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 Hermansky-Pudlak syndrome (HPS) is a triad of tyrosine-positive albinism, platelet dysfunction, and the deposition of an abnormal ceroid-like pigment in the tissues. Complications of the syndrome, such as pulmonary fibrosis, renal failure, and cardiomyopathy, have been described. Granulomatous colitis has been documented in several families with the HPS. The bowel disease of the HPS is a unique type of inflammatory bowel disease with clinical features suggestive of idiopathic ulcerative colitis and pathologic features suggestive of Crohn's disease. Analogous to the presentation of Crohn's disease with perianal and perirectal involvement, we describe the occurrence of perianal disease and a perirectal abscess in a 29-yr-old woman with HPS and mild granulomatous colitis.
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PMID:Perirectal abscess in the Hermansky-Pudlak syndrome. 249 40

In addition to the triad in the Hermansky-Pudlak syndrome (tyrosine-positive oculocutaneous albinism, mild bleeding tendency with a normal platelet-count and widespread accumulation of ceroid-like pigment in various organs), we document severe pulmonary fibrosis, pseudomelanosis coli and deeply pigmented renal cortex. In the liver, innumerable number of pigment-laden Kupffer cells and macrophages in the Glisson capsule were seen. Interestingly, many intralysosomal accumulations of the pigment within the hepatocytes were found by electron microscopy, suggesting that these configurations possibly resulted from a dysfunction of the lysosome itself, especially with regard to loss of digestive and secretory activity. The triad and other complications may also be resultants of a lysosomal dysfunction.
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PMID:Hermansky-Pudlak syndrome with special reference to lysosomal dysfunction. A case report and review of the literature. 642 16

The Hermansky-Pudlak syndrome consists of tyrosine-positive albinism, a defect in the second phase of platelet aggregation, and widespread accumulation of a ceroidlike pigment in tissue. Pulmonary fibrosis has also been reported. In this paper, we describe two families with documented Hermansky-Pudlak syndrome in which four members, two from each family, developed granulomatous colitis. This adds another disease entity to those associated with this syndrome. We discuss possible connecting links between these disease expressions.
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PMID:Hermansky-Pudlak syndrome with granulomatous colitis. 735 Aug 69

The influence of peplomycin (PLM) and azelastine hydrochloride (Azeptin) on reactive oxygen (RO) and cytokine generation was examined in human peripheral blood mononuclear leukocytes, polymorphonuclear leukocytes (PMN), and rabbit alveolar macrophages (RAM). In addition, the influence of these drugs on DNA and collagen synthesis was investigated in human gingival and rabbit pulmonary fibroblasts. In vitro, PLM increased the FMLP- and PMA-induced chemiluminescence and superoxide (O2-) generation in human PMN and RAM in a dose-dependent manner. In contrast to PLM, Azeptin dose-dependently suppressed RO generation. Such contrasting actions of PLM and Azeptin were also observed in RAM and PMN obtained from rabbits treated with PLM or Azeptin. Even when human PMN were preincubated with 10-100 micrograms/ml of PLM, the increase in RO generation was negligible in the presence of 10(-5) M Azeptin in the culture medium. No increases in RO generation were observed in RAM or PMN obtained from rabbits that had received PLM (0.1 mg/kg per day) and Azeptin (0.04 mg/kg per day) concomitantly. PLM suppressed superoxide dismutase activity in RAM and human PMN, while Azeptin did not affect this activity. In vitro, PLM up-regulated the release of interleukin-1 beta, interleukin-6, tumor necrosis factor alpha, and granulocyte-macrophage colony-stimulating factor both from human cells and from RAM and pulmonary fibroblasts. In the generation of these cytokines, Azeptin abrogated the up-regulatory action of PLM. PLM and Azeptin also had contrasting actions in [3H]thymidine and [3H]proline incorporation in human and rabbit fibroblasts. Furthermore, protein tyrosine phosphorylation, in particular that of a 115-kDa protein in human PMN, was suppressed by Azeptin and enhanced by PLM. These results seem to indicate that up-regulated RO and collagen generation are the causative factors of PLM-induced pulmonary fibrosis and that Azeptin may suppress the adverse effect.
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PMID:Contrasting influence of peplomycin and azelastine hydrochloride (Azeptin) on reactive oxygen generation in polymorphonuclear leukocytes, cytokine generation in lymphocytes, and collagen synthesis in fibroblasts. 780 82

Asbestos and the phorbol ester tumor promoter, 12-O-tetradecanoylphorbol-13-acetate (TPA), increase c-fos and c-jun mRNA levels and AP-1 DNA binding activity in rat pleural mesothelial (RPM) cells, a target cell of asbestos-induced mesotheliomas (N. H. Heintz et al., Proc. Natl. Acad. Sci. USA, 90: 3299-3303, 1993). Because protein kinase C (PKC) is the intracellular receptor of phorbol ester tumor promoters and asbestos is a putative tumor promoter in the respiratory tract, we hypothesized that PKC might play a critical role in asbestos-induced cell signaling pathways associated with regulation of proto-oncogenes. Using a panel of PKC antibodies, we identified PKC alpha as the major PKC isozyme in RPM cells. We then pretreated cells with phorbol ester dibutyrate to down-modulate PKC or with calphostin C, a specific PKC inhibitor, to determine if depletion of PKC alpha could block asbestos-induced c-fos/c-jun expression. Quantitation of Northern blots showed that fiber-associated c-fos/c-jun mRNA levels were significantly lower either after PKC alpha down-modulation or pretreatment with calphostin C. In addition, to determine whether tyrosine kinases also were involved in proto-oncogene activation by asbestos, tyrphostin AG82 or herbimycin A was added to RPM cells before exposure to asbestos. These inhibitors decreased crocidolite-induced c-fos but not c-jun levels, suggesting that tyrosine kinases have different regulatory roles in asbestos-induced c-fos versus c-jun signaling pathways. The ability to block induction of asbestos-induced proto-oncogene expression using pharmacological intervention may be important in prevention and treatment of asbestos-induced proliferative diseases including lung cancers, mesothelioma, and pulmonary fibrosis.
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PMID:Inhibition of protein kinase C prevents asbestos-induced c-fos and c-jun proto-oncogene expression in mesothelial cells. 924 32

Inhibition of peplomycin (PLM)-induced pulmonary fibrosis by azelastine hydrochloride (Azeptin) was examined using ICR mice, and the effects of both drugs on signal transduction were investigated. Microscopically, Azeptin (a total of 56 mg/kg for 28 days) suppressed pulmonary fibrosis in mice which received an i.p. injection of a total of 60 or 75 mg/kg PLM. In parallel with the microscopic findings, smaller amounts of collagen were synthesized in the lungs of Azeptin-injected mice. PLM enhanced the expression of interleukin-1 beta- and transforming growth factor-beta-mRNA in lungs. In contrast, Azeptin suppressed the expression. Compatible with these in vivo results, Azeptin and PLM contradictively regulated protein tyrosine phosphorylation and c-myc mRNA expression in human gingival and mouse pulmonary fibroblasts. In addition, NF-kappa B was activated by fibroblast treatment with 5 micrograms/ml PLM for 1 h, but intranuclear NF-kappa B was decreased by cell treatment with 10(-5) M Azeptin. From these results, it is concluded that Azeptin inhibits PLM-induced pulmonary fibrosis by antagonizing the up-regulation of signal transduction.
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PMID:Azelastine hydrochloride (Azeptin) inhibits peplomycin (PLM)-induced pulmonary fibrosis by contradicting the up-regulation of signal transduction. 936 3

Several studies suggest that dietary supplementation with antioxidants can influence the response to chemotherapy as well as the development of adverse side effects that results from treatment with antineoplastic agents. Administration of antineoplastic agents results in oxidative stress, i.e., the production of free radicals and other reactive oxygen species (ROS). Oxidative stress reduces the rate of cell proliferation, and that occurring during chemotherapy may interfere with the cytotoxic effects of antineoplastic drugs, which depend on rapid proliferation of cancer cells for optimal activity. Antioxidants detoxify ROS and may enhance the anticancer effects of chemotherapy. For some supplements, activities beyond their antioxidant properties, such as inhibition of topoisomerase II or protein tyrosine kinases, may also contribute. ROS cause or contribute to certain side effects that are common to many anticancer drugs, such as gastrointestinal toxicity and mutagenesis. ROS also contribute to side effects that occur only with individual agents, such as doxorubicin-induced cardiotoxicity, cisplatin-induced nephrotoxicity, and bleomycin-induced pulmonary fibrosis. Antioxidants can reduce or prevent many of these side effects, and for some supplements the protective effect results from activities other than their antioxidant properties. Certain side effects, however, such as alopecia and myelosuppression, are not prevented by antioxidants, and agents that interfere with these side effects may also interfere with the anticancer effects of chemotherapy.
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PMID:Dietary antioxidants during cancer chemotherapy: impact on chemotherapeutic effectiveness and development of side effects. 1096 14

To explore the mechanism of pulmonary fibrosis by bleomycin and its derivative, peplomycin (PLM), we examined the influence of PLM on signal transduction in human peripheral blood lymphocytes (HL), monocytes (HM) and fibroblasts (HF). Tyrosine phosphorylation of multiple proteins in HL and HM were induced by 0.001 to 0.05 microg/ml and by 0.01 to 0.5 microg/ml of PLM, respectively. In HF, 116-kDa protein was phosphorylated 0.2 to 5 microg/ml of PLM. When HL were treated with 0.01 microg/ml of PLM, phosphorylation of p56lck and activation of extracellular-signal related kinase-2 (ERK2) were induced. ERK2 was also activated in HM. Coordinately, the ratio of p21ras-binding GTP/GDP was increased by PLM. As well as interleukin-2, PLM induced tyrosine phosphorylation of JAK-3. In addition, PLM upregulated the nuclear translocation of nuclear factor-kappa B and the expression of c-myc-mRNA in HL, HM and HF. Furthermore, 0.01 to 0.001 microg/ml PLM enhanced the cytokine generation by HL and HM, and 1 to 5 microg/ml PLM increased cytokine generation and collagen synthesis by HF. These upregulatory effects of PLM were abrogated by pretreatment of the cells with a tyrosine kinase inhibitor. These results indicate that PLM upregulates signal transduction in a variety of cell types and the upregulation may induce pulmonary fibrosis.
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PMID:The upregulation by peplomycin of signal transduction in human cells. 1167 97

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

Cryptogenic fibrosing alveolitis (CFA), also known as idiopathic pulmonary fibrosis (IPF), is the end stage of a heterogeneous group of disorders in which the deposition of excessive amounts of collagen results in the loss of lung function and premature death. The molecular mechanisms underlying the disease are unknown. Accordingly, there is much debate as to whether pulmonary fibrosis is the end result of (1) a chronic inflammatory process or (2) a disturbance in normal epithelium-fibroblast cross talk, or both. In addition, it appears increasingly likely that there is a genetic component in the development of pulmonary fibrosis. The IL-6 cytokine family is a group of pleiotropic mediators produced by a variety of cells in response to a inflammatory stimuli. These cytokines are grouped together on the basis of weak structural homology, overlapping functions, and shared use of the transmembrane glycoprotein beta-subunit gp130 as part of their multimeric receptor complexes. Activation of these receptor complexes results in the recruitment and phosphorylation of specific transcription factors. In addition, membrane-proximal tyrosine residues act as docking sites for molecules involved in the activation of extracellular signal-related kinase (ERK). However, studies in genetically engineered mice that overexpress members of this family have shown that while overlapping biological activities exist, there are effects specific to individual cytokines. Data from both human and animal studies are now emerging to suggest that members of this cytokine family play an important role in the pathogenesis of fibroproliferative diseases and thus represent a novel group of cytokines implicated in pulmonary fibrosis. Importantly, manipulation of signaling pathways activated by these cytokines may suppress fibrosis but leave innate cellular mechanisms necessary for host defense largely untouched. This may provide guides for the development of novel pharmacological treatment for fibroproliferative diseases.
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PMID:The role of gp130/IL-6 cytokines in the development of pulmonary fibrosis: critical determinants of disease susceptibility and progression? 1295 Nov 64


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