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Surfactant Composition and Function Joanna Floros, Ph.D Evan Pugh Professor, Departments of Cellular and Molecular Physiology, Pediatrics, and Obstetrics and Gynecology. The Pennsylvania State University, College of Medicine, Hershey, PA, U.S.A 8th World Hellenic Biomedical Congress Surfactant 1. Characteristics of Surfactant • • • • What is surfactant? What is its composition? Where is it made? What is its structure? 2. Function of surfactant What is Pulmonary Surfactant and What is its Composition? Pulmonary surfactant biochemically, is a lipoprotein complex that lines the internal surface of the alveoli. MAJOR CONSTITUENTS OF PULMONARY SURFACTANT Unsaturated PC PC (DSPC) PE 16:/16:0 Protein Other lipids Cholesterol PG PI Surfactant SP-A SP-B SP-C SP-D Other Proteins Proteins Fishman 2-19 SURFACTANT HETEROGENEITY AND LIFE CYCLE LAMELLAR BODIES TUBULAR MYELIN SP-A SURFACE FILM LARGE AGGREGATES LB, TM, SP-A SMALL AGGREGATES HYPOPHASE FLUID (SUPERNATANT) Surfactant 1. Characteristics of Surfactant • • • • What is surfactant? What is its composition? Where is it made? What is its structure? 2. Function of surfactant and/or surfactant components • Lowering of surface tension. • Innate host defense. • Initiation of parturition (SP-A, a hormone?) Functions of surfactant Surface tension • Stabilizes alveoli and prevents alveolar (lung) collapse with each exhalation by lowering the surface tension at the air-liquid surface. Host defense • Surfactant components play a role in host defense and protect the lung from injuries or infections caused by inhaled microorganisms, particles, toxins, other. Initiation of labor • One of the protein component of surfactant (SP-A) may serve as a hormone in parturition. Air-Liquid Interface Without surfactant With surfactant Surfactant J. Kending MAJOR CONSTITUENTS OF PULMONARY SURFACTANT Unsaturated PC PC (DSPC) PE 16:0/16:0 Protein Other lipids Cholesterol PG PI Surfactant SP-A SP-B SP-C SP-D Other Proteins Proteins Functions of surfactant Surface tension • Stabilizes alveoli and prevents alveolar (lung) collapse with each exhalation by lowering the surface tension at the airliquid surface. Host defense • Surfactant components play a role in host defense and protect the lung from injuries or infections caused by inhaled microorganisms, particles, toxins, other. Initiation of labor • One of the protein component of surfactant (SP-A) may serve as a hormone in parturition. SURFACTANT REGULATION OF IMMUNE CELLS PE SM CHOL SP-A SP-A Stimulation LIPID PI PG PC Inhibition STIMULATION Oxidant Production Splenocyte Proliferation Cell Surface Markers Cytokine Production NF-kB Activation Fibroblast Apoptosis Collagen and Collagenase Production PI PG PC PE SM CHOL SP-A STIMULATION INHIBITION INHIBITION SP-A FUNCTION Surfactant-related Host defense-related Innate Immunity SP-A Innate 800 700 TUBULAR MYELIN LARGE AGGREGATES 600 myr Adaptive 500 present Regulation of inflammatory processes Cell Surface Markers; Cytokine Production; NF-kB Activation; Collagen and Collagenase Production Human SP-A Genes, and Variants Genes Variants C SP-A2 SP-A1 P 1A0 T 6A2 The above variants have been shown to exhibit qualitative and quantitative differences. In addition environmental insults, such as ozone, appear to differentially alter their functional activity and thus contribute to individual differences in disease susceptibility. Differences exist among SP-A variants in their ability to enhance phagocytosis of bacteria by alveolar macrophages in the presence or absence of environmental factors. EXPERIMENTAL APPROACH agar plate suspension of bacteria ozone BAL wash off free bacteria insect cells or mammalian cells SP-A phagocytosis rat alveolar macrophages slide preparation light microscopy analysis RESULTS Microscopic view of live P. aeruginosa, phagocytized by rat alveolar macrophages in the presence or absence of human SP-A No SP-A SP-A SP-A2 products exhibit higher phagocytic ability than SP-A1 Mammalian expressed variants *** Phagocytic index (%) 500 * 400 * hSP-A 300 SP-A2 200 100 SP-A1 1A0 1A 1.56 mg/ml * SP-A2 vs. SP-A1 ; § ** 6A2 6A4 n=5 ** 6A2 vs. 6A4 ; *** hSP-A vs. 6A4 (mammalian); (hSP-A: 25 µg/ml) hSP-A vs. SP-A variants (insect) Bacteria: P.aeruginosa Phagocytic index: % of bacteria-positive AMs the average # of bacteria per bacteria-positive AMs Mikerov et al Ability of SP-A variants to enhance phagocytosis by alveolar macrophages following exposure to ozone. Unexposed Ozone-exposed 1A0 > 6A4 = 1A0/6A4 > 1A0 6A4 1A0/6A4 (SP-A2) (SP-A1) (SP-A2/SP-A1) Functions of surfactant Surface tension • Stabilizes alveoli and prevents alveolar (lung) collapse with each exhalation by lowering the surface tension at the airliquid surface. Host defense • Surfactant components play a role in host defense and protect the lung from injuries or infections caused by inhaled microorganisms, particles, toxins, other. Initiation of labor • One of the protein component of surfactant (SP-A) may serve as a hormone in parturition. Fetal SP-A initiates labor Increased levels of SP-A activate Surfactant lipids Fetal macrophages (Arachidonate derivatives) Increased levels of proinflammatory cytokines (i.e. IL-b1) Prostaglandin synthesis activate NF-kB Increase expression of genes that cause myometrial contractibility P65 antagonizes progesterone receptor activation of genes that modulate uterine quiescence. Summary • Pulmonary surfactant, a lipoprotein complex, is essential throughout life for normal lung function, host defense, and other functions. • Derangement in surfactant either through alterations in composition or modification (i.e. oxidation) can negatively affect normal lung function and host defense. • Genetic differences in surfactant components may contribute to differences in disease risk among individuals.