Human SP-A genetic variants and bleomycin-induced cytokine production by THP-1 cells: effect of ozone-induced SP-A oxidation

Surfactant protein A (SP-A) plays a role in innate host defense. Human SP-A is encoded by two functional genes (SP-A1 and SP-A2), and several alleles have been characterized for each gene. We assessed the effect of in vitro expressed human SP-A genetic variants, on TNF-α and IL-8 production by THP-1 cells in the presence of bleomycin, either before or after ozone-induced oxidation of the variants. The oligomerization of SP-A variants was also examined. We found 1) cytokine levels induced by SP-A2 (1A, 1A0) were significantly higher than those by SP-A1 (6A2, 6A4) in the presence of bleomycin. 2) In the presence of bleomycin, ozone-induced oxidation significantly decreased the ability of 1A and 1A/6A4, but not of 6A4, to stimulate TNF-α production. 3) The synergistic effect of bleomycin/SP-A, either before or after oxidation, can be inhibited to the level of bleomycin alone by surfactant lipids. 4) Differences in oligomerization were also observed between SP-A1 and SP-A2. The results indicate that differences among SP-A variants may partly explain the individual variability of pulmonary complications observed during bleomycin chemotherapy and/or in an environment that may promote protein oxidation.

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Combined SP-A-bleomycin effect on cytokines by THP-1 cells: impact of surfactant lipids on this effect

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00434.2001 ◽

2002 ◽

Vol 283 (1) ◽

pp. L94-L102 ◽

Cited By ~ 20

Author(s):

Weixiong Huang ◽

Guirong Wang ◽

David S. Phelps ◽

Hamid Al-Mondhiry ◽

Joanna Floros

Keyword(s):

Pulmonary Fibrosis ◽

Cytokine Production ◽

Rnase Protection Assay ◽

Protein A ◽

Surfactant Protein ◽

Pulmonary Complications ◽

Enzyme Linked Immunosorbent Assay ◽

Rnase Protection ◽

Tnf Α ◽

Cytokine Levels

Surfactant protein A (SP-A) plays a role in host defense and inflammation in the lung. In the present study, we investigated the hypothesis that SP-A is involved in bleomycin-induced pulmonary fibrosis. We studied the effects of human SP-A on bleomycin-induced cytokine production and mRNA expression in THP-1 macrophage-like cells and obtained the following results. 1) Bleomycin-treated THP-1 cells increased tumor necrosis factor (TNF)-α, interleukin (IL)-8, and IL-1β production in dose- and time-dependent patterns, as we have observed with SP-A. TNF-α levels were unaffected by treatment with cytosine arabinoside. 2) The combined bleomycin-SP-A effect on cytokine production is additive by RNase protection assay and synergistic by enzyme-linked immunosorbent assay. 3) Although the bleomycin effect on cytokine production was not significantly affected by the presence of surfactant lipid, the additive and synergistic effect of SP-A-bleomycin on cytokine production was significantly reduced. We speculate that the elevated cytokine levels resulting from the bleomycin-SP-A synergism are responsible for bleomycin-induced pulmonary fibrosis and that surfactant lipids can help ameliorate pulmonary complications observed during bleomycin chemotherapy.

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Surfactant protein A reduces TLR4 and inflammatory cytokine mRNA levels in neonatal mouse ileum

Scientific Reports ◽

10.1038/s41598-021-82219-y ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Lidan Liu ◽

Chaim Z. Aron ◽

Cullen M. Grable ◽

Adrian Robles ◽

Xiangli Liu ◽

...

Keyword(s):

Proinflammatory Cytokine ◽

Inflammatory Cytokine ◽

Protein A ◽

Surfactant Protein ◽

Surfactant Protein A ◽

Mrna Levels ◽

Wild Type ◽

Cytokine Mrna ◽

Protein Levels ◽

Cytokine Levels

AbstractLevels of intestinal toll-like receptor 4 (TLR4) impact inflammation in the neonatal gastrointestinal tract. While surfactant protein A (SP-A) is known to regulate TLR4 in the lung, it also reduces intestinal damage, TLR4 and inflammation in an experimental model of necrotizing enterocolitis (NEC) in neonatal rats. We hypothesized that SP-A-deficient (SP-A−/−) mice have increased ileal TLR4 and inflammatory cytokine levels compared to wild type mice, impacting intestinal physiology. We found that ileal TLR4 and proinflammatory cytokine levels were significantly higher in infant SP-A−/− mice compared to wild type mice. Gavage of neonatal SP-A−/− mice with purified SP-A reduced ileal TLR4 protein levels. SP-A reduced expression of TLR4 and proinflammatory cytokines in normal human intestinal epithelial cells (FHs74int), suggesting a direct effect. However, incubation of gastrointestinal cell lines with proteasome inhibitors did not abrogate the effect of SP-A on TLR4 protein levels, suggesting that proteasomal degradation is not involved. In a mouse model of experimental NEC, SP-A−/− mice were more susceptible to intestinal stress resembling NEC, while gavage with SP-A significantly decreased ileal damage, TLR4 and proinflammatory cytokine mRNA levels. Our data suggests that SP-A has an extrapulmonary role in the intestinal health of neonatal mice by modulating TLR4 and proinflammatory cytokines mRNA expression in intestinal epithelium.

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Exposure of surfactant protein A to ozone in vitro and in vivo impairs its interactions with alveolar cells

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.1992.262.1.l63 ◽

1992 ◽

Vol 262 (1) ◽

pp. L63-L68 ◽

Cited By ~ 12

Author(s):

R. S. Oosting ◽

J. F. Van Iwaarden ◽

L. Van Bree ◽

J. Verhoef ◽

L. M. Van Golde ◽

...

Keyword(s):

Superoxide Anion ◽

Protein A ◽

Surfactant Protein ◽

Surfactant Protein A ◽

Alveolar Type ◽

Type Ii ◽

Superoxide Anion Production ◽

Anion Production

This study focused on the question of whether exposure of surfactant protein A (SP-A) to ozone affected properties of this protein that may be involved in regulating alveolar type II cell and alveolar macrophage functions. In vitro exposure of human or canine SP-A to ozone reduced the ability of this protein to inhibit phorbol-ester induced secretion of [3H]phosphatidylcholine by alveolar type II cells in culture. Ozone-exposed human SP-A showed a decreased ability to enhance phagocytosis of herpes simplex virus and to stimulate superoxide anion production by alveolar macrophages. Experiments with elastase showed that ozone-exposed canine SP-A was more susceptible to proteolysis. A conformational change of the protein could underlie this phenomenon. Surfactant isolated from ozone-exposed rats (0.4 ppm ozone for 12 h) was also less able to stimulate superoxide anion production by alveolar macrophages than surfactant from control rats, which suggested that SP-A in vivo was also susceptible to ozone. The results of this study suggest that SP-A-alveolar cell interactions can be inhibited by ozone exposure, which may contribute to the toxicity of ozone in the lungs.

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Surfactant Protein A and B Genetic Variants and Respiratory Distress Syndrome: Allele Interactions

Neonatology ◽

10.1159/000047173 ◽

2001 ◽

Vol 80 (1) ◽

pp. 22-25 ◽

Cited By ~ 16

Author(s):

Joanna Floros ◽

Ruzong Fan

Keyword(s):

Respiratory Distress Syndrome ◽

Respiratory Distress ◽

Genetic Variants ◽

Distress Syndrome ◽

Protein A ◽

Surfactant Protein ◽

Surfactant Protein A

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Effects of surfactant protein A and surfactant lipids on lymphocyte proliferation in vitro

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.1994.267.4.l357 ◽

1994 ◽

Vol 267 (4) ◽

pp. L357-L364 ◽

Cited By ~ 21

Author(s):

S. G. Kremlev ◽

T. M. Umstead ◽

D. S. Phelps

Keyword(s):

Lymphocyte Proliferation ◽

Cell Function ◽

Immune Cell ◽

Pulmonary Inflammation ◽

Protein A ◽

Surfactant Protein ◽

Surfactant Protein A ◽

Inhibitory Influence ◽

Surfactant Replacement Therapy

We studied the effects of dipalmitoyl L-alpha-phosphatidylcholine (DPPC), Survanta, surfactant protein A (SP-A), and mixtures of these substances on mitogen-induced lymphocyte proliferation using concanavalin A as a mitogen. A concentration-dependent suppression of proliferation was observed with 50-250 micrograms/ml of DPPC or Survanta. However, when SP-A was added to cultures, proliferation was stimulated. The inhibitory effects of DPPC and Survanta were altered in mixtures that contained SP-A. When added to 50 micrograms/ml of Survanta, SP-A reversed the inhibitory influence of Survanta and caused increased proliferation. These findings suggest that surfactant phospholipids cause a suppression of mitogen-induced lymphocyte proliferation, which is reversed somewhat by addition of SP-A. We hypothesize that immune cell function in the lung varies with changes in the relative amounts of surfactant components. Changes in surfactant composition may occur during pulmonary inflammation or infection or with surfactant replacement therapy and may influence immune and inflammatory processes in the lung.

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