Activity of growth factors in the IL-6 group in the differentiation of human lung adenocarcinoma.
(49/439)
The role of the interleukin-6 (IL-6) group of cytokines in differentiation of two lung adenocarcinoma cell lines has been examined using induction of alkaline phosphatase and expression of surfactant protein A. Oncostatin M was the most active and potent for alkaline phosphatase in A549 cells, with IL-6 having similar activity but less potency. Neither cytokine induced alkaline phosphatase in NCI-H441 cells, although induction was obtained with lung fibroblast-conditioned medium. Surfactant protein A was induced in NCI-H441 cells by conditioned medium and dexamethasone and, to a much lesser extent, by oncostatin M or IL-6. Induction of alkaline phosphatase and surfactant protein A were both dexamethasone-dependent, though some induction of surfactant protein A was obtained with interferon-alpha in the absence of dexamethasone. The activity present in lung fibroblast-conditioned medium suggests paracrine control, but this appears not to be due to oncostatin M or IL-6 as disabling antibodies to either cytokine were not inhibitory, and, although alkaline phosphatase was induced in A549 by both cytokines, it was only induced by conditioned medium in NCI-H441 cells. Furthermore, surfactant protein A was induced in H441 by conditioned medium to a much greater extent than by oncostatin M or IL-6. These data demonstrate that cytokines of the IL-6 group have potential as differentiation inducers in lung adenocarcinoma cells and that there is an equivalent paracrine factor(s) in lung fibroblast conditioned medium. As the production of this factor by fibroblasts is not enhanced by glucocorticoid, although the response of the target cell is, it would appear to be distinct from the fibrocyte pneumocyte factor previously described by Post et al 1984. (+info)
Surfactant protein A prevents silica-mediated toxicity to rat alveolar macrophages.
(50/439)
Silicosis is a serious occupational lung disease associated with irreversible pulmonary fibrosis. The interaction between inhaled crystalline silica and the alveolar macrophage (AM) is thought to be a key event in the development of silicosis and fibrosis. Silica can cause direct injury to AMs and can induce AMs to release various inflammatory mediators. Acute silicosis is also characterized by a marked elevation in surfactant apoprotein A (SP-A); however, the role of SP-A in silicosis is unknown. We investigated whether SP-A directly affects the response of AMs to silica. In this study, the degree of silica toxicity to cultured rat AMs as assessed by a (51)Cr cytotoxicity assay was shown to be dependent on the time of exposure and the concentration and size of the silica particles. Silica directly injured rat AMs as evidenced by a cytotoxic index of 32.9 +/- 2.5, whereas the addition of rat SP-A (5 microg/ml) significantly reduced the cytotoxic index to 16.6 +/- 1.2 (P < 0. 001). This effect was reversed when SP-A was incubated with either polyclonal rabbit anti-rat SP-A antibody or D-mannose. These data indicate that SP-A mitigates the effect of silica on AM viability, and this effect may involve the carbohydrate recognition domain of SP-A. The elevation of SP-A in acute silicosis may serve as a normal host response to prevent lung cell injury after exposure to silica. (+info)
Ovine surfactant protein cDNAs: use in studies on fetal lung growth and maturation after prolonged hypoxemia.
(51/439)
cDNAs for ovine surfactant-associated protein (SP) A, SP-B, and SP-C have been cloned and shown to possess strong similarity to cDNAs for surfactant apoproteins in other species. These reagents were employed to examine the effect of fetal hypoxia on the induction of surfactant apoprotein expression in the fetal lamb. Postnatal lung function is dependent on adequate growth and maturation during fetal development. Insulin-like growth factor (IGF) I and IGF-II, which are present in all fetal tissues studied, possess potent mitogenic and proliferative actions, and their effects can be modulated by IGF-specific binding proteins (IGFBPs). Hypoxia can lead to increases in circulating cortisol and catecholamines that can influence lung maturation. Therefore, the effects of mild hypoxia in chronically catheterized fetal lambs at gestational days 126-130 and 134-136 (term 145 days) on the expression of pulmonary surfactant apoproteins and IGFBPs were examined. Mild hypoxia for 48 h resulted in an increase in plasma cortisol that was more pronounced at later gestation, and in these animals, there was a twofold increase in SP-A mRNA. SP-B mRNA levels also increased twofold, but this was not significant. SP-C mRNA was not altered. No significant changes in apoprotein mRNA were observed with the younger fetuses. However, these younger animals selectively exhibited reduced IGFBP-5 mRNA levels. IGF-I mRNA was also reduced at 126-130 days, although this conclusion is tentative due to low abundance. IGF-II levels were not affected at either gestational age. We conclude that these data suggest that mild prolonged fetal hypoxia produces alterations that could affect fetal cellular differentiation early in gestation and can induce changes consistent with lung maturation closer to term. (+info)
cDNA cloning of ovine pulmonary SP-A, SP-B, and SP-C: isolation of two different sequences for SP-B.
(52/439)
Pulmonary surfactant promotes alveolar stability by lowering the surface tension at the air-liquid interface in the peripheral air spaces. The three surfactant proteins SP-A, SP-B, and SP-C contribute to dynamic surface properties involved during respiration. We have cloned and sequenced the complete cDNAs for ovine SP-A and SP-C and two distinct forms of ovine SP-B cDNAs. The nucleotide sequence of ovine SP-A cDNA consists of 1,901 bp and encodes a protein of 248 amino acids. Ovine SP-C cDNA contains 809 bp, predicting a protein of 190 amino acids. Ovine SP-B is encoded by two mRNA species, which differ by a 69-bp in-frame deletion in the region coding for the active airway protein. The larger SP-B cDNA comprises 1,660 bp, encoding a putative protein of 374 amino acids. With the sequences reported, a more complete analysis of surfactant regulation and the determination of their physiological function in vivo will be enabled. (+info)
Surfactant-associated protein A inhibits LPS-induced cytokine and nitric oxide production in vivo.
(53/439)
The role of surfactant-associated protein (SP) A in the mediation of pulmonary responses to bacterial lipopolysaccharide (LPS) was assessed in vivo with SP-A gene-targeted [SP-deficient; SP-A(-/-)] and wild-type [SP-A(+/+)] mice. Concentrations of tumor necrosis factor (TNF)-alpha, macrophage inflammatory protein-2, and nitric oxide were determined in recovered bronchoalveolar lavage fluid after intratracheal administration of LPS. SP-A(-/-) mice produced significantly more TNF-alpha and nitric oxide than SP-A(+/+) mice after LPS treatment. Intratracheal administration of human SP-A (1 mg/kg) to SP-A(-/-) mice restored regulation of TNF-alpha, macrophage inflammatory protein-2, and nitric oxide production to that of SP-A(+/+) mice. Other markers of lung injury including bronchoalveolar fluid protein, phospholipid content, and neutrophil numbers were not influenced by SP-A. Data from experiments designed to test possible mechanisms of SP-A-mediated suppression suggest that neither binding of LPS by SP-A nor enhanced LPS clearance are the primary means of inhibition. Our data and others suggest that SP-A acts directly on immune cells to suppress LPS-induced inflammation. These results demonstrate that endogenous or exogenous SP-A inhibits pulmonary LPS-induced cytokine and nitric oxide production in vivo. (+info)
Humoral autoreactivity directed against surfactant protein-A (SP-A) in rheumatoid arthritis synovial fluids.
(54/439)
SP-A is found principally in the lung, and has been associated with lamellar bodies also found in the synovial joint. Both SP-A and C1q contain collagen-like regions, and SP-A and C1q have some structural similarities, both having a globular head region and a collagen-like tail. Here we are able to show that (i) autoreactivity to SP-A, as expressed by IgG and IgM autoantibodies, is present in synovial fluid (SF) isolated from patients with rheumatoid arthritis (RA); (ii) in absorption experiments only a limited degree of cross-reactivity between autoantibodies reactive with C1q and SP-A is observed; (iii) there is no cross-reactivity between autoantibodies reactive with type II collagen (CII) and those reactive with SP-A or C1q; (iv) autoantibodies react with polymeric (dimers and larger) SP-A, but not with monomeric SP-A subunits, indicating that a degree of quaternary structure is required for antibody binding. Unlike CII, which not accessible in the normal joint, both SP-A and C1q are available within the SF in patients with RA and may therefore provide antigens driving an autoimmune response directed against collagen-like structures. (+info)
Association between the surfactant protein A (SP-A) gene locus and respiratory-distress syndrome in the Finnish population.
(55/439)
Respiratory-distress syndrome (RDS) in the newborn is a major cause of neonatal mortality and morbidity. Although prematurity is the most-important risk factor for RDS, the syndrome does not develop in many premature infants. The main cause of RDS is a deficiency of pulmonary surfactant, which consists of phospholipids and specific proteins. The genes underlying susceptibility to RDS are insufficiently known. The candidate-gene approach was used to study the association between the surfactant protein A (SP-A) gene locus and RDS in the genetically homogeneous Finnish population. In the present study, 88 infants with RDS and 88 control infants that were matched for degree of prematurity, prenatal glucocorticoid therapy, and sex were analyzed for SP-A genotypes. We show that certain SP-A1 alleles (6A2 and 6A3) and an SP-A1/SP-A2 haplotype (6A2/1A0) were associated with RDS. The 6A2 allele was overrepresented and the 6A3 allele was underrepresented in infants with RDS. These associations were particularly strong among small premature infants born at gestational age <32 wk. In infants protected from RDS (those that had no RDS, despite extreme prematurity and lack of glucocorticoid therapy), compared with infants that had RDS develop despite having received glucocorticoid therapy, the frequencies of 6A2 (.22 vs.71), 6A3 (.72 vs.17), 6A2/1A0 (.17 vs.68), 6A3/1A1 (.39 vs.10), and 6A3/1A2 (.28 vs.06) in the two groups, respectively, were strikingly different. According to the results of conditional logistic-regression analysis, diseases associated with premature birth did not explain the association between the odds of a particular homozygous SP-A1 genotype (6A2/6A2 and 6A3/6A3) and RDS. In the population evaluated in the present study, SP-B intron 4 variant frequencies were low and had no detectable association with RDS. We conclude that the SP-A gene locus is an important determinant for predisposition to RDS in premature infants. (+info)
Human SP-A protein variants derived from one or both genes stimulate TNF-alpha production in the THP-1 cell line.
(56/439)
In humans, two functional genes of surfactant protein (SP) A, SP-A1 and SP-A2, and several alleles of each functional gene have been characterized. SP-A is a multimeric molecule consisting of six trimers. Each trimer contains two SP-A1 molecules and one SP-A2 molecule. Until now, it has been unclear whether a single SP-A gene product is functional or whether there are functional differences either among alleles or between single-gene SP-A products and SP-A products derived from both genes. We tested the ability of in vitro expressed SP-A variants to stimulate tumor necrosis factor (TNF)-alpha production by THP-1 cells. We observed that 1) single-gene products and products derived from both genes stimulate TNF-alpha production, 2) there are differences among SP-A1 and SP-A2 alleles in their ability to stimulate TNF-alpha production, and 3) the increases in TNF-alpha production are lower after treatment with the SP-A1 alleles than after treatment with the SP-A2 alleles. Furthermore, coexpressed SP-As from SP-A1 and SP-A2 genes have a higher activity compared with SP-As from individual alleles or mixed SP-As from SP-A1 and SP-A2 genes. These data suggest that the SP-A-induced increases in TNF-alpha levels differ among SP-A variants and appear to be affected by SP-A genotype and whether SP-A is derived from one or both genes. (+info)