The Action of Lung Lysosomal Phospholipases on Dipalmitoyl Phosphatidylcholine and its Significance for the Synthesis of Pulmonary Surfactant

Heath, M. F.; Jacobson, W.

doi:10.1203/00006450-198003000-00016

Cited by 25 publications

(16 citation statements)

References 28 publications

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“…The existence of an acidic phospholipase A2 activity was first described over 25 years ago (19,20). Such an activity was subsequently described in rabbit lung and in rat and human alveolar macrophages.…”

Section: Discussionmentioning

confidence: 99%

Lysosomal Phospholipase A2 Is Selectively Expressed in Alveolar Macrophages

Abe

Hiraoka

Wild

et al. 2004

Journal of Biological Chemistry

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Lung surfactant is the surface-active agent comprised of phospholipids and proteins that lines pulmonary alveoli. Surfactant stabilizes the alveolar volume by reducing surface tension. Previously, we identified a lysosomal phospholipase A2, termed LPLA2, with specificity toward phosphatidylcholine and phosphatidylethanolamine. The phospholipase is localized to lysosomes, is calcium-independent, has an acidic pH optimum, and transacylates ceramide. Here, we demonstrate that LPLA2 is selectively expressed in alveolar macrophages but not in peritoneal macrophages, peripheral blood monocytes, or other tissues. Other macrophage-associated phospholipase A2s do not show a comparable distribution. LPLA2 is of high specific activity and recognizes disaturated phosphatidylcholine as a substrate. The lysosomal phospholipase A2 activity is six times lower in alveolar macrophages from mice with a targeted deletion of the granulocyte macrophage colonystimulating factor (GM-CSF), a model of impaired surfactant catabolism, compared with those from wild-type mice. However, LPLA2 activity and protein levels are measured in GM-CSF null mice in which GM-CSF is expressed as a transgene under the control of the surfactant protein C promoter. Thus LPLA2 may be a major enzyme of pulmonary surfactant phospholipid degradation by alveolar macrophages and may be deficient in disorders of surfactant metabolism.Previously, in an attempt to identify the enzyme that transacylates ceramide at the 1-hydroxyl position, a novel phospholipase A2 was characterized (1). The phospholipase A2, termed 1-O-acylceramide synthase or lysosomal phospholipase A2 (LPLA2) 1 has the following properties. In the presence of ceramide, the enzyme catalyzes the formation of 1-O-acylceramide by transacylation of fatty acids from the sn-2 position of phosphatidylcholine or phosphatidylethanolamine. In the absence of ceramide or other alcohols as acceptors, the enzyme acts as a traditional phospholipase A2. However, the phospholipase has a pH optimum of 4.5 and is mannose-rich and calcium-independent (2). The phospholipase amino acid sequence is 49% identical to human LCAT (3). The homology with LCAT is highest within the catalytic domain, but the phospholipase does not recognize cholesterol as an acceptor for the fatty acid. The phospholipase colocalizes with other lysosomal proteins in cell fractionates. Upon the initial characterization of this enzyme, the functional role of this phospholipase A2 was not immediately apparent. A role for an acidic phospholipase A2 activity has previously been suggested for the degradation of pulmonary surfactant phospholipids (4). The pulmonary acidic phospholipase A2 activity is also reported to be calcium-independent and inhibited by a transition state analog of arachidonate, MJ33 (5). In rats treated with MJ33 the surfactant phospholipid catabolism was inhibited by ϳ40 -50%, suggesting that the drug-sensitive phospholipase A2 activity contributes significantly to total surfactant degradation (6). In the present paper LPLA2 was stu...

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Section: Discussionmentioning

confidence: 99%

Lysosomal Phospholipase A2 Is Selectively Expressed in Alveolar Macrophages

Abe

Hiraoka

Wild

et al. 2004

Journal of Biological Chemistry

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“…Deacylation is catalyzed by phospholipase A2, an enzyme which is present in lung (91,92). As illustrated in Figure 1, reacylation can occur by at least two mechanisms-reacylation with acyl CoA, catalyzed by lysolecithin acyltransferase, or transacylation, catalyzed by lysolecithin: lysolecithin acyltransferase, in which two molecules of lyso-PC react to form one molecule each of PC and glycerophosphocholine.…”

Section: Synthesis Of Disaturated Pcmentioning

confidence: 99%

Lung surfactant.

Rooney¹

1984

Environ Health Perspect

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Aspects of pulmonary surfactant are reviewed from a biochemical perspective. The major emphasis is on the lipid components of surfactant. Topics reviewed include surfactant composition, cellular and subcellular sites as well as pathways of biosynthesis of phosphatidylcholine, disaturated phosphatidylcholine and phosphatidylglycerol. The surfactant system in the developing fetus and neonate is considered in terms of phospholipid content and composition, rates of precursor incorporation, activities of individual enzymes of phospholipid synthesis and glycogen content and metabolism. The influence of the following hormones and other factors on lung maturation and surfactant production is discussed: glucocorticoids, thyroid hormone, estrogen, prolactin, cyclic AMP, p-adrenergic and cholinergic agonists, prostaglandins and growth factors. The influence of maternal diabetes, fetal sex, stress and labor are also considered. Nonphysiologic and toxic agents which influence surfactant in the fetus, newborn and adult are reviewed.

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“…The first enzymatic reaction in the remodeling pathway is the deacylation of PC by PLA 2 . Numerous PLA 2 isoforms exist in the mammalian genome (47,48), and PLA 2 activity has been localized to distinct subcellular compartments of the lung, including cytosol, microsomes, lysosomes, and lamellar bodies (49)(50)(51)(52)(53)(54)(55)(56). PRDX6 is a Ca 2+ -independent, acidic PLA 2 that localizes to lysosomes and lamellar bodies and is a dual-function enzyme with peroxidase and phospholipase activity (57).…”

Section: Figurementioning

confidence: 99%

LPCAT1 regulates surfactant phospholipid synthesis and is required for transitioning to air breathing in mice

Bridges¹,

Ikegami²,

Brilli³

et al. 2010

J. Clin. Invest.

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Respiratory distress syndrome (RDS), which is the leading cause of death in premature infants, is caused by surfactant deficiency. The most critical and abundant phospholipid in pulmonary surfactant is saturated phosphatidylcholine (SatPC), which is synthesized in alveolar type II cells de novo or by the deacylation-reacylation of existing phosphatidylcholine species. We recently cloned and partially characterized a mouse enzyme with characteristics of a lung lysophosphatidylcholine acyltransferase (LPCAT1) that we predicted would be involved in surfactant synthesis. Here, we describe our studies investigating whether LPCAT1 is required for pulmonary surfactant homeostasis. To address this issue, we generated mice bearing a hypomorphic allele of Lpcat1 (referred to herein as Lpcat1 GT/GT mice) ufsing a genetrap strategy. Newborn Lpcat1 GT/GT mice showed varying perinatal mortality from respiratory failure, with affected animals demonstrating hallmarks of respiratory distress such as atelectasis and hyaline membranes. Lpcat1 mRNA levels were reduced in newborn Lpcat1 GT/GT mice and directly correlated with SatPC content, LPCAT1 activity, and survival. Surfactant isolated from dead Lpcat1 GT/GT mice failed to reduce minimum surface tension to wild-type levels. Collectively, these data demonstrate that full LPCAT1 activity is required to achieve the levels of SatPC essential for the transition to air breathing.

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The Action of Lung Lysosomal Phospholipases on Dipalmitoyl Phosphatidylcholine and its Significance for the Synthesis of Pulmonary Surfactant

Cited by 25 publications

References 28 publications

Lysosomal Phospholipase A2 Is Selectively Expressed in Alveolar Macrophages

Lysosomal Phospholipase A2 Is Selectively Expressed in Alveolar Macrophages

Lung surfactant.

LPCAT1 regulates surfactant phospholipid synthesis and is required for transitioning to air breathing in mice

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