Surfactant protein-A plays an important role in lung surfactant clearance: evidence using the surfactant protein-A gene-targeted mouse

Bates, Sandra R.; Dodia, Chandra; Tao, Jianmin; Fisher, Aron B.

doi:10.1152/ajplung.00341.2007

Cited by 34 publications

(28 citation statements)

References 51 publications

(70 reference statements)

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“…Lipid clearance is ordinarily mediated by ATII cells and, to a lesser extent, AMs (12,13). Lipid-laden AMs, also called "foam cells," are common pathological features in animals models of lung fibrosis (14,15) and in histological specimens from patients with various chronic fibrotic lung diseases (16,17).…”

Section: Clinical Relevancementioning

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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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: Clinical Relevancementioning

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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“…Extracellular SP-A appears to play crucial roles in the formation of tubular myelin, in the regulation of lamellar body exocytosis, and in the uptake of phospholipids by endocytosis and their subsequent remodeling (20,23,30,40). The uptake process is dependent on the association of phospholipids with SP-A, followed by binding of the SP-Aphospholipid complex to a specific cell membrane-localized SP-A receptor (4,5,16), and then internalization of the complex by a clathrin-dependent pathway (21,32,35). Although the pathway for uptake of SP-A seems to be fairly well understood, there is uncertainty regarding the pathway for secretion of newly synthesized SP-A by type II cells.…”

mentioning

confidence: 99%

Pathway to lamellar bodies for surfactant protein A

Fisher

Dodia

Rückert

et al. 2010

American Journal of Physiology-Lung Cellular and Molecular Phys

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surfactant protein A (SP-A) is endocytosed by type II epithelial cells through clathrindependent uptake and targeted to lamellar bodies for resecretion. However, the mechanism for secretion of newly synthesized SP-A, whether regulated exocytosis of lamellar bodies or constitutive secretion, is unresolved. If it is the latter, lamellar body SP-A would represent endocytosed protein. Amantadine, an inhibitor of clathrincoated vesicle budding, was used to evaluate the role of endocytosis in accumulation of SP-A in lamellar bodies. In isolated rat lungs, amantadine (10 mM) inhibited uptake of endotracheally instilled 35 S-labeled biosynthesized surfactant proteins by Ͼ80%. To study trafficking of newly synthesized SP-A, lungs were perfused for up to 6 h with [35 S]methionine, and surfactant was isolated from lung lavage fluid and lamellar bodies were isolated from lung homogenate. With control lungs, the mean specific activity of [ 35 S]SP-A (disintegrations per minute per microgram of SP-A) increased linearly with time of perfusion: it was significantly higher in isolated lamellar bodies than in surfactant and was increased in both compartments by 50 -60% in the presence of 0.1 mM 8-bromo-cAMP. These results suggest a precursor-product relationship between lamellar body and extracellular [35 S]SP-A. Specific activities in both compartments were unaffected by addition of amantadine (10 mM) to the lung perfusate, indicating that uptake from the alveolar space was not responsible for the increase in lamellar body [35 S]SP-A. Thus the pathway for secretion of newly synthesized SP-A is by transfer from the site of synthesis to the storage/secretory organelle prior to lamellar body exocytosis. protein trafficking; surfactant secretion; alveolar epithelial type II cell; protein synthesis; clathrin-dependent endocytosis THERE IS GENERAL AGREEMENT that lung surfactant phospholipids and surfactant proteins B and C (SP-B and SP-C) are synthesized in the endoplasmic reticulum of lung alveolar type II epithelial cells and transported to the lamellar bodies for processing and storage prior to secretion into the alveolar space. However, there is less agreement concerning the intracellular trafficking of SP-A. Like SP-B and SP-C, SP-A is synthesized by type II cells and is secreted into the alveolar space, where it associates with the lung surfactant phospholipids (19,22,37). Extracellular SP-A appears to play crucial roles in the formation of tubular myelin, in the regulation of lamellar body exocytosis, and in the uptake of phospholipids by endocytosis and their subsequent remodeling (20,23,30,40). The uptake process is dependent on the association of phospholipids with SP-A, followed by binding of the SP-Aphospholipid complex to a specific cell membrane-localized SP-A receptor (4,5,16), and then internalization of the complex by a clathrin-dependent pathway (21,32,35). Although the pathway for uptake of SP-A seems to be fairly well understood, there is uncertainty regarding the pathway for secretion of newly synthesized SP-A by ...

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“…Amantadine has classically been used for the prevention and treatment of influenza A and Parkinson's disease (46,54). Amantadine has been further described to inhibit neural proton channel activity (28) and acts as a low-affinity N-methyl-Daspartate (NMDA) receptor antagonist (39,48); however, its specificity inhibiting CME of the PAF receptor is not well understood although it is frequently used as a clathrin inhibitor (3,29,47,50,52,65). Recent work has characterized the early events in PAF-mediated CME (25) including internalization of the ligand:receptor complex and sequestration of these ligated receptors to clathrin-coated vesicle (CCVs) (55).…”

mentioning

confidence: 99%

Amantadine inhibits platelet-activating factor induced clathrin-mediated endocytosis in human neutrophils

Eckels

Banerjee²,

Moore

et al. 2009

American Journal of Physiology-Cell Physiology

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Silliman CC. Amantadine inhibits platelet-activating factor induced clathrin-mediated endocytosis in human neutrophils. Am J Physiol Cell Physiol 297: C886 -C897, 2009. First published March 18, 2009 doi:10.1152/ajpcell.00416.2008.-Receptor signaling is integral for adhesion, emigration, phagocytosis, and reactive oxygen species production in polymorphonuclear neutrophils (PMNs). Priming is an important part of PMN emigration, but it can also lead to PMNmediated organ injury in the host. Platelet-activating factor (PAF) primes PMNs through activation of a specific G protein-coupled receptor. We hypothesize that PAF priming of PMNs requires clathrin-mediated endocytosis (CME) of the PAF receptor (PAFr), and, therefore, amantadine, known to inhibit CME, significantly antagonizes PAF signaling. PMNs were isolated by standard techniques to Ͼ98% purity and tested for viability. Amantadine (1 mM) significantly inhibited the PAF-mediated changes in the cellular distribution of clathrin and the physical colocalization [fluorescence resonance energy transfer positive (FRET ϩ )] of early endosome antigen-1 and Rab5a, known components of CME and similar to hypertonic saline, a known inhibitor of CME. Furthermore, amantadine had no effect on the PAF-induced cytosolic calcium flux; however, phosphorylation of p38 MAPK was significantly decreased. Amantadine inhibited PAFmediated changes in PMN physiology, including priming of the NADPH oxidase and shape change with lesser inhibition of increases in CD11b surface expression and elastase release. Furthermore, rimantadine, an amantadine analog, was a more potent inhibitor of PAF priming of the N-formyl-methionyl-leucyl-phenylalanine-activated oxidase. PAF priming of PMNs requires clathrin-mediated endocytosis that is inhibited when PMNs are pretreated with either amantadine or rimantadine. Thus, amantadine and rimantadine have the potential to ameliorate PMN-mediated tissue damage in humans.

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Surfactant protein-A plays an important role in lung surfactant clearance: evidence using the surfactant protein-A gene-targeted mouse

Cited by 34 publications

References 51 publications

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

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

Pathway to lamellar bodies for surfactant protein A

Amantadine inhibits platelet-activating factor induced clathrin-mediated endocytosis in human neutrophils

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