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Query: UNIPROT:P06889 (Mol)
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Previous studies in our laboratory demonstrated that the synthetic surfactant Exosurf (Burroughs Wellcome Co.) inhibited endotoxin-stimulated cytokine secretion from human alveolar macrophages in vitro. The purpose of the present study was to further characterize the suppressive effects of Exosurf, which consists of dipalmitoylphosphatidylcholine (DPPC), cetyl alcohol (spreading agent), and tyloxapol (nonionic dispersing agent). Suppression was not stimulus specific in that Exosurf also significantly reduced cytokine production elicited by either Staphylococcus aureus or recombinant interleukin-1. Suppression was also mediated by a modified bovine surfactant (Survanta), which, in contrast to Exosurf, contains the surfactant-associated proteins B and C, and several different phospholipids, but no cetyl alcohol or tyloxapol. This suggests that suppression of macrophage cytokines is not specific to Exosurf. Both cell associated and secreted tumor necrosis factor and interleukin-1 were reduced by Exosurf, indicating that Exosurf is not simply blocking cytokine release. At 3 h, cytokine mRNA levels were not different between Exosurf-treated and untreated cells. However, at 8 and 24 h, cytokine mRNA levels were lower in Exosurf-treated cells. The observations that mRNA levels were decreased at 8 and 24 h and that cellular cytokine release was not blocked suggest that Exosurf's effect may in part be pretranslationally mediated. Collectively, these data add to previous work indicating that pulmonary surfactant may play a critical role in reducing inflammatory cytokine production associated with the adult respiratory distress syndrome and similar disorders.
Am J Respir Cell Mol Biol 1994 Apr
PMID:Characterization of exosurf (surfactant)-mediated suppression of stimulated human alveolar macrophage cytokine responses. 813 55

Severe deterioration of surfactant function is noted under conditions of plasma protein leakage into the alveolar space; moreover, fibrinogen has previously been reported to possess strong surfactant inhibitory capacity. Dissolution of alveolar deposits of fibrinogen and fibrin (e.g., hyaline membranes) requires enzymatic degradation by the plasminogen/plasmin system or by leukocyte-derived proteases. We investigated the surfactant inhibitory properties of differently prepared sets of fibrinogen cleavage products. Proteolysis was performed with plasmin, with predominant split products D (mol wt 85,000) and E (mol wt 50,000). In addition, fibrinogen was cleaved by leukocyte elastase and trypsin, with fragments ranging mainly between mol wt of 30,000 and 50,000. To provide split products of even lower molecular weight, fibrinogen was incubated sequentially with trypsin and endoproteinase (split products < mol wt 25,000). Natural surfactant extracts used in clinical replacement studies (CLSE, Alveofact, Curosurf, Survanta) as well as an apoprotein-based phospholipid mixture (PLM-C/B; DPPC:PG:PA = 68.5:22.5:9 with 2% [wt/wt] nonpalmitoylated recombinant human SP-C and 1% [wt/wt] natural bovine SP-B) were employed. Experiments were performed in a pulsating bubble surfactometer (standard phospholipid concentration 2 mg/ml) with assessment of surfactant activity measuring adsorption and dynamic surface tension. Fibrinogen caused dose-dependent, severe deterioration of the surface activities of Curosurf and Survanta, whereas CLSE, Alveofact, and PLM-C/B were only moderately affected up to protein-surfactant ratios of 4:1.(ABSTRACT TRUNCATED AT 250 WORDS)
Am J Respir Cell Mol Biol 1993 Sep
PMID:Proteolytic cleavage of fibrinogen: amplification of its surfactant inhibitory capacity. 839 60

In addition to biophysical properties, pulmonary surfactant has immunomodulatory activity. We previously demonstrated that both synthetic (Exosurf) and modified natural surfactant (Survanta) downregulated endotoxin-stimulated inflammatory c ytokine mRNA levels and protein products (tumor necrosis factor-alpha [TNF], interleukin-1-beta [IL-1], interleukin-6 [IL-6]) in human alveolar macrophages. In this study, we report that both Exosurf and Survanta suppress TNF mRNA and secretion (85 +/- 4% mean percent inhibition +/- SEM by Exosurf; 71 +/- 6% by Survanta) by endotoxin-stimulated THP-1, a human monocytic cell line. Because surfactant downregulated inflammatory cytokine production similarly in both normal human alveolar macrophages and the THP-1 cell line, we used this cell line to investigate whether surfactant affected transcriptional mechanisms. Specifically, we examined nuclear factor-kappa B (NF-kappa B) activation because it is crucial in transcriptional regulation of many inflammatory cytokine genes including TNF, IL-1, and IL-6. Electrophoretic mobility shift assays showed that both surfactants decreased activation of NF-kappa B. The presence of both p65 and p50 NF-kappa B components in LPS-activated THP-1 cells was confirmed by specific antibody induction of supershifts in mobility assays. These results are the first to suggest that surfactant's suppressive effects on inflammatory cytokine production may involve transcriptional regulation through inhibition of NF-kappa B activation.
Am J Respir Cell Mol Biol 1996 Apr
PMID:Surfactant suppresses NF-kappa B activation in human monocytic cells. 860 Sep 42

Pulmonary surfactant components can modulate uptake of microorganisms and viruses by alveolar macrophages (AMs), but little is known about their role in the uptake and clearance of inert environmental particulates. We tested the hypotheses that surfactant components [e.g., surfactant protein A (SpA) and the artificial bovine surfactant Survanta] modulate phagocytosis of inert environmental particulates by acting as particle opsonins, or by direct activation of AMs. AM uptake of a model inert particulate [titanium dioxide (TiO2)] was measured using flow cytometry to quantitate increased right angle scatter caused by particle uptake (e.g., fold increase in right angle scatter versus control: 2.6 +/- 0.3; and 5.0 +/- 0.2 for AMs plus TiO2, 20 and 80 micrograms/ml TiO2, respectively). Opsonization of TiO2 with surfactant components resulted in a modest increase in AM uptake compared with that of unopsonized TiO2 [e.g., fold increase, uptake of TiO2 (50 micrograms/ml), opsonized with SpA, Survanta, and rat immunoglobulin G, respectively: 1.6 +/- 0.1; 1.3 +/- 0.01; 1.5 + 0.02, n = 3-4]. Uptake of inert latex beads was similarly enhanced after opsonizing with SpA and Survanta (beads per cell: unopsonized, 3.2 +/- 0.40; SpA, 5.0 +/- 0.55; Survanta, 6.0 +/- 0.12; n = 3-6). Pretreating AMs with surfactant components and measuring the subsequent uptake of unopsonized TiO2 resulted in approximately the same magnitude of enhancement. The data indicate that surfactant components can increase AM phagocytosis of environmental particulates in vitro, but only slightly relative to the already avid AM uptake of unopsonized particles.
Am J Respir Cell Mol Biol 1996 Feb
PMID:Alveolar macrophage uptake of the environmental particulate titanium dioxide: role of surfactant components. 863 Feb 65

Surfactant can be inhibited in vivo by plasma proteins invading the alveolar space during acute lung injury. The resistance to protein inhibition of surfactant preparations with various synthetic surfactant proteins B and C (B and C) was tested in preterm rabbits. Surfactants consisted of a palmitic acid containing phospholipid mixture (PL) with full-length SP-B peptide (B1-78), one of two SP-B mutants (Bserine and BR236C), the synthetic SP-B mimic KL4 (UCLA-KL4), a natural SP-B (Bbovine), synthetic palmitoylated SP-C peptide (C1-35), a combination of B1-78 + C1-35, a combination of BR236C + C1-35, and the clinical surfactant Survanta. Preterm rabbits born at 28 days of gestation were ventilated and received 100 mg/kg of albumin intratracheally at 30 min and 100 mg/kg of surfactant at 45 min after birth. Dynamic lung compliance (tidal volume/mean airway pressure) decreased from 0.82 to 0.57 mL/kg/cm H2O after albumin instillation and to 0.43 mL/kg/cm H2O over a 60-min period after saline placebo. Treatment with B1-78 + C1-35 and BR236C + C1-35 surfactant and Survanta returned dynamic compliance to prealbumin values, B1-78, BR236C, Bbovine, and C1-35 surfactant stabilized dynamic compliance, but PL, Bserine, and UCLA-KL4 surfactant were unable to prevent a further deterioration in dynamic compliance. These data suggest that a combination of synthetic surfactant peptides B1-78 and C1-35 and the clinical surfactant Survanta confer a high degree of resistance to surfactant inhibition by human albumin in ventilated preterm rabbits.
Mol Genet Metab 1999 Jan
PMID:Sensitivity of synthetic surfactants to albumin inhibition in preterm rabbits. 997 46

Surfactant protein A (SP-A) increases production of proinflammatory cytokines by monocytic cells, including THP-1 cells, as does lipopolysaccharide (LPS). Herein we report differences in responses to these agents. First, polymyxin B inhibits the LPS response but not the SP-A response. Second, SP-A-induced increases in tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta), and IL-8 are reduced by >60% if SP-A is preincubated with Survanta (200 microgram/ml) for 15 min before addition to THP-1 cells. However, the LPS effects on TNF-alpha and IL-8 are inhibited by <20% and the effect on IL-1beta by <50%. Third, at Survanta levels of 1 mg/ml, SP-A-induced responses are reduced by >90%, and although the inhibitory effects on LPS action increase, they still do not reach those seen with SP-A. Finally, we tested whether SP-A could induce tolerance as LPS does. Pretreatment of THP-1 cells with LPS inhibits their response to subsequent LPS treatment 24 h later, including TNF-alpha, IL-1beta, and IL-8. Similar treatment with SP-A reduces TNF-alpha, but IL-1beta and IL-8 are further increased by the second treatment with SP-A rather than inhibited as with LPS. Thus, whereas both SP-A and LPS stimulate cytokine production, their mechanisms differ with respect to inhibition by surfactant lipids and in ability to induce tolerance.
Am J Physiol Lung Cell Mol Physiol 2000 Jul
PMID:Comparison of SP-A and LPS effects on the THP-1 monocytic cell line. 1089 9

During lung injury, fibroblasts migrate into the alveolar spaces where they can be exposed to pulmonary surfactant. We examined the effects of Survanta and surfactant protein A (SP-A) on fibroblast growth and apoptosis and on type I collagen, collagenase-1, and tissue inhibitor of metalloproteinase (TIMP)-1 expression. Lung fibroblasts were treated with 100, 500, and 1,000 microg/ml of Survanta; 10, 50, and 100 microg/ml of SP-A; and 500 microg/ml of Survanta plus 50 microg/ml of SP-A. Growth rate was evaluated by a formazan-based chromogenic assay, apoptosis was evaluated by DNA end labeling and ELISA, and collagen, collagenase-1, and TIMP-1 were evaluated by Northern blotting. Survanta provoked fibroblast apoptosis, induced collagenase-1 expression, and decreased type I collagen affecting mRNA stability approximately 10-fold as assessed with the use of actinomycin D. Collagen synthesis and collagenase activity paralleled the gene expression results. SP-A increased collagen expression approximately 2-fold and had no effect on collagenase-1, TIMP-1, or growth rate. When fibroblasts were exposed to a combination of Survanta plus SP-A, the effects of Survanta were partially reversed. These findings suggest that surfactant lipids may protect against intraluminal fibrogenesis by inducing fibroblast apoptosis and decreasing collagen accumulation.
Am J Physiol Lung Cell Mol Physiol 2000 Nov
PMID:Surfactant components modulate fibroblast apoptosis and type I collagen and collagenase-1 expression. 1105 32

Bulk shear viscosities were measured with a cone and plate microviscometer as a function of concentration, shear rate, and temperature for lavaged calf lung surfactant (LS), Exosurf, Infasurf, Survanta, and synthetic lipid mixtures dispersed in normal saline. Viscosity increased with phospholipid concentration for all surfactants, but its magnitude and shear dependence varied widely among the different preparations. Saline dispersions of Exosurf and synthetic phospholipids had low viscosities of only a few centipoise (cp) and exhibited minimal shear dependence. LS, Infasurf, Survanta, and lipid mixtures containing palmitic acid and tripalmitin had larger non-Newtonian viscosities that increased as shear rate decreased. At 35 mg of phospholipid/ml and 37 degrees C, viscosity values were 52.3 cp (Survanta), 31.1 cp (LS), and 25 cp (Infasurf) at a shear rate of 77 s(-1) and 16.9 cp (Survanta), 10.1 cp (LS), and 6.6 cp (Infasurf) at 770 s(-1). At 25 mg of phospholipid/ml and 37 degrees C, viscosity values at 77 s(-1) were 28.8 cp (Survanta), 4.7 cp (LS), and 12.5 cp (Infasurf). At fixed shear rate, viscosity was substantially decreased at 23 degrees C compared with 37 degrees C for LS and Infasurf but was increased for Survanta. Calcium (5 mM) greatly reduced the viscosity of both Survanta and Infasurf at 37 degrees C. Studies on synthetic mixtures indicated that phospholipid/apoprotein interactions were important in the rheology of lung-derived surfactants and that palmitic acid and tripalmitin contributed to the increased viscosity of Survanta. The viscous behavior of clinical exogenous surfactants potentially influences their delivery and distribution in lungs and varies significantly with composition, concentration, temperature, ionic environment, and physical formulation.
Am J Physiol Lung Cell Mol Physiol 2002 Feb
PMID:Bulk shear viscosities of endogenous and exogenous lung surfactants. 1179 32

Both surfactant- and perfluorochemical (PFC)-based vehicles enhance adenovirus-mediated gene transfer in the lung. To compare the relative effects of surfactant and PFC liquid, we infected orotracheally intubated Sprague-Dawley rats with 4 x 10(9) pfu of an E1a(-)/E3(-) adenovirus expressing either an Escherichia coli lacZ (AdlacZ) mini-gene or no cDNA (Adnull). Surfactant-mediated delivery was achieved via instillation of four, 200-microl aliquots of virus suspended in a 50% surfactant (Survanta) vehicle over a 15-minute period. PFC rats received virus in 100 microl of saline followed by instillation of the PFC liquid FC-75 (10 cc/kg body weight) over a 2- to 3- minute period. Lungs were collected 3 days later for measurement of beta-galactosidase (beta-gal) expression and indices of inflammation. Both PFC liquid and surfactant-based vehicles produced widespread beta-gal expression and increased total beta-gal activity over that observed with instillation of vector alone. Both vehicles comparably increased bronchoalveolar lavage fluid (BALF), total cell counts, neutrophils, total protein, and IFN(gamma). FC-75 was also associated with increased BALF IL1beta. In conclusion, surfactant and FC-75 are similarly effective vehicles for adenovirus-mediated gene transfer to the lung.
Mol Ther 2002 Jul
PMID:Comparison of surfactant and perfluorochemical liquid enhanced adenovirus-mediated gene transfer in normal rat lung. 1209 2

Surfactant plays an important role in lung homeostasis and is also involved in maintaining innate immunity within the lung. Lipopolysaccharide (LPS) from gram-negative bacteria is known to elicit acute proinflammatory responses in lung diseases such as acute respiratory distress syndrome and pneumonia, among others. Our previous studies demonstrated that the clinically used, natural surfactant product Survanta inhibited proinflammatory cytokine secretion from LPS-stimulated human alveolar macrophages. Here we investigated the effect of Survanta on mitogen-activated protein (MAP) and IkappaB kinases. Survanta blocked LPS-induced activation of nuclear factor-kappaB, a key regulatory transcription factor involved in cytokine production, by preventing phosphorylation of IkappaBalpha, and its subsequent degradation. IkappaB is phosphorylated by specific kinases (IKK) before degradation. Survanta inhibited activity of both alpha and beta subunits of IKK, thereby delaying the phosphorylation of IkappaB. Interestingly, IKK-alpha is predominant in alveolar macrophages, whereas IKK-beta predominates in monocytes. Survanta also inhibited extracellular signal-regulated kinase and p38 MAP kinase activity induced by LPS. Data are the first to show that surfactant may regulate lung homeostasis in part by inhibiting proinflammatory cytokine production through reduction of IKK and MAP kinase activity.
Am J Respir Cell Mol Biol 2004 Feb
PMID:Surfactant blocks lipopolysaccharide signaling by inhibiting both mitogen-activated protein and IkappaB kinases in human alveolar macrophages. 1292 56


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