Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UNIPROT:P43026 (lipopolysaccharide)
62,215 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

An imbalance between proteases and antiproteases may play a role in emphysema, which is characterized by increased degradation of extracellular matrix, and in airway remodeling in chronic bronchitis and asthma, in which there is increased collagen deposition. We assessed the effect of smoking on release of matrix metalloprotease-9 (MMP-9) and of its inhibitor, tissue inhibitor of metalloprotease-1 (TIMP-1), from alveolar macrophages, and determined the effects of proinflammatory (interleukin [IL]-1beta and lipopolysaccharide [LPS]) and antiinflammatory (IL-10) stimuli on the release of MMP-9 and TIMP-1. We performed bronchoalveolar lavage in 11 smokers and 11 nonsmokers, and cultured airway macrophages in the presence of control medium, IL-1beta, and LPS. Airway macrophages from smokers released greater amounts of MMP-9 and TIMP-1 at baseline and in response to IL-1beta and LPS than did those of nonsmokers. Airway macrophages from smokers produced more TNF-alpha and IL-10. IL-10 increased TIMP-1 release without modifying that of MMP-9, leading to a decrease in the MMP-9 to TIMP-1 ratio. Anti-IL-10 antibody had no effect on MMP-9 production induced by LPS. We conclude that the release of proteases and antiproteases by airway macrophages is increased in cigarette smokers, and can be regulated by exogenous IL-10.
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PMID:Balance of matrix metalloprotease-9 and tissue inhibitor of metalloprotease-1 from alveolar macrophages in cigarette smokers. Regulation by interleukin-10. 1102 44

Destruction of lung elastin is critical for development of emphysema associated with chronic obstructive pulmonary disease (COPD). Lung macrophages release elastolytic enzymes, including matrix metalloproteinase (MMP)-9, along with tissue inhibitors of MMP (TIMP). We examined the production and activity of macrophage-derived MMP-9 and TIMP-1 from alveolar macrophages (AM) from smokers with COPD, healthy smokers (HS), and nonsmokers (NS). AM were stimulated with either lipopolysaccharide (LPS), interleukin (IL)-1 beta, or cigarette smoke-conditioned culture medium (CSM). AM from patients with COPD released greater amounts of MMP-9 with greater enzymatic activity than HS and NS. In contrast, AM from NS released more TIMP-1 than cells from HS and subjects with COPD. LPS and IL-1 beta caused a dose-dependent increase in MMP-9 release and activity, together with increased levels of TIMP-1. Dexamethasone prevented the increase in MMP-9 release, and increased TIMP-1 release. CSM increased MMP-9 and TIMP-1 release from AM of all groups. Dexamethasone decreased CSM-stimulated MMP-9 release, but had no effect on MMP-9 activity This study suggests that macrophages might be important in the development of COPD because these cells exhibit increased levels of elastolytic activity.
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PMID:Release and activity of matrix metalloproteinase-9 and tissue inhibitor of metalloproteinase-1 by alveolar macrophages from patients with chronic obstructive pulmonary disease. 1197 Sep 13

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

An early response to cigarette smoke is an influx of leukocytes into the lung. Alveolar epithelial type II (ATII) cells may contribute by releasing chemokines in response to cigarette smoke and neutrophil elastase (NE). Human ATII cells were purified from normal regions of lungs resected for carcinoma (n = 14). In vitro, these cells exhibited ATII cell characteristics: lamellar bodies, apical microvilli, tight junctions, and expressed surfactant apoprotein C. Basal ATII cell release of five chemokines ranked as follows: monocyte chemotactic protein (MCP)-1 > interleukin (IL)-8 > growth-related oncogene (GRO)-alpha > macrophage inflammatory protein (MIP)-1alpha > regulated on activation, normal T cell expressed and secreted (RANTES). MIP-1alpha and RANTES were often not detectable. After stimulation with a mixture of lipopolysaccharide/endotoxin (LPS), tumor necrosis factor-alpha, IL-1beta, and IFN-gamma, MCP-1 and IL-8 secretion rose 4-6-fold, whereas GRO-alpha rose 25-fold. NE stimulated IL-8 mRNA expression, and 10nM NE stimulated IL-8 secretion; however, 100 nM NE caused a decrease in extracellular IL-8, MCP-1, and GRO-alpha, attributed to proteolysis. Cigarette smoke extract (CSE) inhibited IL-8 mRNA expression and release of all chemokines. Glutathione protected against the effects of CSE, suggesting oxidative mechanisms. GRO-alpha, important in growth and repair, was sensitive to both stimulation, by LPS:cytokines, and inhibition, by CSE. Thus, contrary to the original hypothesis, high concentrations of NE and CSE resulted in reduced extracellular chemokine levels. We hypothesize that reduced ATII cell-derived chemokine levels compromise alveolar repair, contributing to cigarette smoke-induced alveolar damage and emphysema.
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PMID:Primary human alveolar type II epithelial cell chemokine release: effects of cigarette smoke and neutrophil elastase. 1503 39

During respiratory cycles, airborne particles and pathogens are inhaled into the lung, which can cause cytokine production by respiratory macrophages and inflammatory responses. Secreted cytokines affect surfactant protein expression and homeostasis in the lung. In coculturing experiments in vitro, bronchoalveolar macrophages stimulated human surfactant protein B (hSP-B) gene transcription in primary alveolar type II epithelial cells in lipopolysaccharide-independent and -dependent ways. Neutralization by IL-6 antibody abolished lipopolysaccharide-dependent macrophage stimulation of hSP-B gene transcription. IL-6 treatment enhanced signal transducer and activator of transcription (Stat)3 phosphorylation at Y705 in alveolar type II epithelial cells and Clara cells in vivo. Biochemical analysis of functional domain swapping between Stat1 and Stat3 identified that the SH2 domain and the DNA binding domain are critical for Stat3 stimulation of hSP-B gene transcription. Glutathione-S-transferase pull-down study determined functional domains required for protein-protein interaction between Stat3 and retinoic acid receptor-alpha. Cotransfection of Stat3 and retinoic acid receptor-alpha into respiratory epithelial cells resulted in synergistic DNA binding and transcriptional activation on the hSP-B gene. To assess Stat3 physiological function, overexpression of a dominant negative Stat3 in respiratory epithelial cells in a doxycycline-controlled double transgenic mouse line caused pulmonary emphysema and increase of animal death during hyperoxia. Therefore, the IL-6/Stat3 signaling axis plays an important role in surfactant protein homeostasis and respiratory inflammation in the lung.
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PMID:Synergy between signal transducer and activator of transcription 3 and retinoic acid receptor-alpha in regulation of the surfactant protein B gene in the lung. 1504 88

Since the discovery of the first matrix metalloproteinase (MMP), this ever-growing family of proteinases has been the subject of intense research. Although it was initially believed that MMPs were solely involved in matrix turnover and degradation, there are now data suggesting MMPs are actively involved in the inflammatory process. In previous studies, we have demonstrated an increase in MMP expression in human cell-based assays and in preclinical rat models of airway inflammation. Therefore, the aim of this study was to characterize the role of MMPs in these models by profiling the impact of a broad-spectrum MMP inhibitor. In lipopolysaccharide (LPS)-stimulated THP-1 cells and primary human lung tissue macrophages, the MMP inhibitor had no significant effect on the release of tumor necrosis factor-alpha, interleukin (IL)-8, IL-1 beta, growth-regulated oncogene-alpha, macrophage inflammatory protein-1 alpha, or IL-6 whereas dexamethasone has a significant impact on all cytokines from both cell types. Similarly, in the more biologically complex LPS-driven rat model of airway inflammation, the MMP inhibitor did not have an impact on mediator release and cellular burden. The compound did, however, significantly reduce levels of lung MMP-9. Furthermore, in a "disease" model, the compound did not affect cellular inflammation but did significantly reduce elastase-induced experimental emphysema. In summary, these data demonstrate for the first time that MMPs do not play a role in the increase in inflammatory mediators or cellular burden observed in these preclinical models. However, they do appear to be involved in the elastase-driven breakdown of airway structure, which is not due to a direct effect of the stimulus.
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PMID:Role of matrix metalloproteinases in the inflammatory response in human airway cell-based assays and in rodent models of airway disease. 1669 Jul 22

Chronic lipopolysaccharide (LPS) exposure may contribute to the pathogenesis of a number of lung diseases including COPD and emphysema. We sought to develop a large-animal model of emphysema using repeated LPS administration into sheep lung segments. An experimental protocol was designed to facilitate comparisons with elastase-treated and control segments within the same lung of individual sheep. Histopathologic evaluation of segments treated with LPS demonstrated low-grade inflammation characterized by an increase in the number of intra-alveolar macrophages and lymphocytes. Treated segments demonstrated a significant reduction in airspace surface area (ASA), an increase in percent disrupted alveolar attachments and the distance between normal alveolar attachments, and a reduction in the number of normal alveolar attachments surrounding nonrespiratory bronchioles. Coefficient of variation of individual ASA measurements in elastase-treated segments was indicative of a heterogeneous parenchymal response, in contrast to that associated with chronic LPS treatment. Our results demonstrate that chronic LPS treatment of individual lung segments in sheep induces microscopic emphysema qualitatively and quantitatively consistent with both accepted pathologic definitions of this condition and with that produced by airway instillation of elastolytic enzymes. Development of this phenotype is associated with evidence of downregulated activation of transforming growth factor beta.
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PMID:Local lung responses following endobronchial elastase and lipopolysaccharide instillation in sheep. 1804 96

Chronic airway inflammation is a cardinal feature of chronic obstructive pulmonary disease (COPD), a destructive cigarette smoke-induced lung disease. Although it is apparent that dendritic cells (DCs) are an important constituent of the chronic inflammatory cell influx found in airways of COPD patients, the functional roles of DCs in the pathogenesis of smoking-induced emphysema are unknown. We postulated that DCs activated by cigarette smoke constituents directly participate in the chronic inflammation that characterizes COPD airways. Concordant with this hypothesis, we observed that incubation of DCs with cigarette smoke extract (CSE), and chronic exposure of mice to cigarette smoke, both augmented the generation of neutrophilic chemokines by immature and lipopolysaccharide (LPS) or CD40L-matured DCs. The generation of interleukin-8 (CXCL8/IL-8) by human DCs conditioned with CSE was suppressed by the anti-oxidant n-acetyl cysteine (NAC), implying the involvement of oxidant sensitive pathways as a primary mechanism involved in the enhanced CXCL8/IL-8 generation. Cigarette smoke extract and nicotine also augment the production of secreted prostaglandin-E2 and intra-cellular cyclo-oxygenase-2 (COX-2) in maturing DCs. Whereas NAC suppressed production of CXCL8 by CSE-conditioned DCs, it augmented production of PGE2 and cellular COX-2 levels in maturing DCs. These studies indicate that the stimulation of DCs by cigarette smoke-induced oxidative stress and nicotine promote the generation of pro-inflammatory responses that promote chronic inflammation in smokers. Certain pharmacologic strategies such as anti-oxidant therapy may be only partially effective in mitigating cigarette smoke-induced pro-inflammatory DC-mediated responses in smokers.
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PMID:Nicotine and oxidative cigarette smoke constituents induce immune-modulatory and pro-inflammatory dendritic cell responses. 1853 67

CX3CR1 is expressed on monocytes, dendritic cells, macrophages, subsets of T lymphocytes, and natural killer cells and functions in diverse capacities such as leukocyte adhesion, migration, and cell survival on ligand binding. Expression of the CX3CL1 gene, whose expression product is the sole ligand for CX3CR1, is up-regulated in human lungs with chronic cigarette smoke-induced obstructive lung disease. At present, it is unknown whether CX3CL1 up-regulation is associated with the recruitment and accumulation of immune cells that express CX3CR1. We show that mice chronically exposed to cigarette smoke up-regulate CX3CL1 gene expression, which is associated with an influx of CX3CR1+ cells in the lungs. The increase in CX3CR1+ cells is primarily comprised of macrophages and T lymphocytes and is associated with the development of emphysema. In alveolar macrophages, cigarette smoke exposure increased the expression of both CX3CR1 and CX3CL1 genes. The inducibility of CX3CR1 expression was not solely dependent on a chronic stimulus because lipopolysaccharide up-regulated CX3CR1 in RAW264.7 cells in vitro and in mononuclear phagocytes in vivo. Our findings suggest a mechanism by which macrophages amplify and promote CX3CR1+ cell accumulation within the lungs during both acute and chronic inflammatory stress. We suggest that one function of the CX3CR1-CX3CL1 pathway is to recruit and sustain divergent immune cell populations implicated in the pathogenesis of cigarette smoke-induced emphysema.
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PMID:CX3CL1 up-regulation is associated with recruitment of CX3CR1+ mononuclear phagocytes and T lymphocytes in the lungs during cigarette smoke-induced emphysema. 1877 44

Gram-negative bacterial endotoxin lipopolysaccharide (LPS) administration has been used as an animal model of sepsis-related acute lung injury and adult respiratory distress syndrome (ALI/ARDS). This paper describes the lung histology following lung injury induced by the intraperitoneal (i.p.) administration of endotoxin to rats, in comparison with earlier findings. ALI was induced by the i.p. administration of Esherichia coli LPS 2 (n = 8) or 3 (n = 5) mg/kg, whereas physiological saline was administered to the control animals (n = 5). Eighteen hours after the LPS injections, the animals were euthanized. The lungs and heart were removed in one block for histological study (hematoxylin and eosin [H&E], periodic acid-Schiff [PAS], Mason's trichrome; light microscopy). The lung tissue injury (bronchial wall, vessels, alveoli, interstitium) was graded via a scoring system (0 to 3+). The control animals showed intact lung tissue. Ten of the 13 LPS group had bronchus-associated lymphoid tissue (BALT) hyperplasia. Pathological signs of ALI/ARDS, diffuse alveolar damage (DAD) and emphysema, were observed in 5 and 8 cases, respectively. LPS injection induces primarily BALT hyperplasia and also the less characteristic DAD. This rat model is suitable for the investigation not only of ALI/ARDS but also of BALT hyperplasia occurring as a consequence of chronic pulmonary inflammatory processes.
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PMID:Development of bronchus-associated lymphoid tissue hyperplasia following lipopolysaccharide-induced lung inflammation in rats. 1933 2


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