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122602 Hydrophobic Surfactant Proteins in Lung Function

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122602 Hydrophobic Surfactant Proteins in Lung Function MECHANISMS OF DISEASE Review Article Mechanisms of Disease monary surfactant that creates a lipid-rich phase sep- arating alveolar gas and liquid at the surfaces of epithe- lial cells (Fig. 1). Pulmonary surfactant phospholipids form monolayers and multilayers that reduce surface tension in the alveolus to negligible levels, thereby sta- HYDROPHOBIC SURFACTANT bilizing the alveoli and maintaining lung volumes at PROTEINS IN LUNG FUNCTION end-expiration. Lack of pulmonary surfactant, wheth- AND DISEASE er caused by premature birth, lung injury, or muta- tions in genes critical to surfactant production or func- JEFFREY A. WHITSETT, M.D., tion, causes respiratory failure. AND TIMOTHY E. WEAVER, PH.D. Pulmonary surfactant is a macromolecular com- plex composed primarily of lipids and proteins that is present in the alveolus in structurally distinct forms.1 HE hydrophobic surfactant proteins B and C Surfactant is synthesized by type II epithelial cells lin- are essential for lung function and pulmonary ing the alveoli and stored in characteristic intracellular Thomeostasis after birth. These proteins enhance inclusions called lamellar bodies. After secretion, alve- the spreading, adsorption, and stability of surfactant olar forms of surfactant include lamellar bodies, highly lipids required for the reduction of surface tension in organized structures termed “tubular myelin,” and the alveolus. Surfactant proteins B and C also partici- monolayered and multilayered, phospholipid-rich pate in the regulation of intracellular and extracellular sheets and vesicles (Fig. 1). The multiplicity of these processes critical for the maintenance of respiratory structural forms is influenced by the stoichiometry structure and function. Mutations in the genes en- of lipids and specific proteins, by mechanical forces coding surfactant protein B and surfactant protein C exerted on the material during the respiratory cycle, (SFTPB and SFTPC, respectively) are associated with and by the uptake, recycling, and degradation of sub- acute respiratory failure and interstitial lung diseases. groups of particles by respiratory epithelial cells and In this article, we review the current knowledge re- alveolar macrophages. Alveolar macrophages regulate garding the structure and functions of surfactant pro- catabolism of both lipids and proteins — activities teins B and C and their roles in the pathogenesis of that are under strict control of the signaling of gran- acute and chronic lung disease in children and adults. ulocyte–macrophage colony-stimulating factor (GM- STRUCTURE AND FUNCTION CSF). Indeed, deletion of the gene encoding GM- OF ALVEOLAR SURFACTANT CSF, the gene encoding the GM-CSF receptor, or autoantibodies that block GM-CSF activity causes The lung provides an extensive surface area medi- an accumulation of surfactant that is characteristic of ating gas exchange between epithelial cells and the pulmonary alveolar proteinosis in mice and humans.2-4 capillaries in the alveolus. Since lung cells are in direct Surface tension at the air–liquid interface is reduced contact with environmental gases and particles, an in- by phospholipid films that are stable during the expan- tegrated system has evolved to maintain fluid balance sion and compression associated with the respiratory and innate functions of host defense, the latter medi- cycle. These films are rich in phosphatidylcholine and ated by mucociliary clearance and pathways of innate phosphatidylglycerol, which account for most of the and acquired immunity. The requirement for an ex- molecular mass of surfactant films. However, at 37°C, tensive, hydrated surface for gas exchange presents a pure phospholipids are in a rigid state, resulting in slow most interesting bioengineering problem, since surface formation of films and poor surfactant function. Rap- tension at air–liquid interfaces creates collapsing forces id formation, stability during compression and de- that prevent respiration. The solution to the problem compression, and resistance to interference by serum posed by such large surface areas in the lung is a pul- and cellular proteins — properties typical of mamma- lian surfactants — are critically dependent on the From the Divisions of Neonatology and Pulmonary Biology, Cincinnati presence of the hydrophobic surfactant proteins, sur- Children’s Hospital Medical Center and University of Cincinnati College factant protein B and surfactant protein C.5-7 Either of Medicine, Cincinnati. Address reprint requests to Dr. Whitsett at the protein alone or a mixture of the two proteins con- Cincinnati Children’s Hospital Medical Center, Divisions of Neonatology and Pulmonary Biology, 3333 Burnet Ave., Cincinnati, OH 45229-3039, fers surfactant-like properties on the phospholipids or at [email protected]. present in the alveolus. N Engl J Med, Vol. 347, No. 26 · December 26, 2002 · www.nejm.org · 2141 Downloaded from www.nejm.org at COLUMBIA UNIV HEALTH SCIENCES LIB on January 31, 2006 . Copyright © 2002 Massachusetts Medical Society. All rights reserved. The New England Journal of Medicine Alveolus Lung Monolayer–multilayer film Tubular Adsorption myelin Lipid vesicle Turnover Alveolar Clearance macrophage Secretion Recycling Alveolar type II cell Multivesicular Lamellar Synthetic body body SP-B, SP-C Figure 1. Freeze-Frame View of the Alveolar Space with a Magnified View of the Air–Liquid Interface, with Formation of Pulmonary Surfactant Films. Surfactant phospholipids and proteins are synthesized by alveolar type II cells lining the alveoli. Surfactant lipids and surfactant protein B (SP-B) precursor protein and surfactant protein C (SP-C) are transported to multivesicular bodies and, after proteolytic processing, stored in lamellar bodies. SP-B, SP-C, and surfactant lipids are secreted into the alveolar subphase and interact with surfactant protein A to form a tubular myelin reservoir from which multilayers and monolayers form a film, thus reducing surface tension at the air–liquid interface. Surfactant remnants are taken up and reutilized or catabolized by type II epithelial cells. Alveolar macrophages play a critical part in the clearance and catabolism of surfactant lipids and proteins. Formation of the active surface film is required to maintain lung volumes, thereby preventing atelectasis and respiratory failure. The freeze-frame view is courtesy of Debra Yager. SURFACTANT PROTEIN B transported from the endoplasmic reticulum to the Structure and Function Golgi apparatus and thence to multivesicular bodies Human surfactant protein B is a relatively small, and is ultimately packaged in lamellar bodies. Prote- 79-amino-acid, amphipathic peptide produced by pro- olytic processing of surfactant protein B precursor teolytic processing of a 381-amino-acid precursor in protein occurs in a pulmonary-cell–specific manner type II epithelial cells lining the alveoli (Fig. 2).8,9 during transit from multivesicular bodies to lamellar Surfactant protein B is encoded by a single gene lo- bodies, where the active surfactant protein B peptide cated on chromosome 2 and occurs in various class- is stored with surfactant protein C and surfactant es of vertebrates, including fish (lungfish), amphibians, phospholipids.5 The contents of lamellar bodies are reptiles, and mammals. Surfactant protein B is ex- secreted into the air space and interact with surfac- pressed in a highly cell-specific manner. It is synthe- tant protein A to form tubular myelin (Fig. 1) from sized as a precursor protein that is glycosylated and which the surfactant films that line the alveolus are 2142 · N Engl J Med, Vol. 347, No. 26 · December 26, 2002 · www.nejm.org Downloaded from www.nejm.org at COLUMBIA UNIV HEALTH SCIENCES LIB on January 31, 2006 . Copyright © 2002 Massachusetts Medical Society. All rights reserved. MECHANISMS OF DISEASE ecules into the expanding surface film and enhancing Surfactant protein B precursor protein their stability during the compression and expansion that occur during the respiratory cycle. Because of its surfactant-enhancing properties, surfactant protein B is an active component of surfactant-replacement 1 201 279 381 preparations used in the treatment of respiratory dis- tress syndrome in preterm infants. The level of sur- factant protein B is low in preterm infants who are at risk for respiratory distress syndrome, as it is in adults who are at risk for adult respiratory distress syndrome.10-12 Critical Role in Perinatal Lung Function In mice, targeted deletion of the gene encoding surfactant protein B resulted in respiratory failure im- mediately after birth.13 This animal model has pro- vided insight into the various roles of surfactant pro- tein B precursor protein and surfactant protein B in the functions of type II cells and surfactants. Although the composition of surfactant phospholipids was nor- 1 24 58 197 mal, pulmonary-function testing demonstrated de- Surfactant protein C precursor protein creased lung volumes, a lack of hysteresis, and an ab- sence of residual volume at end-expiration in newborn mice without the gene encoding surfactant protein B Figure 2. Proteolytic Processing of Surfactant Proteins B and C. — findings similar to those in preterm infants with Surfactant protein B is a small, amphipathic polypeptide pro- respiratory distress syndrome. Type II epithelial cells duced by proteolytic processing as a 381-amino-acid precursor, in these mice lack typical lamellar bodies and contain surfactant protein B precursor protein, by type II alveolar epi- enlarged, aberrant
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