacterial inhibitors...). These inhibitors are mostly generated in situ from macrophages, monocytes or polymorphonuclear cells so allowing to control fast local elastolytic activity. Since alveolar macrophage can internalize leucocyte elastase, synthetize metalloelastases, and secrete their inhibitors and activators, it plays a complex role in the lung defense and during various pulmonary pathogenesis. In conclusion, the lung response to bacterial or viral infections, the intensity of alveolitis, the nature and the gravity of emphysematous or fibrotic lung lesions, as well as the tumour growth or metastatic pulmonary invasion may depend upon the lung elastolytic activities.

Topics: Animals; Elastin; Endopeptidases; Humans; Lung; Lung Diseases; Pancreatic Elastase; Pulmonary Alveoli; Pulmonary Emphysema; Pulmonary Fibrosis

Topics: Aerosols; alpha 1-Antitrypsin Deficiency; Animals; Blood Platelets; Cadmium; Collagen; Disease Models, Animal; Elastin; Emphysema; Forecasting; Hexanes; Lathyrism; Macrophages; Mice; Mice, Mutant Strains; Microscopy, Electron; Neutrophils; Nutrition Disorders; Oxygen; Pancreatic Elastase; Papain; Physical Exertion; Pulmonary Fibrosis; Pulmonary Gas Exchange; Pulmonary Heart Disease; Respiration; Trypsin

Topics: Animals; Chemotaxis; Collagen; Connective Tissue; Connective Tissue Diseases; Elastin; Fibronectins; Humans; Lung; Phagocytosis; Pneumonia; Proteoglycans; Pulmonary Emphysema; Pulmonary Fibrosis

Transforming growth factor-β (TGF-β) has a strong impact on the pathogenesis of pulmonary fibrosis. Therefore, in this study, we investigated whether derrone promotes anti-fibrotic effects on TGF-β1-stimulated MRC-5 lung fibroblast cells and bleomycin-induced lung fibrosis. Long-term treatment with high concentrations of derrone increased the cytotoxicity of MRC-5 cells; however, substantial cell death was not observed at low concentrations of derrone (below 0.05 μg/mL) during a three-day treatment. In addition, derrone significantly decreased the expressions of TGF-β1, fibronectin, elastin, and collagen1α1, and these decreases were accompanied by downregulation of α-SMA expression in TGF-β1-stimulated MRC-5 cells. Severe fibrotic histopathological changes in infiltration, alveolar congestion, and alveolar wall thickness were observed in bleomycin-treated mice; however, derrone supplementation significantly reduced these histological deformations. In addition, intratracheal administration of bleomycin resulted in lung collagen accumulation and high expression of α-SMA and fibrotic genes-including TGF-β1, fibronectin, elastin, and collagen1α1-in the lungs. However, fibrotic severity in intranasal derrone-administrated mice was significantly less than that of bleomycin-administered mice. Molecular docking predicted that derrone potently fits into the ATP-binding pocket of the TGF-β receptor type 1 kinase domain with stronger binding scores than ATP. Additionally, derrone inhibited TGF-β1-induced phosphorylation and nuclear translocations of Smad2/3. Overall, derrone significantly attenuated TGF-β1-stimulated lung inflammation in vitro and bleomycin-induced lung fibrosis in a murine model, indicating that derrone may be a promising candidate for preventing pulmonary fibrosis.

Topics: Adenosine Triphosphate; Animals; Bleomycin; Elastin; Fibroblasts; Fibronectins; Lung; Mice; Mice, Inbred C57BL; Molecular Docking Simulation; Pulmonary Fibrosis; Signal Transduction; Transforming Growth Factor beta1

Fibrotic diseases are characterized by progressive and often irreversible scarring of connective tissue in various organs, leading to substantial changes in tissue mechanics largely as a result of alterations in collagen structure. This is particularly important in the lung because its bulk modulus is so critical to the volume changes that take place during breathing. Nevertheless, it remains unclear how fibrotic abnormalities in the mechanical properties of pulmonary connective tissue can be linked to the stiffening of its individual collagen fibers. To address this question, we developed a network model of randomly oriented collagen and elastin fibers to represent pulmonary alveolar wall tissue. We show that the stress-strain behavior of this model arises via the interactions of collagen and elastin fiber networks and is critically dependent on the relative fiber stiffnesses of the individual collagen and elastin fibers themselves. We also show that the progression from linear to nonlinear stress-strain behavior of the model is associated with the percolation of stress across the collagen fiber network, but that the location of the percolation threshold is influenced by the waviness of collagen fibers.

Topics: Biomechanical Phenomena; Collagen; Elastin; Humans; Models, Biological; Pulmonary Alveoli; Pulmonary Fibrosis; Stress, Mechanical

Glutaminolysis is the metabolic process of glutamine, aberration of which has been implicated in several pathogeneses. Although we and others recently found a diversity of metabolic dysregulation in organ fibrosis, it is unknown if glutaminolysis regulates the profibrotic activities of myofibroblasts, the primary effector in this pathology. In this study, we found that lung myofibroblasts demonstrated significantly augmented glutaminolysis that was mediated by elevated glutaminase 1 (Gls1). Inhibition of glutaminolysis by specific Gls1 inhibitors CB-839 and BPTES as well as Gls1 siRNA blunted the expression of collagens but not that of fibronectin, elastin, or myofibroblastic marker smooth muscle actin-α. We found that glutaminolysis enhanced collagen translation and stability, which were mediated by glutaminolysis-dependent mTOR complex 1 activation and collagen proline hydroxylation, respectively. Furthermore, we found that the amount of the glutaminolytic end product α-ketoglutarate (α-KG) was increased in myofibroblasts. Similar to glutaminolysis, α-KG activated mTOR complex 1 and promoted the expression of collagens but not of fibronectin, elastin, or smooth muscle actin-α. α-KG also remarkably inhibited collagen degradation in fibroblasts. Taken together, our studies identified a previously unrecognized mechanism by which a major metabolic program regulates the exuberant production of collagens in myofibroblasts and suggest that glutaminolysis is a novel therapeutic target for treating organ fibrosis, including idiopathic pulmonary fibrosis.

Topics: Actins; Animals; Benzeneacetamides; Cells, Cultured; Collagen; Disease Models, Animal; Elastin; Enzyme Activation; Fibronectins; Glutaminase; Glutamine; Humans; Hydroxylation; Ketoglutaric Acids; Mice; Mice, Inbred C57BL; Myofibroblasts; Proline; Pulmonary Fibrosis; RNA Interference; RNA, Small Interfering; Sulfides; Thiadiazoles; TOR Serine-Threonine Kinases

Pulmonary fibrosis is a progressive scarring disorder of the lung with dismal prognosis and no curative therapy. Clusterin, an extracellular chaperone and regulator of cell functions, is reduced in bronchoalveolar lavage fluid of patients with pulmonary fibrosis. However, its distribution and role in normal and fibrotic human lung are incompletely characterized. Immunohistochemical localization of clusterin revealed strong staining associated with fibroblasts in control lung and morphologically normal areas of fibrotic lung but weak or undetectable staining in fibrotic regions and particularly fibroblastic foci. Clusterin also co-localized with elastin in vessel walls and additionally with amorphous elastin deposits in fibrotic lung. Analysis of primary lung fibroblast isolates in vitro confirmed the down-regulation of clusterin expression in fibrotic compared with control lung fibroblasts and further demonstrated that TGF-β

Topics: Bronchoalveolar Lavage Fluid; Cell Differentiation; Cells, Cultured; Clusterin; Down-Regulation; Elastin; Female; Fibroblasts; Humans; Lung; Male; Middle Aged; Protective Agents; Pulmonary Fibrosis; Signal Transduction; Transforming Growth Factor beta1

Although fibrosis and emphysema are in many ways on opposite ends of the pulmonary parenchymal disease spectrum, they seem to share common pathomechanistic steps. This is illustrated by the coexistence of both entities in lungs of individuals with combined pulmonary fibrosis and emphysema. Macroproteins elastin and collagen are major constituents of the pulmonary extracellular matrix. The prevailing paradigm states that emphysema is caused by an imbalance between destructive proteolytic and protective antiproteolytic enzymes leading to accelerated degradation of elastin fibers in the lungs. Rates of elastin breakdown, however, are equally enhanced in patients with idiopathic pulmonary fibrosis (IPF) and emphysema. Excessive accumulation of collagen is a hallmark of IPF. Surprisingly, collagen levels in the lung parenchyma of patients with emphysema are also higher than in controls. The concentration of elastin fibers is elevated in fibrotic lungs, despite accelerated elastinolysis, suggesting that elastin repair is also enhanced in IPF. Since elastin concentrations are reduced in emphysematous lungs, the factor of divergence between emphysema and fibrosis seems to be the degree of elastin repair. Multiple elastin repair steps can be deduced of which tropoelastin synthesis and crosslinking of tropoelastin polymers by the copper dependent enzyme lysyl oxidase seem to be the most important ones. We suspect that the distinction in the pathogeneses of lung fibrosis and emphysema depends on the local availability of copper to activate sufficient lysyl oxidase for elastin crosslinking, and suggest assessing the effects of inhalation therapy with copper plus heparin in emphysema and heparin monotherapy in IPF.

Topics: Animals; Collagen; Copper; Elastin; Extracellular Matrix; Heparin; Humans; Lung; Male; Mice; Middle Aged; Pulmonary Emphysema; Pulmonary Fibrosis; Smoking; Tropoelastin

Lung fibrosis is characterized by excessive deposition of extracellular matrix. This not only affects tissue architecture and function, but it also influences fibroblast behavior and thus disease progression. Here we describe the expression of elastin, type V collagen and tenascin C during the development of bleomycin-induced lung fibrosis. We further report in vitro experiments clarifying both the effect of myofibroblast differentiation on this expression and the effect of extracellular elastin on myofibroblast differentiation. Lung fibrosis was induced in female C57Bl/6 mice by bleomycin instillation. Animals were sacrificed at zero to five weeks after fibrosis induction. Collagen synthesized during the week prior to sacrifice was labeled with deuterium. After sacrifice, lung tissue was collected for determination of new collagen formation, microarray analysis, and histology. Human lung fibroblasts were grown on tissue culture plastic or BioFlex culture plates coated with type I collagen or elastin, and stimulated to undergo myofibroblast differentiation by 0-10 ng/ml transforming growth factor (TGF)β1. mRNA expression was analyzed by quantitative real-time PCR. New collagen formation during bleomycin-induced fibrosis was highly correlated to gene expression of elastin, type V collagen and tenascin C. At the protein level, elastin, type V collagen and tenascin C were highly expressed in fibrotic areas as seen in histological sections of the lung. Type V collagen and tenascin C were transiently increased. Human lung fibroblasts stimulated with TGFβ1 strongly increased gene expression of elastin, type V collagen and tenascin C. The extracellular presence of elastin increased gene expression of the myofibroblastic markers α smooth muscle actin and type I collagen. The extracellular matrix composition changes dramatically during the development of lung fibrosis. The increased levels of elastin, type V collagen and tenascin C are probably the result of increased expression by fibroblastic cells; reversely, elastin influences myofibroblast differentiation. This suggests a reciprocal interaction between fibroblasts and the extracellular matrix composition that could enhance the development of lung fibrosis.

Topics: Animals; Bleomycin; Cell Differentiation; Collagen Type V; Elastin; Female; Fibroblasts; Gene Expression Regulation, Developmental; Humans; Lung; Mice; Myofibroblasts; Pulmonary Fibrosis; Tenascin

This study presents four patients who underwent bone marrow transplantation and subsequently developed pleuroparenchymal fibroelastosis, hitherto reported as an idiopathic condition. All presented clinically with pneumothorax and subpleural fibrosis on high-resolution computed tomography. In addition to the expected obliterative bronchiolitis, histopathology showed coexistent subpleural changes, and the relationship of pathology in multiple anatomic compartments in post bone marrow transplantation pulmonary disease is discussed.

Topics: Adolescent; Adult; Autopsy; Bone Marrow Transplantation; Bronchiolitis Obliterans; Elastin; Fatal Outcome; Female; Glucocorticoids; Humans; Lung; Male; Middle Aged; Pleural Diseases; Pneumonectomy; Pneumothorax; Pulmonary Fibrosis; Recurrence; Thoracic Surgery, Video-Assisted; Tomography, X-Ray Computed; Treatment Outcome; Young Adult

Altered transforming growth factor (TGF)-β expression levels have been linked to a variety of human respiratory diseases, including bronchopulmonary dysplasia and pulmonary fibrosis. However, a causative role for aberrant TGF-β in neonatal lung diseases has not been defined in primates. Exogenous and transient TGF-β1 overexpression in fetal monkey lung was achieved by transabdominal ultrasound-guided fetal intrapulmonary injection of adenoviral vector expressing TGF-β1 at the second or third trimester of pregnancy. The lungs were then harvested near term, and fixed for histology and immunohistochemistry. Lung hypoplasia was observed where TGF-β1 was overexpressed during the second trimester. The most clearly marked phenotype consisted of severe pulmonary and pleural fibrosis, which was independent of the gestational time point when TGF-β1 was overexpressed. Increased cell proliferation, particularly in α-smooth muscle actin-positive myofibroblasts, was detected within the fibrotic foci. But epithelium to mesenchyme transdifferentiation was not detected. Massive collagen fibres were deposited on the inner and outer sides of the pleural membrane, with an intact elastin layer in the middle. This induced fibrotic pathology persisted even after adenoviral-mediated TGF-β1 overexpression was no longer evident. Therefore, overexpression of TGF-β1 within developing fetal monkey lung results in severe and progressive fibrosis in lung parenchyma and pleural membrane, in addition to pulmonary hypoplasia.

Topics: Animals; Azo Compounds; Cell Proliferation; Elastin; Female; Fibrosis; Gene Expression Regulation, Developmental; Haplorhini; Humans; Lung; Macaca mulatta; Pregnancy; Pregnancy, Animal; Pulmonary Fibrosis; Transforming Growth Factor beta1

Topics: Aged; Autoantibodies; Case-Control Studies; Cohort Studies; Elastin; Emphysema; Female; Humans; Male; Middle Aged; Pulmonary Fibrosis; Smoking

The mechanical dysfunction accompanying parenchymal diseases such as pulmonary fibrosis and emphysema may follow a different course from the progression of the underlying microscopic pathophysiology itself, particularly in the early stages. It is tempting to speculate that this may reflect the geographical nature of lung pathology. However, merely ascribing mechanical dysfunction of the parenchyma to the vagaries of lesional organization is unhelpful without some understanding of how the two are linked.. We attempt to forge such a link through a concept known as percolation, which has been invoked to account for numerous natural processes involving transmission of events across complex networks.. We numerically determined the bulk stiffness (corresponding to the inverse of lung compliance) of a network of springs representing the lung parenchyma. We simulated the development of fibrosis by randomly stiffening individual springs in the network, and the development of emphysema by preferentially cutting springs under the greatest tension.. When the number of stiff springs was increased to the point that they suddenly became connected across the network, the model developed a sharp increase in its bulk modulus. Conversely, when the cut springs became sufficiently numerous, the elasticity of the network fell to zero. These two conditions represent percolation thresholds that we show are mirrored structurally in both tissue pathology and macroscopic computed tomography images of human idiopathic fibrosis and emphysema.. The concept of percolation may explain why the development of symptoms related to lung function and the development of parenchymal pathology often do not progress together.

Topics: Collagen; Disease Progression; Elastin; Humans; Lung; Lung Compliance; Microscopy, Electron, Scanning; Models, Biological; Nonlinear Dynamics; Pulmonary Emphysema; Pulmonary Fibrosis; Severity of Illness Index; Tomography, X-Ray Computed

This study tested the hypotheses that chronic allergic inflammation induces not only bronchial but also lung parenchyma remodeling, and that these histologic changes are associated with concurrent changes in respiratory mechanics. For this purpose, airway and lung parenchyma remodeling were evaluated by quantitative analysis of collagen and elastin, immunohistochemistry (smooth-muscle actin expression, eosinophil, and dendritic cell densities), and electron microscopy. In vivo (airway resistance, viscoelastic pressure, and static elastance) and in vitro (tissue elastance, resistance, and hysteresivity) respiratory mechanics were also analyzed. BALB/c mice were sensitized with ovalbumin and exposed to repeated ovalbumin challenges. A marked eosinophilic infiltration was seen in lung parenchyma and in large and distal airways. Neutrophils, lymphocytes, and dendritic cells also infiltrated the lungs. There was subepithelial fibrosis, myocyte hypertrophy and hyperplasia, elastic fiber fragmentation, and increased numbers of myofibroblasts in airways and lung parenchyma. Collagen fiber content was increased in the alveolar walls. The volume proportion of smooth muscle-specific actin was augmented in distal airways and alveolar duct walls. Airway resistance, viscoelastic pressure, static elastance, and tissue elastance and resistance were significantly increased. In conclusion, prolonged allergen exposure induced remodeling not only of the airway wall but also of the lung parenchyma, leading to in vivo and in vitro mechanical changes.

Topics: Actins; Airway Resistance; Animals; Asthma; Bronchi; Collagen; Disease Models, Animal; Elastin; Hyperplasia; Hypertrophy; In Vitro Techniques; Lung; Mice; Mice, Inbred BALB C; Microscopy, Electron; Muscle, Smooth; Pulmonary Alveoli; Pulmonary Eosinophilia; Pulmonary Fibrosis; Respiratory Hypersensitivity; Respiratory Mechanics

We investigated in vivo and in vitro oscillatory mechanics in bleomycin-induced fibrotic lungs and correlated these with morphometric changes in the collagen-elastin matrix and contractile cells. Fischer rats received bleomycin sulfate (BLEO,1.5 U) or saline intratracheally. Four weeks later tracheal flow and tracheal and alveolar pressure (using alveolar capsules) were measured in open-chested rats during mechanical ventilation (V T = 8 ml/kg, f = 1 Hz, PEEP = 4 cm H(2)O). Total lung, tissue, and airway resistance (R) and lung elastance (E) were calculated. In addition, excised parenchymal strips (10 x 2 x 2 mm) were studied in the organ bath. Strips were attached to a force transducer at one end and to a servo-controlled lever arm that effected length (L) changes at the other. Sinusoidal oscillations were applied (f = 1 Hz, amplitude = 2. 5% resting L and tension = 0.7 g) and R, E, and hysteresivity (eta) were calculated. Strips were then exposed to acetylcholine (ACh, 10(-)(3) M). The amount of collagen and elastic fibers in the parenchymal strip was assessed semiquantitatively by point-counting in 5-micrometer-thick sections stained with either Sirius Red or Weigert's Resorcin-fuchsin. alpha-Smooth-muscle-specific actin was detected immunohistochemically. Both in vivo and in vitro, R, E, and eta were significantly increased in BLEO rats (p < 0.05). The % increase in R, E and eta after Ach was greater in BLEO rats (p < 0. 01). There was also a significant increase in the volume proportion of collagen, elastic fibers, and actin in the parenchyma (p < 0.01). In BLEO rats, baseline R and E were correlated with the volume proportion of collagen in the parenchyma. We conclude that changes in the collagen-elastin matrix contribute to changes in the viscoelastic properties of bleomycin-treated rat lungs. Dolhnikoff M, Mauad T, Ludwig MS. Extracellular matrix and oscillatory mechanics of rat lung parenchyma in bleomycin-induced fibrosis.

Topics: Acetylcholine; Actins; Airway Resistance; Animals; Bleomycin; Collagen; Elasticity; Elastin; Extracellular Matrix; Immunohistochemistry; In Vitro Techniques; Lung; Muscle, Smooth; Pulmonary Fibrosis; Rats; Rats, Inbred F344; Stress, Mechanical; Viscosity

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.

Topics: Animals; Blotting, Northern; Butylated Hydroxytoluene; Elastin; Gene Expression; In Situ Hybridization; Lung; Male; Mice; Mice, Inbred BALB C; Pulmonary Fibrosis; RNA, Messenger; Up-Regulation

Transforming growth factor (TGF)-beta1 has been implicated in the pathogenesis of fibrosis based upon its matrix-inducing effects on stromal cells in vitro, and studies demonstrating increased expression of total TGF-beta1 in fibrotic tissues from a variety of organs. The precise role in vivo of this cytokine in both its latent and active forms, however, remains unclear. Using replication-deficient adenovirus vectors to transfer the cDNA of porcine TGF-beta1 to rat lung, we have been able to study the effect of TGF-beta1 protein in the respiratory tract directly. We have demonstrated that transient overexpression of active, but not latent, TGF-beta1 resulted in prolonged and severe interstitial and pleural fibrosis characterized by extensive deposition of the extracellular matrix (ECM) proteins collagen, fibronectin, and elastin, and by emergence of cells with the myofibroblast phenotype. These results illustrate the role of TGF-beta1 and the importance of its activation in the pulmonary fibrotic process, and suggest that targeting active TGF-beta1 and steps involved in TGF-beta1 activation are likely to be valuable antifibrogenic therapeutic strategies. This new and versatile model of pulmonary fibrosis can be used to study such therapies.

Topics: Actins; Adenoviridae; Animals; Collagen; Elastin; Fibronectins; Gene Transfer Techniques; Genetic Vectors; Hydroxyproline; Lung; Male; Peptide Fragments; Protein Precursors; Proteins; Pulmonary Fibrosis; Rats; Rats, Sprague-Dawley; Time Factors; Transforming Growth Factor beta; Transforming Growth Factor beta1

Clinical and epidemiological studies have given discordant results on the usefulness of the level of circulating elastin peptide (EP), a potential marker of both elastin destruction (a key phenomenon in pulmonary emphysema) and neosynthesis, for assessing structural changes in the lung extracellular matrix. The aim of the present study was to explore the relationship between levels of EP and forced expiratory volume in one second (FEV1) and single breath transfer factor for carbon monoxide (TLCO and KCO) in coal miners.. The study population comprised 227 working coal miners aged 34-50 years consisting of 75 miners heavily exposed to underground coal dust with pulmonary radiographs classified as 0/1 or 1/0 by the International Labour Office classification, 75 exposed miners with radiographs classified as normal (0/0), and 77 miners slightly exposed to coal dust with normal radiographs. The subjects answered a standardised questionnaire and performed spirometric tests and a carbon monoxide (CO) transfer test.. No association was observed between EP levels and % predicted FEV1 (or FEV1/FVC). The level of EP increased significantly with decreased % predicted TLCO (r = -0.20). Miners in the lowest % predicted KCO quintile had higher EP levels than the rest (3.28 (1.37) vs 2.47 (1.16)). A significantly lower EP level was observed in miners with radiographs classified as 1/0 or 0/1, especially in those with round opacities, compared with miners with a normal radiograph, and in current smokers compared with the rest.. The results of this study suggest that the level of EP may reflect some remodelling activity in emphysema and lung fibrosis.

Topics: Adult; Carbon Monoxide; Coal Mining; Cohort Studies; Elastin; Humans; Lung; Male; Middle Aged; Occupational Diseases; Pulmonary Emphysema; Pulmonary Fibrosis; Pulmonary Gas Exchange

Interstitial pulmonary fibrosis is characterized by increased production of connective tissue components, including collagen and elastin. The role of elastin turnover in pulmonary fibrosis is not clear, and it is not known whether elastin and collagen are regulated separately or together during the inflammatory process. Mice with bleomycin-induced pulmonary fibrosis were investigated to determine the temporal and spatial changes in localization of elastin mRNA expression, as well as to compare elastin mRNA expression with that of alpha 1(I) collagen mRNA expression. In control (saline-treated) lungs, elastin mRNA was detected by in situ hybridization in arterial walls. No signal was found in alveolar or airway walls or in pleura; alpha 1(I) collagen mRNA was detected in the tissue underlying the airway epithelium. An increase in elastin mRNA expression in muscular arteries was observed 3 days after bleomycin instillation. Expression was also seen in the adventitia of terminal airways and adjacent small blood vessels. Expression of alpha 1(I) collagen mRNA increased in the tissue underlying the airway epithelium. In the pleura, alpha 1(I) collagen mRNA expression was found, although no pleural thickening was evident. The alpha 1(I) collagen mRNA expression was particularly increased in the adventitia of terminal airways and in associated small blood vessels. Obvious in areas of fibrosis, elastin mRNA expression was occasionally increased in the pleura and airway wall 7 days after bleomycin treatment; alpha 1(I) collagen mRNA expression was generally stronger than elastin mRNA expression in areas of fibrosis and was frequently intense in the adventitia of airways and associated blood vessels. The fibrotic areas showed increased elastin mRNA expression 14 and 30 days after bleomycin treatment. The arteries in fibrotic areas showed normal elastin mRNA levels. In the areas of fibrosis and in the adventitia of airways and adjacent blood vessels, alpha 1(I) collagen mRNA expression was very high. In conclusion, lung elastin biosynthesis is markedly altered by bleomycin treatment. The localization and intensity of elastin mRNA expression is different from the expression of alpha 1(I) collagen mRNA.

Topics: Animals; Bleomycin; Collagen; Elastin; Female; In Situ Hybridization; Intubation, Intratracheal; Mice; Mice, Inbred C57BL; Oligonucleotide Probes; Pulmonary Fibrosis; RNA, Messenger

To determine if a new class of agents, the 21-aminosteroids, which are reportedly potent inhibitors of iron-dependent lipid peroxidation, could protect rats from bleomycin-induced pulmonary fibrosis.. Fifty-five adult male Sprague-Dawley rats.. Prospective, randomized, blinded, controlled trial.. The rats were subjected to intratracheal bleomycin (or saline vehicle), and were then treated with the 21-aminosteroid, U74389F (20 mg/kg/day), or vehicle, for the next 7 days.. At 21 days after bleomycin administration, pulmonary fibrosis was assessed histologically as percent of lung fields with evidence of fibrosis. Pulmonary fibrosis was assessed biochemically by measuring pulmonary elastin and hydroxyproline content. To determine if a protective effect of U74389F was linked to the 21-aminosteroid's ability to suppress lipid peroxidation, two products of lipid peroxidation were assayed in the lungs at 7 and 14 days after bleomycin exposure. By histologic assessment, the 21-aminosteroid-treated, bleomycin-exposed animals were found to have significantly decreased the extent of pulmonary fibrosis when compared with the bleomycin control group (mean 48.6 +/- 20.0 [SD] % [n = 9] vs. 68.4 +/- 19.6% [n = 11]; p < .05). In addition, lung elastin was decreased by approximately 75% (p < .05) and hydroxyproline was decreased by approximately 50% (NS) in the 21-aminosteroid-treated group when compared with the bleomycin control group. At 7 and 14 days after bleomycin exposure, all bleomycin-exposed animals had evidence of increased lipid peroxidation (conjugated dienes and thiobarbituric acid-reactive substances), but the 21-aminosteroid-treated, bleomycin-exposed animals had significantly decreased evidence of lipid peroxidation when compared with bleomycin controls.. The 21-aminosteroid can substantially protect animals from bleomycin-induced pulmonary fibrosis and may prove useful in other lung diseases where iron-dependent, free-radical reactions and/or lipid peroxidation are presumed mechanisms of toxicity.

Topics: Animals; Antioxidants; Bleomycin; Elastin; Hydroxyproline; Lipid Peroxidation; Lung; Male; Pregnatrienes; Prospective Studies; Pulmonary Fibrosis; Random Allocation; Rats; Rats, Sprague-Dawley; Thiobarbituric Acid Reactive Substances

Increased production of EGF or TGF-alpha by the respiratory epithelial cells has been associated with the pathogenesis of various forms of lung injury. Growth factors and cytokines are thought to act locally, via paracrine and autocrine mechanisms, to stimulate cell proliferation and matrix deposition by interstitial lung cells resulting in pulmonary fibrosis. To test whether TGF-alpha mediates pulmonary fibrotic responses, we have generated transgenic mice expressing human TGF-alpha under control of regulatory regions of the human surfactant protein C (SP-C) gene. Human TGF-alpha mRNA was expressed in pulmonary epithelial cells in the lungs of the transgenic mice. Adult mice bearing the SP-C-TGF-alpha transgene developed severe pulmonary fibrosis. Fibrotic lesions were observed in peribronchial, peribronchiolar, and perivascular regions, as well as subjacent to pleural surfaces. Lesions consisted of fibrous tissue that included groups of epithelial cells expressing endogenous SP-C mRNA, consistent with their identification as distal respiratory epithelial cells. Peripheral fibrotic regions consisted of thickened pleura associated with extensive collagen deposition. Alveolar architecture was disrupted in the transgenic mice with loss of alveoli in the lung parenchyma. Pulmonary epithelial cell expression of TGF-alpha in transgenic mice disrupts alveolar morphogenesis and produces fibrotic lesions mediated by paracrine signaling between respiratory epithelial and interstitial cells of the lung.

Topics: Animals; Collagen; Elastin; Epithelium; Female; Lung; Male; Mice; Mice, Transgenic; Pulmonary Alveoli; Pulmonary Fibrosis; RNA, Messenger; Transforming Growth Factor alpha

Sprague-Dawley rats were exposed for 6 h daily to 0.8 ppm of ozone and 14.4 ppm of nitrogen dioxide. Approximately 7 to 10 wk after the initiation of exposure, animals began to demonstrate respiratory insufficiency and severe weight loss. About half of the rats died between Days 55 and 78 of exposure; no overt ill effects were observed in animals exposed to filtered air, to ozone alone, or to nitrogen dioxide. Biochemical findings in animals exposed to ozone and nitrogen dioxide included increased lung content of DNA, protein, collagen, and elastin, which was about 300% higher than the control values. The collagen-specific crosslink hydroxy-pyridinium, a biomarker for mature collagen in the lung, was decreased by about 40%. These results are consistent with extensive breakdown and remodeling of the lung parenchyma and its associated vasculature. Histopathologic evaluation showed severe fibrosis, alveolar collapse, honeycombing, macrophage and mast cell accumulation, vascular smooth muscle hypertrophy, and other indications of severe progressive interstitial pulmonary fibrosis and end-stage lung disease. This unique animal model of progressive pulmonary fibrosis resembles the final stages of human idiopathic pulmonary fibrosis and should facilitate studying underlying mechanisms and potential therapy of progressive pulmonary fibrosis.

Topics: Administration, Inhalation; Animals; Collagen; Desmosine; Disease Models, Animal; DNA; Elastin; Environmental Exposure; Hydroxyproline; Lung; Male; Nitrogen Dioxide; Ozone; Proteins; Pulmonary Fibrosis; Pyridines; Rats; Rats, Sprague-Dawley; Survival Rate

The important processes in fetal pulmonary development are devoted to gain large surfaces for gas exchange and surfactant production. Basement membrane components, collagen fibers and elastic fibers are formed immediately around the epithelium in the early stage of lung development. Primordia of alveolar septa composed of elastic fibers and smooth muscle cells, develop in the glandular stage and form alveolar septa by protruding into the glandular lumina in later stages. The differentiation of alveolar walls, including the appearance of surfactant-producing cells, begins earlier in the proximal portion than in the distal portion of primitive alveoli. The process of fibrosis and regeneration in lung fibrosis defectively mimics the embryogenesis of the lung. Pulmonary structural remodeling occurs when the epithelial basement membrane, a scaffold for regenerating epithelial cells, is lost because of intra-alveolar fibrosis. In panacinar emphysema, simple and dilated air spaces are formed by the degradation of elastic fibers in alveolar septa, and this process may be reverse to the formation of alveolar septa in developing lung.

Topics: Basement Membrane; Cell Differentiation; Collagen; Connective Tissue; Elastin; Fibronectins; Humans; Lung; Pulmonary Alveoli; Pulmonary Emphysema; Pulmonary Fibrosis; Pulmonary Surfactants

Topics: Collagen; Elastin; Fibronectins; Humans; Laminin; Prostaglandins; Proteoglycans; Pulmonary Alveoli; Pulmonary Fibrosis

To determine whether lung elastin is lost during the evolution of cadmium-induced air-space enlargement with pulmonary fibrosis, the lung elastin of 5- to 7-day-old golden Syrian hamster pups was radiolabeled by giving [3H]valine. At maturity, a single intratracheal instillation of 0.5 ml of 0.025% CdCl2 solution was given. Lung mechanics, histologic examination, and biochemistry were studied 5, 10, 21, 42, 105, and 180 days after the cadmium treatment. The animals developed fibrosis and air-space enlargement with decreased lung volumes, compliance, and forced expiratory flow; their functional residual capacity was increased. The total lung collagen and total lung elastin were increased, but there was no loss of radiolabel in lung elastin. We conclude that CdCl2-induced air-space enlargement with pulmonary fibrosis is not accompanied by loss of neonatally formed lung elastic fibers. We hypothesize that air-space enlargement with fibrosis represents a stereotyped response of the lung to fibrosing injuries, which we hypothesize is due to forces from more fibrotic and atelectatic areas causing overdistension of less abnormal air spaces. The air-space enlargement of fibrosing human diseases such as sarcoidosis and eosinophilic granuloma may have a similar basis. Evidence is reviewed that human centrilobular emphysema may be a form of focal air-space enlargement with interstitial fibrosis; there may be mechanisms in addition to elastase-antielastase imbalance that cause human emphysema.

Topics: Animals; Cadmium; Cadmium Chloride; Elastin; Emphysema; Forced Expiratory Flow Rates; Humans; Lung; Organ Size; Pulmonary Fibrosis; Total Lung Capacity; Vital Capacity

To study the morphologic alterations of pulmonary elastic fibers in cynomolgus monkeys with paraquat toxicity, peroxidase- and ferritin-labeled antielastin antibodies were used for the light and electron microscopic localization of elastin. One week after paraquat, alveolitis, tissue damage and alveolar dilatation were present; elastic fibers were frayed and more diffusely and intensely stained than those of control animals. In the latter, staining was localized in peripheral regions of the amorphous components and, to a lesser extent, in some microfibrils of elastic fibers. At 3 to 4 weeks, diffuse staining was evident in damaged interstitial elastic fibers and in newly formed elastic fibers in areas of intraalveolar fibrosis. At 8 weeks, the interstitium contained many elastic fibers which showed staining only in peripheral regions of the amorphous components. These observations suggest that: 1) preembedding immunohistochemical staining for elastin is localized in peripheral regions of normal elastic fibers because the antielastin antibody can penetrate into mature and undamaged amorphous components only to a very limited extent; 2) in early stages of paraquat toxicity this staining is more diffuse and intense because elastase from inflammatory cells partially degrades the elastic fibers and permits greater penetration of the antibody into the amorphous materials; 3) in later stages the staining pattern returns to normal as inflammation subsides and elastic fibers are repaired; however, newly formed elastic fibers in areas of intraalveolar fibrosis stain diffusely, reflecting increased penetration of the antibody because of immaturity and incomplete cross-linking, and 4) degeneration of elastic fibers of alveolar walls in paraquat lung may lead to alveolar dilatation, which is associated with irregular fibrosis and constitutes one of the processes of pulmonary structural remodeling in paraquat lung.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Disease Models, Animal; Elastin; Immunohistochemistry; Lung; Macaca fascicularis; Microscopy, Electron; Paraquat; Pulmonary Fibrosis

Both synthesis and total content of lung elastin were measured after induction of interstitial pulmonary fibrosis in hamsters by a single intratracheal insufflation of amiodarone. Elastin synthesis, as measured by 14C-lysine incorporation into desmosine and isodesmosine, was significantly elevated (P less than 0.05) above control values for a 3-week interval after induction of lung injury. Total lung elastin content in the amiodarone-treated animals was 32% greater than in controls (P less than 0.05) 2 weeks after insufflation of the agent. Furthermore, the time course of elastin synthesis in this experimental model was similar to that observed in bleomycin-induced pulmonary fibrosis in hamsters. Increases in elastin may therefore be a common feature of interstitial pulmonary fibrosis and may contribute to the altered lung mechanics seen in this disease.

Topics: Amiodarone; Animals; Cricetinae; Elastin; Female; Lung; Lysine; Mesocricetus; Pulmonary Fibrosis

Topics: Cells, Cultured; Connective Tissue; Elastin; Emphysema; Humans; Lung Injury; Pulmonary Fibrosis

We have characterized the messenger RNAs (mRNAs) coding for procollagen alpha 1(I), elastin, fibronectin, and actin in the lungs of Syrian golden hamsters by Northern blot analyses. While elastin, fibronectin, and beta-actin were each coded for by a single mRNA species of 4.1 kilobases (kb), 9.1 kb, and 2.1 kb in size, respectively, we identified a major (5.4 kb) and a minor (6.5 kb) procollagen alpha 1(I) mRNA species in the hamster lungs. The mRNAs for the three extracellular matrix proteins showed increased accumulation followed by steady decline in the bleomycin-treated lungs. There were significant differences among the three mRNAs in the relative increase and the time of maximum accumulation. After reaching the peak levels between 2-3 wk posttreatment, the levels of procollagen alpha 1(I) and elastin mRNAs declined to near normal values around the fourth week. In contrast, the accumulation of fibronectin mRNA was maximum in the first week after bleomycin treatment. The procollagen alpha 1(I) mRNA accumulated most dramatically (sevenfold above the levels in the untreated animals) compared with a five-fold increase in mRNA coding for fibronectin. Elastin mRNA increased approximately twofold above the control values. Nuclear runoff transcription experiments demonstrated a selective increase in the rates of transcription of genes coding for procollagen alpha 1(I), fibronectin, and elastin; the extent of transcriptional stimulation of procollagen alpha 1(I) and fibronectin genes was significantly greater than that of elastin. Since the amount of actin mRNA, as well as the rate of transcription of actin gene(s), varied only slightly after bleomycin treatment, we conclude that the metabolism of mRNAs coding for extracellular matrix proteins may be preferentially perturbed during pulmonary fibrosis.

Topics: Actins; Animals; Bleomycin; Cricetinae; Elastin; Extracellular Matrix; Fibronectins; Gene Expression Regulation; Lung; Procollagen; Pulmonary Fibrosis; RNA, Messenger; Time Factors; Transcription, Genetic

Lung biopsies from 17 patients with cryptogenic fibrosing alveolitis of a cellular rather than fibrotic pattern were examined by transmission electron microscopy in the hope that such cases would show features of pathogenetic significance. Further selection was made by choosing minimally affected areas. There was no ultrastructural evidence of immune complex deposition but alveolar epithelial and capillary damage was frequently found (17 and 14 of the 17 cases respectively). Alveolar epithelial injury consisted of patchy necrosis and regenerative hyperplasia. Alveolar capillary injury consisted of cytoplasmic swelling and basement membrane thickening and reduplication. Many of these features have not been emphasized in previous reports and their prominence in early stages of the disease suggest that they may have pathogenetic significance, possible mechanisms of which are discussed. Similar findings identified during the course of this study in 8 asbestos workers suggest that similar pathogenetic mechanisms may operate in asbestosis.

Topics: Asbestosis; Basement Membrane; Capillaries; Collagen; Elastin; Humans; Lung; Microscopy, Electron; Pulmonary Alveoli; Pulmonary Fibrosis

Cross-linked elastin synthesis was measured in the intratracheal bleomycin model of interstitial pulmonary fibrosis by incorporation of 14C-lysine into the elastin-specific crosslinks, desmosine and isodesmosine. Detection of the labeled crosslinks was facilitated by development of a highly sensitive assay utilizing thin-layer electrophoresis. The results indicate that crosslinked elastin synthesis is significantly elevated from controls (p less than 0.05) at 1 to 3 weeks after exposure to bleomycin and returns to normal by 5 weeks. The increases in labeled elastin synthesis are not directly related to changes in either total lung protein synthesis or the pool size of the 14C-lysine. In comparison with collagen and glycosaminoglycan synthesis in this model of lung injury, maximal increases in cross-linked elastin formation occur later, but overlap with the elevated synthesis of these other connective tissue components. The marked increase from normal in cross-linked elastin synthesis in this model suggests that this tissue component is an important part of the fibrotic response of the pulmonary parenchyma and may play a role in the observed alterations in lung structure and function.

Topics: Amino Acids; Animals; Bleomycin; Carbon Radioisotopes; Cricetinae; Desmosine; Elastin; Female; Isodesmosine; Lysine; Mesocricetus; Pulmonary Fibrosis

72 cases of diffuse interstitial lung diseases were observed from 1969 to 1976. Specimens removed from 47 patients were subjected to the whole spectrum of reactions. According to variation of both elastin and collagen, the following groups were outlined: group A: mycobacteriosis, farmer's lung, sarcoidosis and silicosis; group B: chronic eosinophilic pneumonia, lymphocytic interstitial pneumonia, post-tuberculous pulmonary fibrosis, and group C: X-ray pneumopathy, desquamative interstitial pneumonia, sclerodermic pneumopathy and chronic pulmonary fibrosis (primary chronic fibroadenomyosis). Each of these groups presents a close relationship between histochemical, radiological, clinical and functional findings.

Topics: Collagen; Elastin; Glycosaminoglycans; Heparin; Humans; Lung; Lung Diseases; Phosphatidylcholines; Pulmonary Fibrosis

Topics: Animals; Collagen; Connective Tissue; Connective Tissue Diseases; Elastin; Humans; Lung; Pulmonary Emphysema; Pulmonary Fibrosis; Smoking

Proline analogs inhibit collagen biosynthesis and prevent accumulation of collagen in tissues. The antifibrotic effects of three proline analogs, cis-hydroxyproline, L-azetidine-2-carboxylic acid, and L-3,4-dehydroproline, were compared in a rat oxygen toxicity model. The specificity of these agents for collagen was examined by measuring their effects on noncollagen protein and elastin accumulation in the lung. Increased lung collagen was produced by exposing rats to 95% O2 for 60 hr followed by a 2-week recovery period. Animals were treated with the proline analogs for the 2-week period. Oxygen exposure in untreated animals increased lung collagen 26% above air-breathing controls, and this increase was prevented by all three analogs. Increased noncollagen protein was also prevented by these agents, suggesting they were not entirely specific for collagen. Elastin accumulation, however, was not inhibited by cis-hydroxyproline. It was concluded that proline analogs were antifibrotic, but affected the metabolism of noncollagen protein.

Topics: Animals; Azetidinecarboxylic Acid; Desmosine; Elastin; Hydroxyproline; Male; Organ Size; Oxygen; Proline; Proteins; Pulmonary Fibrosis; Rats; Rats, Inbred Strains

At 5, 15, and 45 days following induction of interstitial pulmonary fibrosis by intratracheal administration of bleomycin in hamsters, glycosaminoglycan synthesis was measured, using [35S]sulfate. Total labeled sulfate incorporation into lung glycosaminoglycans was maximally increased over that of saline-instilled controls at 5 days (P less than or equal to 0.05), declined markedly at 15 days, and returned to control values at 45 days. Separation of the various labeled glycosaminoglycans by chondroitinase digestion and chromatography revealed a transient rise from controls (P less than or equal to 0.05) in the proportion of labeled chondroitin 4-sulfate at 5 days, followed by an increase from controls (P less than or equal to 0.05) in proportionate labeling of dermatan sulfate at 15 and 45 days postbleomycin. Autoradiography, using [35S]sulfate, performed at 21 days postbleomycin, revealed an increase from controls in film grain formation in areas of interstitial reaction. Grain formation was greatly reduced by pretreatment of the slide sections with hyaluronidase and chondroitinase, demonstrating the specificity of the label for glycosaminoglycans. The results indicate that glycosaminoglycan synthesis is significantly altered from normal in this model of interstitial lung disease and that dermatan sulfate is preferentially synthesized during the fibrotic phase of the lung reaction.

Topics: Animals; Autoradiography; Bleomycin; Collagen; Cricetinae; Elastin; Female; Glycosaminoglycans; Lung; Mesocricetus; Pulmonary Fibrosis; Sulfates; Time Factors

Cadmium chloride, administered intratracheally to golden Syrian hamsters, causes an acute lung injury which evolves into a lesion with functional and morphological features of diffuse fibrosis. With simultaneous feeding of a lathyrogen, beta-aminoproprionitrile, this same injury evolves into functional and morphological changes of bullous emphysema. These results suggest that the same lung injury might result in either fibrosis or emphysema, connective tissue synthesis during the healing phase being the critical determinant.

Topics: Aminopropionitrile; Animals; Cadmium; Cadmium Chloride; Collagen; Connective Tissue; Cricetinae; Elastin; Female; Intubation, Intratracheal; Lung; Mesocricetus; Pulmonary Emphysema; Pulmonary Fibrosis

Pulmonary fibrosis induced by bleomycin is associated with accumulation of collagen and elastin in the lungs. The excess connective tissue proteins persist despite resolution of inflammation after cessation of treatment. In the present study, mild lung injury was produced in 9 juvenile baboons by twice-weekly injections of bleomycin to a total dose of 66 units/kg. Treated animals showed losses in body weight, lung volume, and diffusing capacity. Right middle lobectomies were performed in 3 animals shortly after cessation of bleomycin. Only minimal histologic changes were present, but lobar connective tissue protein concentrations and the rate of collagen synthesis were increased. Biopsies obtained in 3 additional animals 3 months later revealed similar changes. All animals were killed 6 months after cessation of treatment. Mild fibrosis was present, and lobar contents of collagen and elastin, as well as synthetic rates of collagen and elastin, remained elevated. Accumulation of lung connective tissue proteins in this model was associated with increased rates of synthesis that persisted after discontinuance of the drug.

Topics: Animals; Bleomycin; Collagen; Connective Tissue; Dose-Response Relationship, Drug; Elastin; Lung; Papio; Pulmonary Fibrosis

Pulmonary fibrosis was induced in rabbits by an intratracheal instillation of bleomycin. Histologically, at 2 weeks there was inflammation but only limited evidence of increased collagen deposition; at 8 weeks the inflammatory response had subsided and increased collagen deposition, characteristic of early interstitial fibrosis, was observed. Biochemical analyses showed bleomycin treatment caused marked increases in the total amounts of RNA, DNA, mixed protein, collagen and elastin when compared to controls (P less than 0.001 in all cases). Furthermore the increases were essentially complete by 2 weeks where the contents had increased by 110 +/- 13%, 60 +/- 11%, 148 +/- 12%, 94 +/- 15% and 89 +/- 11% respectively (P less than 0.001 in all cases). When collagen and elastin were expressed as concentrations with respect to wet weight, total protein or DNA content, the changes were not statistically significant. No changes were observed in the relative amounts of type I and type III collagen. It is concluded that: (1) compared to biochemical analysis, histology is relatively insensitive in detecting the early increases in connective tissue proteins; (2) measurements of lung collagen and elastin should be expressed as total lung contents wherever possible; the concentration of these proteins may remain unchanged, especially in the early stages of fibrosis, due to concomitant increases in other lung constituents; (3) changes in the relative amounts to types I and III collagens do not play a major role in the pathology of this form of pulmonary fibrosis.

Topics: Animals; Bleomycin; Collagen; DNA; Elastin; Lung; Male; Pulmonary Fibrosis; Rabbits; RNA

Topics: Animals; Bleomycin; Collagen; Elastin; Humans; Lung Compliance; Lung Volume Measurements; Pulmonary Fibrosis

Lung volumes and volume pressure (V-P) relationships were measured in anesthetized hamsters 8, 30, 60, and 90 days after induction of interstitial pulmonary fibrosis by intratracheal administration of bleomycin. Subsequently, total collagen, elastin, protein, deoxyribonucleic acid (DNA), and dry weight were determined in the lungs of each animal. The mean volume of air in the lungs at a transpulmonary pressure of 25 cm H2O and mean quasi-static compliance were decreased at 8 and 30 days and had returned toward normal by 60 and 90 days. Dry lung weight and total protein content were increased at 8 days, peaked at 30 days, and were still greater than normal at 90 days; DNA peaked at 8 days, remained unchanged through day 60, and returned to normal by day 90. Collagen and elastin content, although not significantly different from control at day 8, was increased at day 30 with peak values attained at day 90. Ratios of collagen or elastin to dry weight, total protein, and DNA were decreased at 8 days, normal at 30 days, and increased at 90 days. The ratios of collagen or elastin to total protein, dry lung weight, or DNA cannot be used as indicators of the amounts of these proteins in the whole lung. We conclude that in interstitial pulmonary fibrosis induced with bleomycin the pattern of changing biochemical composition of the lungs cannot be inferred from the lung volumes or V-P relations.

Topics: Administration, Topical; Animals; Bleomycin; Collagen; Cricetinae; DNA; Elastin; Functional Residual Capacity; Lung; Lung Compliance; Organ Size; Proteins; Pulmonary Fibrosis; Residual Volume; Respiration; Total Lung Capacity; Vital Capacity

Topics: Animals; Bleomycin; Collagen; Cricetinae; Elastin; Lung; Mesocricetus; Pulmonary Fibrosis

Topics: Animals; Cobalt Radioisotopes; Collagen; Disease Models, Animal; DNA; Elastin; Haplorhini; Lung; Lung Volume Measurements; Papio; Pulmonary Alveoli; Pulmonary Fibrosis; Radiation Injuries, Experimental

Topics: Collagen; Elastin; Humans; Models, Biological; Proteoglycans; Pulmonary Alveoli; Pulmonary Fibrosis

Topics: Aerosols; Cerium Radioisotopes; Collagen; Connective Tissue; Elastin; Glucosamine; Hydroxyproline; Lung; Proline; Pulmonary Fibrosis; Radiation Effects; Respiration; Time Factors

Topics: Animals; Aspartic Acid; Autoanalysis; Chromatography, Ion Exchange; Collagen; Connective Tissue; Dogs; Elastin; Glutamates; Hydroxyproline; Lung; Lysine; Proline; Pulmonary Fibrosis; Radiation Injuries, Experimental; Serine; Threonine