A Common Pathway for the Uptake of Surfactant Lipids by Alveolar Cells

Poelma, D. L. H.; Ju, M. R.; Bakker, Sjoerd C.; Zimmermann, Luc J. I.; Lachmann, Burkhard; Iwaarden, J. Freek van

doi:10.1165/rcmb.2003-0127oc

Cited by 44 publications

(37 citation statements)

References 33 publications

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“…Moreover, expression of the M2 marker Ym1 ( Figure 5B) and the lipid receptor/ transporter genes (Cd36, Sra-1, Lxr-a, Abca1, and Abcg1; see Figures E3A and E3B) were increased in macrophages from the bleomycin-injured lung. No differences in expression of the M1 marker Tnf-a were observed in macrophages from control and bleomycin-injured lungs, further suggesting a shift toward an M2 or "reparative" macrophage phenotype (25,26) that favors collagen deposition and fibrosis.…”

Section: Foam Cell Formation Induces the Production Of Tgf-b1mentioning

confidence: 89%

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A Pneumocyte–Macrophage Paracrine Lipid Axis Drives the Lung toward Fibrosis

Romero¹,

Shah²,

Duong³

et al. 2015

Am J Respir Cell Mol Biol

125

107

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Lipid-laden macrophages, or "foam cells," are observed in the lungs of patients with fibrotic lung disease, but their contribution to disease pathogenesis remains unexplored. Here, we demonstrate that fibrosis induced by bleomycin, silica dust, or thoracic radiation promotes early and sustained accumulation of foam cells in the lung. In the bleomycin model, we show that foam cells arise from neighboring alveolar epithelial type II cells, which respond to injury by dumping lipids into the distal airspaces of the lungs. We demonstrate that oxidized phospholipids accumulate within alveolar macrophages (AMs) after bleomycin injury and that murine and human AMs treated with oxidized phosphatidylcholine (oxPc) become polarized along an M2 phenotype and display enhanced production of transforming growth factor-b1. The direct instillation of oxPc into the mouse lung induces foam cell formation and triggers a severe fibrotic reaction. Further, we show that reducing pulmonary lipid clearance by targeted deletion of the lipid efflux transporter ATPbinding cassette subfamily G member 1 increases foam cell formation and worsens lung fibrosis after bleomycin. Conversely, we found that treatment with granulocyte-macrophage colony-stimulating factor attenuates fibrotic responses, at least in part through its ability to decrease AM lipid accumulation. In summary, this work describes a novel mechanism leading to foam cell formation in the mouse lung and suggests that strategies aimed at blocking foam cell formation might be effective for treating fibrotic lung disorders.

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Section: Foam Cell Formation Induces the Production Of Tgf-b1mentioning

confidence: 89%

“…The uptake of liposomes was performed as described previously (25). Details are provided in the online supplement.…”

Section: Measurement Of Liposome Uptake By Atii Cellsmentioning

confidence: 99%

A Pneumocyte–Macrophage Paracrine Lipid Axis Drives the Lung toward Fibrosis

Romero¹,

Shah²,

Duong³

et al. 2015

Am J Respir Cell Mol Biol

125

107

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“…Alveolar type II epithelial cells produce and secrete pulmonary surfactant, a phospholipid-rich material lining the inside of the alveolar cells, and old surfactant is cleared from the alveolar space by alveolar type II epithelial cells and alveolar macrophages for degradation 36 . Inorganic phosphate released from the degraded phospholipids is transported from the alveolar space by the type IIb sodium-phosphate cotransporter, which is primarily expressed in alveolar type II epithelial cells 37 . This metabolism of pulmonary surfactant and inorganic phosphate in the alveolar space suggests that calcium phosphate may be more likely to be precipitated under conditions of alveolar type II epithelial cell damage, and calcium phosphate precipitate is bound by alendronate and then efficiently phagocytosed by alveolar macrophages.…”

Section: Discussionmentioning

confidence: 99%

Alendronate inhalation ameliorates elastase-induced pulmonary emphysema in mice by induction of apoptosis of alveolar macrophages

et al. 2015

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Alveolar macrophages play a crucial role in the pathogenesis of emphysema, for which there is currently no effective treatment. Bisphosphonates are widely used to treat osteoclastmediated bone diseases. Here we show that delivery of the nitrogen-containing bisphosphonate alendronate via aerosol inhalation ameliorates elastase-induced emphysema in mice. Inhaled, but not orally ingested, alendronate inhibits airspace enlargement after elastase instillation, and induces apoptosis of macrophages in bronchoalveolar fluid via caspase-3-and mevalonate-dependent pathways. Cytometric analysis indicates that the F4/80 þ CD11b high CD11c mild population characterizing inflammatory macrophages, and the F4/80 þ CD11b mild CD11c high population defining resident alveolar macrophages take up substantial amounts of the bisphosphonate imaging agent OsteoSense680 after aerosol inhalation. We further show that alendronate inhibits macrophage migratory and phagocytotic activities and blunts the inflammatory response of alveolar macrophages by inhibiting nuclear factor-kB signalling. Given that the alendronate inhalation effectively induces apoptosis in both recruited and resident alveolar macrophages, we suggest this strategy may have therapeutic potential for the treatment of emphysema.

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“…PG is the second major component after phosphatidylcholine, and in vitro studies have demonstrated a significant effect of PG on the uptake (25,27). However, extrapolation of the results of in vitro experiments on the uptake of liposomes to the in vivo situation is not always valid; our group has already demonstrated significant differences when comparing in vivo and in vitro uptake of surfactant-like liposomes (26).…”

mentioning

confidence: 86%

“…Especially SP-A is known to affect the uptake of surfactant by alveolar cells (1,14,15,33). However, in vitro studies have demonstrated that, apart from these SPs, the different lipid components also affect the uptake (25,27). Significant differences in lipid composition between adults and neonates have been described (2,(11)(12)(13).…”

mentioning

confidence: 99%

Influence of phosphatidylglycerol on the uptake of liposomes by alveolar cells and on lung function

Poelma¹,

Lachmann²,

Haitsma³

et al. 2005

Journal of Applied Physiology

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-The effect of phosphatidylglycerol on the uptake of surfactant-like liposomes by alveolar type II cells and alveolar macrophages as well as the effect on endogenous surfactant function was studied in vivo. Healthy ventilated rats were intratracheally instilled with fluorescent labeled liposomes with different concentrations of phosphatidylglycerol. Lung function was determined by monitoring arterial oxygenation and, at the end of the experiment, by recording static pressure-volume curves. In addition, alveolar cells were isolated, and cell-associated fluorescence was determined using flow cytometry. The results show that, in the presence of cofactors (Ca 2ϩ , Mg 2ϩ ), phosphatidylglycerol stimulates the uptake by alveolar macrophages but hardly affects the uptake by alveolar type II cells. High concentrations of phosphatidylglycerol reduce the number of alveolar macrophages in the alveolar space and deteriorate lung function. On the other hand, the presence of cofactors protects the lung against the negative effects of phosphatidylglycerol on endogenous surfactant and alveolar macrophages. This study indicates that the phosphatidylglycerol concentration may play a fundamental role in the surfactant function and metabolism depending on the presence of so-called cofactors like calcium and magnesium; further study is needed to clarify the mechanisms involved. lung; surfactant; metabolism THE ALVEOLUS IS LINED WITH a thin layer of lipids and proteins, called surfactant, and this surface active agent has an essential role in maintaining normal lung function. Pulmonary surfactant is produced by alveolar type II cells. By weight, ϳ90% of surfactant consists of lipids. Although the lipid composition varies in different species, its major component is phosphatidylcholine (70 -

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A Common Pathway for the Uptake of Surfactant Lipids by Alveolar Cells

Cited by 44 publications

References 33 publications

A Pneumocyte–Macrophage Paracrine Lipid Axis Drives the Lung toward Fibrosis

A Pneumocyte–Macrophage Paracrine Lipid Axis Drives the Lung toward Fibrosis

Alendronate inhalation ameliorates elastase-induced pulmonary emphysema in mice by induction of apoptosis of alveolar macrophages

Influence of phosphatidylglycerol on the uptake of liposomes by alveolar cells and on lung function

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