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Query: UMLS:C0034069 (pulmonary fibrosis)
 7,050 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The universal features of the histopathology of fibrotic lung disease are derangement of parenchymal collagen and infiltration of the parenchyma with chronic inflammatory cells. To determine if this cellular reaction might be associated with autoimmunity to a consitituent of the alveolar interstitium, peripheral blood lymphocytes were exposed to human type I collagen in vitro and evaluated for the production of migration inhibition factor and cytotoxicity. Data from 18 patients with idiopathic pulmonary fibrosis, 8 patients with pulmonary fibrosis other than idiopathic pulmonary fibrosis, 12 patients with nonfibrotic lung disease, and 9 normals demonstrated that circulating lymphocytes from more than 94% of patients with fibrotic lung disease take part in processes where the recognition of collagen results in migration inhibition factor production and lysis of collagen-coated sheep red blood cells. These collagen-induced cell-mediated phenomena are obviated with human T-lymphocyte antiserum. Collagen-induced migration inhibition factor production and cytotoxicity were found in less than 20% of patients with nonfibrotic disease and were not found in normals. Qualitatively, there was no organ (lung, skin) or species (human, rabbit) collagen specificity in these assays, but human lung alpha 2 chains were recognized more often than alpha 1(I) chains. Circulating lymphocytes from patients with fibrotic disease are present in a normal T to B ratio. These lymphocytes did not incorporate [3H]thymidine when exposed to collagen but did when exposed to T-cell mitogens. These in vitro observations suggest that circulating T-lymphocytes and lung collagen may be intimately associated in the pathogenesis of human fibrotic lung disease.
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PMID:Pathogenic mechanisms in pulmonary fibrosis: collagen-induced migration inhibition factor production and cytotoxicity mediated by lymphocytes. 6 60

Although pulmonary fibrosis results from exposure to a high level of asbestos, the relative contributions of increased synthesis and/or reduced degradation of total collagen and of any specific type of collagen are not clear. To examine collagen turnover, rats were instilled with crocidolite fibers via the trachea and killed at 1, 2, 4, 6, and 8 weeks. The left lobe was used to determine collagen synthesis by incubating lung pieces with [3H]proline and subsequently measuring 3-hydroxyproline (HYP). Collagenolytic activity was estimated from the release of soluble HYP after incubation of lung homogenates for 48 h. Ratios of collagen types I and III were assayed by gel electrophoresis, both on whole lung and on the labeled homogenate. As fibrosis develops, both total HYP and HYP per dry weight increase at 2 weeks and continue to rise over the experimental period with no differences in the ratio of total types I:III collagens. However, newly synthesized collagen showed an increase in type III at 2 weeks and later a higher proportion of type I collagen when compared with the control. Total collagenolytic activity of asbestos-treated lungs was the same as controls when expressed per dry weight, but was reduced when calculated per unit of collagen. However, active collagenolytic activity was lower than control values when expressed by HYP content and per dry weight at all times after asbestos. The results suggest that reduced degradation of collagen contributes to the fibrotic process in addition to the progressive increase in collagen synthesis, particularly the type I form.
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PMID:Collagen synthesis and degradation during the development of asbestos-induced pulmonary fibrosis. 157 28

Endotracheal bleomycin administration in rats and other animal species causes rapid development of pulmonary fibrosis, characterized by increased lung collagen synthesis and deposition. To clarify the mechanism, lung fibroblasts from bleomycin-treated rats (BRF) were isolated and maintained in tissue culture. They were then compared with those from normal untreated control animals, with respect to several key parameters of collagen metabolism. BRF synthesized collagen at a rate 35-82% above normal rat lung fibroblasts (NRF). This difference did not appear to be due to the selection of a clone by the subculture process. Furthermore, analysis of newly synthesized collagen type composition, revealed a significantly lower ratio of type III to type I collagen. Noncollagenous protein synthesis, however, was not significantly different from normal. Collagenase production and growth rate were also unaffected. BRF, however, was morphologically indistinguishable from NRF, even at the ultrastructural level. Upon further bleomycin (1 microgram/ml) exposure in vitro, BRF could be further stimulated to synthesize collagen at 82% above the rate for untreated BRF. This is comparable to the 90% increase in NRF treated in vitro (compared with untreated NRF). These results would favor the conclusion that bleomycin induces pulmonary fibrosis, by causing directly and/or indirectly lung fibroblasts (or a certain line of lung fibroblasts) to synthesize collagen at a higher rate without any associated increase in growth rate. The data, however, do not rule out the possibility that the fibroblast isolation procedure has selected for a certain population of fibroblasts that may not be typical of the in vivo situation.
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PMID:Rat lung fibroblast collagen metabolism in bleomycin-induced pulmonary fibrosis. 241 Apr 57

Fibroblasts in healthy adult lung are quiescent, synthesizing little collagen. We studied lung biopsies from 30 patients with pulmonary fibrosis, using immunohistochemistry with monoclonal antibodies against the propeptides of type I collagen to localize fibroblasts actively synthesizing collagen. Adjacent sections were stained with antibodies to type III and IV collagen, fibrin, cytokeratin, plasma fibronectin, or EDIIIa-containing "cellular" fibronectin (cFN). In rapid pulmonary fibrosis, including the proliferative phase of diffuse alveolar damage, organizing pneumonia, and subacute idiopathic fibrosis, collagen-synthesizing cells were numerous in organizing exudate filling airspaces but were also seen in the interstitium of the alveolar walls, interlobular septa, and walls of blood vessels. The new matrix deposited in the airspaces also contained type III collagen and EDIIIa-containing fibronectin. In chronic pulmonary fibrosis, more than half of the biopsies showed foci of collagen synthesis and cFN deposition near the air-tissue interface. The foci were consistently localized outside remnants of basal lamina and therefore within airspaces. The results indicate that (1) fibrosis in chronic idiopathic pulmonary fibrosis results mainly from organization of exudate within airspaces, just as it does after acute lung injury, and (2) during this process, fibroblasts increase their synthesis of collagen and fibronectin coordinately. Foci of active matrix deposition provide evidence for the progressive nature of chronic pulmonary fibrosis.
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PMID:An immunohistochemical study of architectural remodeling and connective tissue synthesis in pulmonary fibrosis. 260 97

Sheep antibodies to bovine type I collagen were employed in the immunohistochemical detection of type I collagen in lung tissue sections of irradiated LAF1 mice. A video image digitizing system was developed to estimate collagen levels, by assigning a numerical value (0-63) to each of approximately 53,800 picture elements (pixels) in the microscope field, according to the collagen-dependent fluorescence intensity at each locus. For lungs harvested 52 weeks subsequent to graded doses of 60Co gamma radiation between 0 and 10 Gy, a dose-dependent increase in type I collagen was observed in the alveolar walls. A reproducible increase was evident for doses as low as 5 Gy: doses of 7 to 10 Gy elicited type I collagen levels significantly elevated with respect to those of age-matched controls. These results are consistent with a role for type I collagen in the development of radiation-induced pulmonary fibrosis. The assay system developed here will be used to explore the role of connective tissue macromolecules in the development of radiation pneumonitis and fibrosis.
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PMID:A semiquantitative probe for radiation-induced normal tissue damage at the molecular level. 351 95

Fibrosis in the lung is well described histologically. There is destruction of the normal architecture with the appearance of inflammatory cells and connective tissue components, particularly collagen. Biochemical evidence for an increased deposition of collagen in man has been demonstrated in patients with both acute and chronic forms of pulmonary fibrosis. Studies of collagen metabolism in man are equivocal but there is convincing evidence for an increased synthesis rate in animal models of pulmonary fibrosis. Collagen degradation has been little studied but may be important, given the recent evidence indicating quite rapid turnover of lung collagen and a decreased degradation of collagen in experimental disease. The distribution of collagen types has been studied in man, where there is some evidence for the production of type III collagen in the early active phase of disease with a preponderance of type I collagen in the late stages. The cellular mechanisms leading to these changes are uncertain but the alveolar macrophage may play a central role, since it is capable of releasing factors which expand the fibroblast population as well as attracting new fibroblasts to the site of injury. These pathways are described for what is essentially the normal physiological response of scar formation, which has pathological consequences in the lung, a tissue requiring thin membranes at its epithelial and endothelial surfaces, in order to perform its main function of gas exchange.
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PMID:Biochemical pathways leading to collagen deposition in pulmonary fibrosis. 385 24

Previous reports have suggested that immune mechanisms are involved in the induction of certain types of pulmonary fibrosis. In this study endotracheal bleomycin was used to induce pulmonary fibrosis in rats, and they were then examined for cellular sensitivity to homologous interstitial collagens isolated from lung. Results indicate that rats treated with bleomycin develop transient cellular sensitivity to homologous collagen. Immunity appears to be selective to type I collagen with minimal response to type III collagen. The kinetics of the development of autoimmunity paralleled the transient increase in collagen synthesis in response to bleomycin treatment. This response was abolished upon prior treatment of the challenging antigen with purified bacterial collagenase, but was resistant to trypsin digestion. This finding confirms the true collagenous nature of the stimulating antigen and eliminates the possibility of a noncollagenous contaminant as the effective agent in the antigen preparation. The data suggest that cellular sensitivity to homologous collagen in response to bleomycin treatment may play a role in the overall fibrotic response.
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PMID:Cellular sensitivity to collagen in bleomycin-treated rats. 618 Nov 64

Type V collagen was first isolated in 1976; there is still controversy as to how many molecular species of type V collagen exist. Although its structural and functional roles remain unclear, reports of changes in the relative amount of type V collagen from that present in normal tissue have been reported in such diverse pathologic conditions as atherosclerotic aortas, prolapsed mitral valves, and fibrotic lungs. Methods for quantitating type V collagen relative to other collagens have consisted of solubilizing the collagen with pepsin and then analyzing the ratios of the intact chains by gel electrophoresis or by column chromatography. In tissues in which only a small percentage of the total collagen can be solubilized by pepsin, such analyses may not accurately reflect changes in the total collagen present. In this report, a method for quantitating type V collagen relative to types I and III collagens based on CNBr peptide mapping is presented. CNBr solubilizes virtually all the collagen present in any tissue. The method is applied to a model of bleomycin-induced pulmonary fibrosis in rats. It was found that type I collagen increased relative to types III and V collagens, which seemed to remain at values comparable to those observed in lungs from control (normal) rats, both in terms of newly synthesized collagen (collagen synthesized by lung minces during 4 h in culture) and total unlabeled lung collagen (collagen synthesized during the life of the animal).
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PMID:Type V collagen. Quantitation in normal lungs and in lungs of rats with bleomycin-induced pulmonary fibrosis. 618 72

The immune response to connective tissue components of basement membrane (type IV collagen and laminin) and to interstitial collagen (type I) has been examined in human and murine systems. We also examined the role that immunologic sensitization to autologous connective tissue components might play in inducing an inflammatory response resulting in pathologic sequelae. Mice receiving a single subcutaneous injection of 5 micrograms type IV or type I murine collagens, or murine laminin in complete Freund's adjuvant mount a delayed-type hypersensitivity response characterized by a mononuclear cell infiltrate when challenged in the footpad with the sensitizing antigen. Cell-mediated immunity to these connective tissue antigens can be transferred to normal syngeneic mice with sensitized T-lymphocytes. In addition, repeated immunizations with these homologous connective tissue components elicit antibody responses in mice. Our data demonstrate the immunogenic nature of types IV and I collagen, and of laminin in a syngeneic murine model. We have demonstrated autoantibodies to the basement membrane and interstitial collagens in the sera of patients with scleroderma (systemic sclerosis); ELISA ratios correlate directly with the extent of pulmonary fibrosis in these patients. Anti-type IV collagen autoantibodies were found to be primarily IgM and anti-type I collagen antibodies, primarily IgG. An antibody response to autologous connective tissue antigens could lead to complement activation, immune complex formation, and deposition of the complexes along vascular endothelium with recruitment of blood monocytes in situ, mirroring the early scleroderma lesion (perivascular mononuclear cell filtrates). In vitro we examined the role of human peripheral blood mononuclear cells in the activation of fibroblasts. Adherent human blood monocytes release mediators which stimulate fibroblast proliferation and collagen deposition. A model is presented for the induction of immunity to autologous connective tissue components, leading to mononuclear cell inflammation, fibroblast activation and fibrosis. Selective immunity to basement membrane collagens may influence the clinical expression of diffuse connective tissue syndromes such as scleroderma (systemic sclerosis).
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PMID:Immune response to connective tissue components of the basement membrane. 621 63

Increased synthesis of type I collagen, leading to increased ratios of type I to type III collagen in the lungs, has been observed in the lungs of animals with experimental pulmonary fibrosis. Similar changes in collagen type ratios have been observed in lungs of humans dying of idiopathic pulmonary fibrosis and of adult respiratory distress syndrome. In this study, lung collagen type ratios were examined in infants with acute and chronic lung disease. Tissue from the right lower lobes of neonates was obtained post mortem. Specific collagen types were quantitated by solubilization of lung collagen with CNBr and fractionation of the resulting mixture of peptides by column chromatography and polyacrylamide gel electrophoresis. Ratios of type I/III collagen were calculated for each lung sample using two independent pairs of marker peptides for these determinations. In some cases the ratio of type V to type III collagen in these same lung samples was also quantitated. We observed a significant increase in the ratio of type I/III collagen in infants with a premortem diagnosis of chronic lung disease, usually preceded by respiratory distress syndrome. We also observed two infants with large changes in collagen type ratios who might have had pulmonary fibroplasia secondary to intrauterine lung disease. These data suggest that there may be several subsets of infants with respiratory distress syndrome, each having a different prognosis.
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PMID:Elevated ratios of type I/III collagen in the lungs of chronically ventilated neonates with respiratory distress. 651 44


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