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)

Silica-induced pulmonary fibrosis usually follows exposure to increased levels of this particulate and its retention in interstitial macrophages of the lung. It is suggested that accelerated clearance of particles from the pulmonary interstitium may ameliorate subsequent fibrosis. To test this hypothesis, one group of mice received 2-mg intratracheal (IT) silica; some particles were phagocytized and cleared during the subsequent inflammatory response, other particles were translocated across the epithelium to reach interstitial macrophages by 2 weeks. These mice later showed increased fibroblast growth, a doubling of lung collagen levels and large silicotic nodules by 16 weeks when much of the silica was still present in the lung. A second group of mice received IT silica, then 2 and 3 weeks later received IT injections of N-formyl-L-methionyl-leucyl-phenylalanine (FMLP), a leukocyte chemoattractant. Subsequently, a significant increase in inflammatory cells was seen and silica was observed mostly in phagocytes within the alveolar spaces. Few interstitial particles were found at 4 weeks, and extensive fibrosis did not develop by 16 weeks; only a few small nodules were seen and little silica was present in the lung. The results indicate that clearance of interstitial particles by a controlled inflammatory response is possible, and that removal of silica from the interstitium decreases the fibrotic response.
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PMID:Instillation of chemotactic factor to silica-injected lungs lowers interstitial particle content and reduces pulmonary fibrosis. 132 17

A single endotracheal administration of bleomycin causes pulmonary fibrosis in several animal species. In view of the functional deficits in neutrophil function as a result of the beige mouse (bg/bg) mutation, its effect on bleomycin-induced pulmonary fibrosis was examined to evaluate the role of the neutrophil in such a response. Neutrophils from beige mice showed a selective defect in the ability to degranulate in response to cytochalasin B and formyl-methionyl-leucyl-phenylalanine, without impairing their ability to produce superoxide anion and H2O2 in response to the same stimuli as well as phorbol myristate acetate. Despite this functional deficit, beige mice responded more intensely to bleomycin than did their heterozygote controls at both 2 wk and 1 month after drug instillation, as assessed by both lung collagen and deposition. This suggests that the inability to mobilize hydrolytic enzymes has no effect on the ability to mount a fibrogenic response, and it would even be detrimental by enhancing such a response caused by decreased connective tissue catabolism as a consequence of the inability to release the granule enzymes to the extracellular space.
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PMID:Effect of the beige mutation on bleomycin-induced pulmonary fibrosis in mice. 618 93

A thermolysin-like metalloendopeptidase, optimally active at a neutral pH, was identified in human serum. The enzyme cleaves the synthetic substrate glutaryl-Ala-Ala-Phe-2-naphthylamide at the Ala-Phe bond. Activity was determined by measuring the rate of formation of Phe-2-naphthylamide in a coupled enzyme assay in the presence of excess aminopeptidase M. 2-Naphthylamine released during the reaction was determined by a diazotization procedure. Enzyme activity is not affected by inhibitors of serine, thiol, or carboxyl proteases, but is sensitive to inhibition by metal chelators such as EDTA and o-phenanthroline. Dialysis against EDTA leads to loss of activity, which can be fully restored by zinc and cobalt ions. The serum enzyme closely resembles a membrane-bound metalloendopeptidase (EC 3.4.24.11) abundant in lung, spleen, and kidney in that both enzymes are inhibited by the same active-site-directed inhibitors. In addition, an antiserum obtained against the metalloendopeptidase from rabbit kidney shows strong cross-reactivity with the serum enzyme. Metalloendopeptidase activity was measured in 150 controls and in 95 patients with sarcoidosis; the two groups had significantly different enzyme activities (p less than 0.001). The mean enzyme activity in the sarcoidosis group was more than threefold higher than that of the control group. The mean enzyme activity for patients with active disease was more than double that of patients with inactive disease and more than four times that of controls (p less than 0.001). This is noteworthy because angiotensin converting enzyme, a zinc-dipeptidyl carboxypeptidase with a mechanism of action similar to that of the metalloendopeptidase, has also been reported to be increased in the serum of patients with active sarcoidosis. Enzyme activity in patients with active tuberculosis, primary pulmonary neoplasms, and idiopathic interstitial pulmonary fibrosis did not differ significantly from that of controls.
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PMID:Identification of a thermolysin-like metalloendopeptidase in serum: activity in normal subjects and in patients with sarcoidosis. 636 93

It has been suggested that increased recruitment of phagocytes and subsequent clearance of particles may follow instillation of a leukocyte chemoattractant to lungs containing silica. The present study quantitated serially the silica content in alveolar spaces, in lung tissue and in hilar lymph nodes of mice that received 2 mg silica only, compared to a group that also received 100 micrograms intratracheal chemotactic factor N-formyl-L-methionyl-leucyl-phenylalanine (FMLP) at 2 and 3 weeks after silica. These mice showed a supplemental increase in alveolar macrophages and neutrophils, and an increase in silica was measured in lavaged cells and fluid soon after FMLP injection. At all times to 16 weeks, the silica content of lung tissue was significantly lower in mice that also received FMLP, and in this group, pulmonary fibrosis was much reduced, as shown morphologically and biochemically. In addition, there was reduced translocation of silica to lymph nodes in FMLP-treated mice. The results indicate that induction of a controlled inflammatory response in the alveoli at a time when particles are present in the pulmonary interstitium can accelerate clearance by increasing phagocyte traffic to the alveoli. The subsequent reduction in particle content of the lung is associated with a lower level of pulmonary fibrosis.
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PMID:Enhanced clearance of silica from mouse lung after instillation of a leukocyte chemotactic factor. 792 40

An increase of alkaline phosphatase (ALP) activity has been observed in the bronchoalveolar lavage fluid (BALF) of patients affected by pulmonary fibrosis in chronic interstitial lung disorders. To characterize the ALP isoenzymes in such cases, we used gel filtration, agarose gel electrophoresis, heat and amino acid inhibition assays, wheat-germ agglutinin (WGA) precipitation, and an immunoassay specific for the bone-isoform of ALP. Only one anodic band representing a high-molecular-weight isoform of ALP (Mr approximately 2,000 kDa) was observed on electrophoresis of BALF. The inhibition assay results were consistent for a tissue-nonspecific isoenzyme sensitive to a temperature of 56 degrees C (71.9 +/- 2.5% inhibition) and to homoarginine (65.7 +/- 1.9%), and resistant to L-phenylalanine and L-leucine. Less than 13% of ALP activity was heat-stable. After incubation of BALF specimens with glycosyl-phosphatidylinositol-phospholipase D plus Nonidet P-40, or with phosphatidylinositol-phospholipase C alone, an electrophoretic cathodic band (Mr approximately 220 kDa) appeared near the bone band of a standard serum. With the WGA assay, 84.4 +/- 3.3% of ALP precipitated and the band disappeared. After immunoassay for the bone isoform, a mean of less than 5% enzyme activity was measured. We conclude that the ALP found in BALF is a pulmonary isoform of a tissue nonspecific isoenzyme.
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PMID:Identification of human pulmonary alkaline phosphatase isoenzymes. 910 92

To identify the physiological role of Hck, a functionally redundant member of the Src family of tyrosine kinases expressed in myelomonocytic cells, we generated Hck(F/F) "knock-in" mice which carry a targeted tyrosine (Y) to phenylalanine (F) substitution of the COOH-terminal, negative regulatory Y(499)-residue in the Hck protein. Unlike their Hck(-/-) "loss-of-function" counterparts, Hck(F/F) "gain-of-function" mice spontaneously acquired a lung pathology characterized by extensive eosinophilic and mononuclear cell infiltration within the lung parenchyma, alveolar airspaces, and around blood vessels, as well as marked epithelial mucus metaplasia in conducting airways. Lungs from Hck(F/F) mice showed areas of mild emphysema and pulmonary fibrosis, which together with inflammation resulted in altered lung function and respiratory distress in aging mice. When challenged transnasally with lipopolysaccharide (LPS), Hck(F/F) mice displayed an exaggerated pulmonary innate immune response, characterized by excessive release of matrix metalloproteinases and tumor necrosis factor (TNF)alpha. Similarly, Hck(F/F) mice were highly sensitive to endotoxemia after systemic administration of LPS, and macrophages and neutrophils derived from Hck(F/F) mice exhibited enhanced effector functions in vitro (e.g., nitric oxide and TNFalpha production, chemotaxis, and degranulation). Based on the demonstrated functional association of Hck with leukocyte integrins, we propose that constitutive activation of Hck may mimic adhesion-dependent priming of leukocytes. Thus, our observations collectively suggest an enhanced innate immune response in Hck(F/F) mice thereby skewing innate immunity from a reversible physiological host defense response to one causing irreversible tissue damage.
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PMID:Constitutive activation of the SRC family kinase Hck results in spontaneous pulmonary inflammation and an enhanced innate immune response. 1220 75

Macrophage activation is a key feature of inflammatory reactions occurring during bacterial infections, immune responses and tissue injury. We previously demonstrated that human macrophages of different origin express the tyrosine kinase receptor recepteur d'origine nantaise, the human receptor for MSP (RON) and produce superoxide anion (O(2)(-)) when challenged with macrophage-stimulating protein (MSP), the endogenous ligand for RON. This study was aimed to evaluate the role of MSP in alveolar macrophages (AM) isolated from healthy volunteers and patients with interstitial lung diseases (sarcoidosis, idiopathic pulmonary fibrosis), either smokers or non-smokers, by evaluating the respiratory burst, cytokine release and nuclear factor-kappa B (NF-kappaB) activation. MSP effects were compared with those induced by known AM stimuli, for example, phorbol myristate acetate, N-formyl-methionyl-leucyl-phenylalanine, lipopolysaccharide.MSP evokes O(2)(-) production, cytokine release and NF-kappaB activation in a concentration-dependent manner. By evaluating the respiratory burst, we demonstrate a significantly increased O(2)(-) production in AM from healthy smokers or smokers with pulmonary fibrosis, as compared to non-smokers, thus suggesting MSP as an enhancer of cigarette smoke toxicity. Besides inducing interleukin-1 beta (IL-1beta) and interleukin-10 (IL-10) production, MSP triggers an enhanced tumor necrosis factor-alpha release, especially in healthy and pulmonary fibrosis smokers. On the contrary, MSP-induced IL-10 release is higher in AM from healthy non-smokers. MSP activates the transcription factor NF-kappaB; this effect is more potent in healthy and fibrosis smokers (2.5-fold increase in p50 subunit translocation). This effect is receptor-mediated, as it is prevented by a monoclonal anti-human MSP antibody. The higher effectiveness of MSP in AM from healthy smokers and patients with pulmonary fibrosis is suggestive of its role in these clinical conditions.
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PMID:Macrophage-stimulating protein differently affects human alveolar macrophages from smoker and non-smoker patients: evaluation of respiratory burst, cytokine release and NF-kappaB pathway. 1663 52