Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P43026 (lipopolysaccharide)
 62,215 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Regeneration of alveolar epithelial cells is one of the important repair processes in many types of lung injury. We have examined sequential analysis of histopathology and gene expressions of surfactant protein A (SP-A), SP-B, and SP-C mRNA in alveolar type II cells of rats with lipopolysaccharide-induced (LPS-induced) lung injury. A small dose (1 to 2 mg/kg) of LPS was injected by intratracheal instillation in adult rats, and after a given period, the lungs were processed for examination using light and electron microscopy, for immunohistochemical study using anti-bromodeoxyuridine (anti-BrdU) and anti-SP-A antibodies, and for in situ hybridization using type-specific, surfactant cDNA probes. Northern blot analysis was also performed. From 3 to 7 days after LPS administration, alveolar septa were thickened, with increased numbers of epithelial and interstitial cells. BrdU-incorporated cells apparently increased in number in these areas, and many alveolar epithelial cells were intracellularly immunoreactive to anti-SP-A antibody, with many lamellar bodies found on examination using electron microscopy. By in situ hybridization, the number of autoradiographic silver grains for SP-A, SP-B, and SP-C mRNA increased strikingly, in alveolar type II epithelial cells of the lungs from LPS-administered rats. These responses of surfactant gene expression to LPS seemed to be stronger in alveolar epithelial cells than in the bronchiolar epithelium. By Northern blot analysis, the relative abundances of SP-A, SP-B, and SP-C mRNA were also higher in the LPS-administered lungs and correlated well with the results of in situ hybridization. The present study demonstrates that intratracheal administration of LPS induces the marked proliferation of alveolar epithelial cells in association with the concurrently increased SP-A, SP-B, and SP-C mRNA, as well as the SP-A production in the early response to lung injury. These results suggest that proliferation and differentiation of alveolar epithelial cells may play important roles in the repair process of the damaged alveoli after acute lung injury.
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PMID:Overexpression of surfactant protein SP-A, SP-B, and SP-C mRNA in rat lungs with lipopolysaccharide-induced injury. 856 84

The objectives of this investigation were 1) to report that pulmonary surfactant inhibits lipopolysaccharide (LPS)-induced nitric oxide (. NO) production by rat alveolar macrophages, 2) to study possible mechanisms for this effect, and 3) to determine which surfactant component(s) is responsible. NO produced by the cells in response to LPS is due to an inducible. NO synthase (iNOS). Surfactant inhibits LPS-induced. NO formation in a concentration-dependent manner;. NO production is inhibited by approximately 50 and approximately 75% at surfactant levels of 100 and 200 microg phospholipid/ml, respectively. The inhibition is not due to surfactant interference with the interaction of LPS with the cells or to disruption of the formation of iNOS mRNA. Also, surfactant does not seem to reduce. NO formation by directly affecting iNOS activity or by acting as an antioxidant or radical scavenger. However, in the presence of surfactant, there is an approximately 80% reduction in the amount of LPS-induced iNOS protein in the cells. LPS-induced. NO production is inhibited by Survanta, a surfactant preparation used in replacement therapy, as well as by natural surfactant. NO formation is not affected by the major lipid components of surfactant or by two surfactant-associated proteins, surfactant protein (SP) A or SP-C. However, the hydrophobic SP-B inhibits. NO formation in a concentration-dependent manner;. NO production is inhibited by approximately 50 and approximately 90% at SP-B levels of 1-2 and 10 microgram/ml, respectively. These results show that lung surfactant inhibits LPS-induced. NO production by alveolar macrophages, that the effect is due to a reduction in iNOS protein levels, and that the surfactant component responsible for the reduction is SP-B.
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PMID:Pulmonary surfactant inhibits LPS-induced nitric oxide production by alveolar macrophages. 988 71

The adenoviral E3-14.7K protein is a cytoplasmic protein synthesized after adenoviral infection. To assess the contribution of E3-14. 7K-sensitive pathways in the modulation of inflammation by the respiratory epithelium, inflammatory responses to intratracheal lipopolysaccharide (LPS) and tumor necrosis factor (TNF)-alpha were assessed in transgenic mice bearing the adenoviral E3-14.7K gene under the direction of the surfactant protein (SP) C promoter. When E3-14.7K transgenic mice were administered LPS intratracheally, lung inflammation as indicated by macrophage and neutrophil accumulation in bronchoalveolar lavage fluid was decreased compared with wild-type control mice. Lung inflammation and epithelial cell injury were decreased in E3-14.7K mice 24 and 48 h after LPS administration. Intracellular staining for surfactant proprotein (proSP) B, proSP-C, and SP-B was decreased and extracellular staining was markedly increased in wild-type mice after LPS administration, consistent with LPS-induced lung injury. In contrast, intense intracellular staining of proSP-B, proSP-C, and SP-B persisted in type II cells of E3-14.7K mice, whereas extracellular staining of proSP-B and proSP-C was absent. Inhibitory effects of intratracheal LPS on SP-C mRNA were ameliorated by expression of the E3-14.7K gene. Similar to the response to LPS, lung inflammation after intratracheal administration of TNF-alpha was decreased in E3-14.7K transgenic mice. Levels of TNF-alpha after LPS administration were similar in wild-type and E3-14.7K-bearing mice. Cell-selective expression of E3-14.7K in the respiratory epithelium inhibited LPS- and TNF-alpha-mediated lung inflammation, demonstrating the critical role of respiratory epithelial cells in LPS- and TNF-alpha-induced lung inflammation.
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PMID:Adenoviral E3-14.7K protein in LPS-induced lung inflammation. 1074 39

This study examines the relationships between inflammation, surfactant protein (SP) expression, surfactant function, and lung physiology in a murine model of acute lung injury (ALI). 129/J mice received aerosolized endotoxin lipopolysaccharide [LPS] daily for up to 96 h to simulate the cytokine release and acute inflammation of ALI. Lung elastance (E(L)) and resistance, lavage fluid cell counts, cytokine levels, phospholipid and protein content, and surfactant function were measured. Lavage and lung tissue SP content were determined by Western blot and immunohistochemistry, and tissue messenger RNA (mRNA) levels were assessed by Northern blot and in situ hybridization. Tumor necrosis factor-alpha and neutrophil counts in bronchoalveolar lavage fluid increased within 2 h of LPS exposure, followed by increases in total protein, interleukin (IL)-1beta, IL-6, and interferon-gamma. E(L) increased within 24 h of LPS exposure and remained abnormal up to 96 h. SP-B protein and mRNA levels were decreased at 24, 48, and 96 h. By contrast, SP-A protein and mRNA levels and SP-C mRNA levels were not reduced. Surfactant dysfunction occurred coincident with changes in SP-B levels. This study demonstrates that lung dysfunction in mice with LPS-ALI corresponds closely with abnormal surfactant function and reduced SP-B expression.
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PMID:Decreased surfactant protein-B expression and surfactant dysfunction in a murine model of acute lung injury. 1147 73

Infection of the respiratory tract is a frequent cause of lung pathologies, morbidity, and death. When bacterial endotoxin [lipopolysaccharide (LPS)] reaches the alveolar spaces, it encounters the lipid-rich surfactant that covers the epithelium. Although binding of hydrophilic surfactant protein (SP) A and SP-D with LPS has been established, nothing has been reported to date on possible cross talks between LPS and hydrophobic SP-B and SP-C. We designed a new binding technique based on the incorporation of surfactant components to lipid vesicles and the separation of unbound from vesicle-bound LPS on a density gradient. We found that among the different hydrophobic components of mouse surfactant separated by gel filtration or reverse-phase HPLC, only SP-C exhibited the capacity to bind to a tritium-labeled LPS. The binding of LPS to vesicles containing SP-C was saturable, temperature dependent, related to the concentrations of SP-C and LPS, and inhibitable by distinct unlabeled LPSs. Unlike SP-A and SP-D, the binding of SP-C to LPS did not require calcium ions. This LPS binding capacity of SP-C may represent another antibacterial defense mechanism of the lung.
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PMID:Interaction of bacterial lipopolysaccharide with mouse surfactant protein C inserted into lipid vesicles. 1155 81

Intra-amniotic lipopolysaccharide (LPS) and cytokines may decrease respiratory distress syndrome (RDS) and increase chronic lung disease in the newborn. The aim was to identify the primary inflammatory mediators regulating the expression of surfactant proteins (SP) in explants from immature (22-day-old fetus) and mature (30-day term fetus and 2-day-old newborn) rabbits. In immature lung, interleukin (IL)-1alpha and IL-1beta upregulated the expression of SP-A and SP-B. These effects of IL-1 were diminished, and SP-C mRNA was suppressed additively in the presence of tumor necrosis factor (TNF)-alpha and either LPS or interferon (IFN)-gamma. LPS, TNF-alpha, or IFN-gamma had no effect alone. In explants from the term fetus and the newborn, LPS, IL-1alpha, and TNF-alpha additively suppressed the SPs. LPS acutely induced IL-1alpha in alveolar macrophages in mature lung but not in the immature lung. IFN-gamma that generally has low expression in intrauterine infection decreased the age dependence of the other agonists' effects on SPs. The present study serves to explain the variation of the pulmonary outcome after an inflammatory insult. We propose that IL-1 from extrapulmonary sources induces the SPs in premature lung and is responsible for the decreased risk of RDS in intra-amniotic infection.
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PMID:Regulation of surfactant proteins by LPS and proinflammatory cytokines in fetal and newborn lung. 1188 Mar 7

In addition to their effects on alveolar surface tension, some components of lung surfactant also have immunological functions. We found recently that the hydrophobic lung surfactant protein SP-C specifically binds to the lipid A region of lipopolysaccharide (LPS). In this study, we show that SP-C also interacts with CD14. Four observations showed cross talk between the three molecules SP-C, LPS, and CD14. (i) Like LBP, SP-C allows the binding of a fluorescent LPS to cells expressing CD14 (the other surfactant components were ineffective). (ii) Recombinant radiolabeled CD14 and SP-C (or a synthetic analog of SP-C) interact in a dose-dependent manner. (iii) LPS blocks the binding of radiolabeled CD14 to SP-C-coated wells. (iv) SP-C enhances the binding of radiolabeled CD14 to LPS-coated wells. These results, obtained with native murine SP-C and with three synthetic analogs, suggest that LPS and CD14 interact with the same region of SP-C and that binding of SP-C modifies the conformation of CD14 or the accessibility of its LPS-binding site, allowing it to bind LPS. This ability of SP-C to interact with the pattern recognition molecule CD14 extends the possible immunological targets of SP-C to a large panel of microorganisms that can enter the airways.
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PMID:Interaction of pulmonary surfactant protein C with CD14 and lipopolysaccharide. 1249 49

In both humans and mice, a deficiency of surfactant protein B (SP-B) is associated with a decreased concentration of mature SP-C and accumulation of a larger SP-C peptide, denoted SP-C(i), which is not observed under normal conditions. Isolation of hydrophobic polypeptides from the lungs of children who died with two different SP-B mutations yielded pure SP-C(i) and showed only trace amounts of mature SP-C. Determination of the SP-C(i) covalent structure revealed a 12-residue N-terminal peptide segment, followed by a 35-residue segment that is identical to mature SP-C. The SP-C(i) structure determined herein is similar to that of a proposed late intermediate in the processing of proSP-C, suggesting that SP-C(i) is the immediate precursor of SP-C. In bronchoalveolar lavage fluid from transgenic mice with a focal deficiency of SP-B, SP-C(i) was detected in the biophysically active, large aggregate fraction and was associated with membrane structures that are typical for a large aggregate surfactant. However, unlike SP-C, SP-C(i) exhibited a very poor ability to promote phospholipid adsorption, gave high surface tension during cyclic film compression, and did not bind lipopolysaccharide in vitro. SP-C(i) is thus capable of associating with surfactant lipids, but its N-terminal dodecapeptide segment must be proteolytically removed to generate a biologically functional peptide. The results of this study indicate that the early postnatal fatal respiratory distress seen in SP-B-deficient children is combined with the near absence of active variants of SP-C.
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PMID:N-terminally extended surfactant protein (SP) C isolated from SP-B-deficient children has reduced surface activity and inhibited lipopolysaccharide binding. 1504 96

The role of the degree of oligomerization in the structure and function of human surfactant protein A (SP-A) was investigated using a human SP-A1 mutant (SP-A1(DeltaAVC,C6S)), expressed in mammalian cells, resulting from site-directed substitution of serine for Cys(6) and substitution of a functional signal peptide for the cysteine-containing SP-A signal sequence. This Cys(6) mutant lacked the NH(2)-terminal Ala(-3)-Val(-2)-Cys(-1) (DeltaAVC) extension present in some SP-A1 isoforms. SP-A1(DeltaAVC,C6S) was assembled exclusively as trimers as detected by electron microscopy and size exclusion chromatography. Trimeric SP-A1(DeltaAVC,C6S) was compared with supratrimeric SP-A1, which is structurally and functionally comparable to the octadecameric protein isolated from human lung lavages. SP-A1(DeltaAVC,C6S) showed reduced thermal stability of the collagen domain, studied by circular dichroism, and increased susceptibility to trypsin degradation. The T(m) was 32.7 degrees C for SP-A1(DeltaAVC,C6S) and 44.5 degrees C for SP-A1. Although SP-A1(DeltaAVC,C6S) was capable of binding to calcium, rough lipopolysaccharide, and phospholipid vesicles, this mutant was unable to induce rough lipopolysaccharide and phospholipid vesicle aggregation, to enhance the interfacial adsorption of SP-B/SP-C-surfactant membranes, and to undergo self-association in the presence of Ca(2+). On the other hand, the lack of supratrimeric assembly hardly affected the ability of SP-A1(DeltaAVC,C6S) to inhibit the production of tumor necrosis factor-alpha by macrophage-like U937 cells stimulated with either smooth or rough lipopolysaccharide. We conclude that supratrimeric assembly of human SP-A is essential for collagen triple helix stability at physiological temperatures, protection against proteases, protein self-association, and SP-A-induced ligand aggregation. The supratrimeric assembly is not essential for the binding of SP-A to ligands and anti-inflammatory effects of SP-A.
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PMID:Role of the degree of oligomerization in the structure and function of human surfactant protein A. 1561 13

After penetration into the lower airways, bacterial lipopolysaccharide (LPS) interacts with alveolar cells in a fluid environment consisting of pulmonary surfactant, a lipid-protein complex which prevents alveolar collapsing and participates in lung defense. The two hydrophilic surfactant components SP-A and SP-D are proteins with collagen-like and lectin domains (collectins) able to interact with carbohydrate-containing ligands present on microbial membranes, and with defined regions of LPS. This explains their capacity to damage the bacterial envelope and induce an antimicrobial effect. In addition, they modulate LPS-induced production of pro-inflammatory mediators in leukocytes by interaction with LPS or with leukocyte receptors. A third surfactant component, SP-C, is a small, highly hydrophobic lipopeptide which interacts with lipid A and reduces LPS-induced effects in macrophages and splenocyte cultures. The interaction of the different SPs with CD14 might explain their ability to modulate some LPS responses. Although the alveolar fluid contains other antiLPS and antimicrobial agents, SPs are the most abundant proteins which might contribute to protect the lung epithelium and reduce the incidence of LPS-induced lung injury. The presence of the surfactant collectins SP-A and SP-D in non-pulmonary tissues, such as the female genital tract, extends their field of action to other mucosal surfaces.
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PMID:Interactions between LPS and lung surfactant proteins. 1594 47


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