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)

Alveolar macrophages (AM) recovered from the lower respiratory tract of individuals with interstitial lung disease (ILD) proliferate at a 2- to 15-fold increased rate (P.B. Bitterman et al. 1984. J. Clin. Invest. 74:460-469). Normal AM stimulated with immune complexes or asbestos release platelet-derived growth factor and insulin-like growth factor-I (IGF-I), and AM activated in vivo in ILD release these growth factors. We evaluated normal unstimulated and activated AM for the receptor for IGF-I to determine if macrophage IGF-I could be involved in the enhanced macrophage proliferation. Although normal AM did not have specific 125I-labeled recombinant IGF-I binding, AM activated by chrysotile asbestos or lipopolysaccharide in vitro or from individuals with ILD had detectable binding that could be inhibited by an anti-IGF-I receptor monoclonal antibody in a dose-dependent fashion. Autoradiography with 125I-labeled recombinant IGF-I revealed binding to the IGF-I receptor on the surface of activated AM, and the percentage of labeled cells was reduced with anti-IGF-I receptor monoclonal antibody or excess unlabeled recombinant IGF-I. Hybridization of total AM RNA to a 32P-labeled IGF-I receptor riboprobe using solution hybridization demonstrated IGF-I receptor mRNA transcripts in AM from an individual with asbestosis, consistent with active expression of the IGF-I receptor gene. In the context of the known role of IGF-I as a growth factor for many cells, these data are consistent with the concept that IGF-I and its receptor may play an important role in the proliferation of AM in the inflamed lower respiratory tract.
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PMID:Activated alveolar macrophages express the insulin-like growth factor-I receptor. 185 Jun 6

Alveolar macrophages (AM) play a key role in local immunoregulation. The objective of these studies was to compare the production of the pro- and mature forms of both interleukin-1 alpha (IL-1 alpha) and interleukin-1 beta (IL-1 beta) by AM from nine nonsmoking control subjects, six asymptomatic smokers, and nine patients with interstitial lung disease (ILD). IL-1 alpha and IL-1 beta steady-state mRNA levels in AM cultured over 20 h were determined using specific cDNA probes. IL-1 alpha, 35-kD pro-IL-1 beta, and 17-kD mature IL-1 beta protein levels in cell lysates and supernatants were determined by individual specific ELISAs. Before culture, the isolated AM contained no IL-1 alpha or IL-1 beta mRNA. AM from nonsmoking control subjects and asymptomatic smokers produced comparable levels of IL-1 alpha protein, 5.01 +/- 1.02 ng/ml and 4.54 +/- 1.07 ng/ml, respectively, only after stimulation with lipopolysaccharide (LPS) and not with granulocyte-macrophage colony-stimulating factor (GM-CSF). The majority of the IL-1 alpha was present in the cell lysates as 35-kD pro-IL-1 alpha, as determined by Western blot analysis. AM from patients with ILD produced higher levels of LPS-induced cell-associated IL-1 alpha protein (9.78 +/- 1.80 ng/ml, p = 0.031). LPS-induced IL-1 beta production by AM from nonsmoking control subjects (5.22 +/- 1.89 ng/ml) and asymptomatic smokers (4.39 +/- 0.66 ng/ml) was equivalent to total IL-1 alpha protein production.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Human alveolar macrophages produce predominantly the 35-kD pro-forms of interleukin-1 alpha and interleukin-1 beta when stimulated with lipopolysaccharide. 773 21

To evaluate the activity of PAM, levels of IL-1 released by PAM in patients with ILD (non smokers) were measured using lipopolysaccharide (LPS) stimulation and thymocyte proliferation method, healthy non-smokers as control group. The results showed that IL-1 released by PAM in patient groups both with and without LPS stimulation were significantly higher than that in control group, and also IL-1 released by PAM in healthy smokers was significantly higher than that in health non-smokers. It was indicated that IL-1 might play an important role in the process of ILD and chronic pulmonary inflammation.
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PMID:[Changes in interleukin-1 released by pulmonary alveolar macrophage in patients with interstitial lung disease]. 822 60

Alveolar macrophages (AMs) from patients with interstitial lung diseases, such as sarcoidosis and idiopathic pulmonary fibrosis, suppress the phytohaemagglutinin (PHA) stimulation of autologous peripheral lymphocytes. The aim of this study was to determine whether the suppressive effect of alveolar macrophages of patients with interstitial lung disease is due, not only to the secretion of soluble factors prostaglandin E2 (PGE2), interleukin-1 (IL-1) but is also correlated to a direct effect of AMs on the expression of IL-2 receptors (IL-2R: CD25) and on the induction of IL-2 activity. We studied 26 subjects, 8 with sarcoidosis, 7 with idiopathic pulmonary fibrosis, and 11 controls. Alveolar macrophages of sarcoid and idiopathic pulmonary fibrosis patients suppressed proliferation of autologous peripheral lymphocytes by 68 +/- 14% and 53 +/- 4.5%, respectively, compared to enhancement of 19 +/- 11% in three controls and suppression of 25 +/- 11% in the other six controls; the difference between subjects with interstitial lung disease and controls was significant. As already reported, the alveolar macrophages of sarcoid patients secreted large amounts of IL-1 (184 +/- 59 U.ml-1) whereas the alveolar macrophages from idiopathic pulmonary fibrosis patients secreted large amounts of PGE2 (3.6 +/- 2 ng.ml-1 x 10(-5) cells) compared with 23 +/- 19 U.ml-1 IL-1 and 0.34 +/- 0.15 ng.ml-1 x 10(-5) cells respectively, of controls. Suppression by supernatants recovered from lipopolysaccharide (LPS) stimulated alveolar macrophages can only partially explain the high suppressive effect of alveolar macrophages of interstitial lung diseases.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Suppressive mechanisms of alveolar macrophages in interstitial lung diseases: role of soluble factors and cell-to-cell contact. 837 Apr 44

Cyclosporin A (CsA) is an immunomodulator drug that has been used in the treatment of several types of advanced pulmonary interstitial disease. This beneficial effect occurs mainly in circumstances in which alveolitis due to CD4 lymphocytes is absent, suggesting that CsA acts on other types of cells. The present study was undertaken to determine the effect of CsA on inflammatory cytokine secretion by human alveolar macrophages (AMs). Human AMs were collected by bronchoalveolar lavage from four control subjects and 13 patients with interstitial lung disease. Purified human AMs were incubated with different concentrations of CsA (200, 20 and 2 ng ml-1) in the presence or absence of lipopolysaccharide (LPS). Interleukin-1 beta (IL-1 beta), tumour necrosis factor-alpha (TNF-alpha), IL-6 and IL-8 levels were measured in supernatants using specific enzyme-linked immunosorbent assays. It was found that CsA inhibits basal secretion of TNF-alpha and IL-8 at 20 and 200 ng ml-1. However, none of the different concentrations of CsA modified basal secretion of IL-1 beta nor IL-6. By contrast, a lower concentration of CsA (2 ng ml-1) inhibits LPS-stimulated secretion of all inflammatory cytokines. It is concluded that CsA exerts a modest effect on inflammatory cytokine production by human AMs.
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PMID:Effect of cyclosporin A on inflammatory cytokine production by human alveolar macrophages. 971 30

Tumor necrosis factor-alpha (TNF-alpha) is an important proinflammatory cytokine. Recently, pentoxifylline (POF) has been shown to suppress the synthesis of TNF-alpha from lipopolysaccharide (LPS)-stimulated human monocytes in cell cultures and in vivo. The aim of this study was to investigate whether POF-induced suppression of TNF-alpha secretion affects peripheral blood monocytes (PBM) and alveolar macrophages (AM) equally, and whether POF is able to suppress the spontaneous TNF-alpha production from AM in pulmonary sarcoidosis in vitro. In seven patients without interstitial lung disease we studied the effect of POF on LPS-stimulated PBM and AM cultured for 24 h. In six patients with sarcoidosis we investigated the effect of POF on the enhanced spontaneous TNF-alpha production by AM in vitro. POF induced a dose-dependent suppression of the LPS-stimulated TNF-alpha production which was not different for PBM and AM, respectively. In sarcoidosis, POF inhibited the spontaneous TNF-alpha production of AM at 0.1 mM by 91% and at 1 mM by 98%. In conclusion, POF inhibits LPS-induced TNF-alpha production from PBM and AM to a similar extent and can also inhibit the exaggerated spontaneous TNF-alpha production from AM in sarcoidosis in vitro. This may be the basis for further clinical trials to evaluate POF as an immunotherapeutic agent in sarcoidosis.
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PMID:Pentoxifylline inhibits TNF-alpha production from human alveolar macrophages. 992 65

To examine whether the development of hard metal (HM)-induced occupational asthma and interstitial lung disease involves alterations in nitric oxide (NO) pathways, we examined the effects of an industrial HM mixture on NO production, interactions between HM and lipopolysaccharide (LPS) on NO pathways, and alterations in airway reactivity to methacholine in rat lungs. HM (2.5 to 5 mg/100 g intratracheal) increased NO synthase (NOS; EC 1.14.23) activity of rat lungs at 24 h without increasing inducible NOS (iNOS) or endothelial NOS (eNOS) mRNA abundance or iNOS, eNOS, or brain NOS (bNOS) proteins. The increase in NOS activity correlated with the appearance histologically of nitrotyrosine immunofluorescence in polymorphonuclear leukocytes (PMN) and macrophages. Intraperitoneal injection of LPS (1 mg/kg) caused up-regulation of iNOS activity, mRNA, and protein at 8 h but not at 24 h. HM at 2.5 mg/100 g, but not at 5 mg/100 g, potentiated the LPS-induced increase in NOS activity, iNOS mRNA, and protein. However, HM decreased eNOS activity at 8 h and eNOS protein at 24 h. Whole body plethysmography on conscious animals revealed that HM caused basal airway obstruction and a marked hyporeactivity to inhaled methacholine by 6-8 h, which intensified over 30-32 h. HM-treatment caused protein leakage into the alveolar space, and edema, fibrin formation, and an increase in the number of inflammatory cells in the lungs and in the bronchoalveolar lavage. These results suggest that a HM-induced increase in NO production by pulmonary inflammatory cells is associated with pulmonary airflow abnormalities in rat lungs.
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PMID:Effects of hard metal on nitric oxide pathways and airway reactivity to methacholine in rat lungs. 1037 2

The alveolar macrophage (AM) secretes interleukin 1beta (IL-1beta), tumour necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6) and interleukin-8 (IL-8), all of them inflammatory cytokines involved in the pathogenesis of many lung diseases. The aim of the present work was to evaluate the basal and stimulated secretion of these cytokines by human AMs. Human AMs were collected by bronchoalveolar lavage (BAL) from four healthy controls and 13 patients with diffuse interstitial lung disease (five cases of sarcoidosis, three of hypersensitivity pneumonitis and five of idiopathic pulmonary fibrosis). AMs were cultured in the presence or absence of different concentrations of lipopolysaccharide (LPS), phorbolmyristate and gamma-interferon. IL-1beta, TNF-alpha, IL-6 and IL-8 levels were measured in BAL fluid and culture supernatant using specific enzyme-linked immunosorbent assays. The substance found to stimulate the secretion of inflammatory cytokines to the greatest extent was LPS at a concentration of 10 microg/ml. Regarding the secretion of IL-1beta, four observations were of interest: basal secretion was very low; LPS exerted a potent stimulatory effect; considerable within-group variability was observed; and there were no significant differences in the comparisons among groups. With respect to TNF-alpha secretion, the results were similar. The only striking finding was the higher basal secretion of this cytokine with respect to that of IL-1beta. Regarding the secretion of IL-6, the same pattern followed by TNF-alpha was found. However, it should be stressed that the increase induced by LPS was smaller than in the two previous cytokines. Regarding the secretion of IL-8, three findings were patent: the strong basal secretion of this cytokine; the moderate increase induced by LPS; and the existence of significant differences among the different groups with respect to the stimulated secretion of this cytokine, which reached maximum values in patients with idiopathic pulmonary fibrosis. Finally, it should be noted that the pattern of cytokines observed in the BAL fluid was similar to that found in cultured AM supernatants. The pattern of inflammatory cytokine secretion by AMs differs from that of other cells of the mononuclear phagocyte system (MPS). In this sense. AMs secrete low amounts of IL-1, moderate amounts of TNF-alpha and IL-6, and high quantities of IL-8. Adherence is an important stimulus in the secretion of these molecules and LPS elicits an increased secretion inverse to the basal secretion. There is considerable individual variability in the secretion of inflammatory cytokines by the AMs of patients with interstitial lung disease and the AMs of these patients are primed in vivo for the secretion of these cytokines. The results of our study, carried out in vitro, can be extrapolated to the in vivo setting.
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PMID:Evaluation of inflammatory cytokine secretion by human alveolar macrophages. 1070 89

Systems y+ and y+L represent the main routes for arginine transport in mammalian cells. While system y+ activity is needed for the stimulated NO production in rodent alveolar macrophages (AM), no information is yet available about arginine transport in human AM. We study here arginine influx and genes for arginine transporters in AM from bronchoalveolar lavage of normal subjects. These cells express the y+ -related genes SLC7A1/CAT1 and SLC7A2/CAT2B, as well as the y+L genes SLC7A7/y+LAT1 and SLC7A6/y+LAT2. However, compared with human endothelial cells, AM express much less SLC7A2 mRNA and higher levels of SLC7A7 mRNA. Granulocyte macrophage colony-stimulating factor or IFN-gamma do not change the expression of any transporter gene, while lipopolysaccharide induces SLC7A2/CAT2B. Under all the conditions tested, leucine inhibits most of the arginine transport in the presence of Na+ and N-ethylmaleimide, an inhibitor of system y+, is completely ineffective, indicating that system y+L operates most of the arginine influx. Comparable results are obtained in AM from patients with interstitial lung disease, such as Nonspecific Interstitial Pneumonia (NSIP), although these cells have a higher SLC7A1 and a lower SLC7A7 expression than AM from normal subjects. It is concluded that AM from normal subjects or patients with NSIP lack a functional transport system y+, a situation that may limit arginine availability for NO synthesis. Moreover, since mutations of SLC7A7/y+LAT1 cause Lysinuric Protein Intolerance, a disease often associated with AM impairment and alveolar proteinosis, the high SLC7A7 expression observed in human AM suggests that y+LAT1 activity is important for the function of these cells.
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PMID:Alveolar macrophages from normal subjects lack the NOS-related system y+ for arginine transport. 1736 79

Interstitial lung disease (ILD) is reported as a serious adverse event in lung cancer patients treated with gefitinib, an epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI). However, the mechanisms of ILD associated with gefitinib remain unknown. To address the molecular mechanisms of ILD-associated gefitinib, we determined the effect of gefitinib treatment on surfactant protein expression in vitro and in vivo. Gefitinib treatment suppressed surfactant protein (SP)-A expression in H441 human lung adenocarcinoma cells expressing SP-A, -B, -C and -D by inhibiting epidermal growth factor signal. Next, gefitinib (200 mg/kg) was given p.o. to the mice daily for 1 week. Daily administration of gefitinib gradually reduced SP-A level in the bronchoalveolar lavage fluid. When lipopolysaccharide (LPS) was instilled intratracheally to the mice pretreated with gefitinib for 1 week, lung inflammation by LPS was exacerbated and prolonged. This exacerbation of lung inflammation was rescued by intranasal administration of SP-A. These results demonstrated that pretreatment with gefitinib exacerbated LPS-induced lung inflammation by reducing SP-A expression in the lung. This study suggests that epidermal growth factor receptor tyrosine kinase inhibitor may reduce SP-A expression in the lungs of lung cancer patients and thus patients treated with epidermal growth factor receptor tyrosine kinase inhibitor may be susceptible to pathogens.
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PMID:Suppression of surfactant protein A by an epidermal growth factor receptor tyrosine kinase inhibitor exacerbates lung inflammation. 1875 83


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