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surfactant SEMINAR PAPER 1 dhinesh.pdf
1. SURFACTANT AND DISORDERS OF
SURFACTANT
HOMEOSTASIS(INTRODUCTION)
CHAIRPERSON:
Dr.Nagaraja C
Professor
Department of Pulmonary Medicine
BMCRI
MODERATOR:
Dr.Arun B J
Assistant Professor
Department of Pulmonary Medicine
BMCRI
PRESENTER:
Dr.Anupama R
1st Year post graduate
Department of Pulmonary Medicine
BMCRI
1
2. Contents
• Surfactant – definition
• Discovery of surfactant
• Composition
• Synthesis and secretion
• Metabolic trafficking
• Functions
• Phospholipids and surfactant proteins in
detail 2
3. Contents
• Recycling and catabolism
• Regulation of surfactant production
• Disorders of surfactant homeostasis
• IRDS
• ARDS
• Surfactant replacement therapy
3
4. Surfactant
DEFINITION:
• Pulmonary surfactant is a complex mixture of
phospholipids and proteins that creates a unique interface
separating alveolar gas and liquids at the alveolar cell
surface,reducing surface tension,and maintaining lung
volumes at end expiration.
• Secreted by Type 2 pneumocytes and clara cells.
4
5. Discovery Of Surfactant
• In 1929 Von Neergaard discovered the difference in the
mechanics and elastic properties of the respiratory system
depending on whether lung was inflated with air or saline.
• More pressure was required to inflate the lungs with air than
with saline,but once inflated alveoli remained open even at
low lung volumes.
• Leads to the hypothesis that the surface tension of the distal
lung was lower than predicted for a simple air-water interface
due to an “antiatelectasis factor”.
5
7. Discovery Of Surfactant
• In 1950s,Clements and Pattle used lung extracts to
demonstrate that surfactant was responsible for
lowering alveolar surface tension.
• Avery and Mead demonstrated a deficiency in
surface active material in the lungs of premature
infants.
7
9. Synthesis Of Surfactant
• Begins in the canalicular stage of lung development
between 22 to 24 weeks of gestation.
• Secreted by Type 2 pneumocytes.
• Peaks at about 35 weeks of gestation.
• Premature infants at risk of IRDS.
9
11. Type 2 Pneumocytes
• Comprises 3-5% of alveolar surface area,constitutes 60% of
the alveolar epithelial cells.
• Cuboidal in shape,have microvilli.
• Primary role in synthesis of surfactant and transport them
into alveolar space and also in recycling and resorption of it.
• Progenitor cells for maintaining alveolar epithelium and also
help in host defense.
11
13. Type 2 Pneumocytes
• Contains specialized cytoplasmic,osmiophilic
,lamellated organelles from which surfactant is
released into the alveolar lumen.
• Two unique enzymes of lipid metabolism :
1.Fatty acid synthase
2.Stearoyl CoA desaturase I
13
14. Type 2 Pneumocytes
• Lipid metabolism and energy capacity of AT2 cells are highly
specialized:
1. Highly enriched in genes involved in lipid metabolism.
2. Metabolism is geared towards high glucose and oxygen
consumption.
3. High density of mitochondria.
14
15. Immune Functions Of Type2
Pneumocytes
• Initial innate immune response in the alveoli to
environmental insults.
• Target specific respiratory viruses like SARS CoV19 and
influenza.
• Pathogenesis of idiopathic pulmonary fibrosis.
• Bronchoalveolar carcinomas and some
adenocarcinomas likely arise in type 2 cells.
15
19. ABCA3 Gene Mutation
• ABCA3 is a large membrane spanning transport
protein present in the limiting membrane of lamellar
bodies in type 2 epithelial cells.
• Inherited as autosomal recessive.
• Atypical lamellar bodies in AT2 cells and absence of
tubular mylein in the airways.
19
21. ABCA3 Gene Mutation
• Affected infants present with severe respiratory
failure within the first days of life.
• Pathological findings include alveolar
proteinosis,lipiod pneumonia,cuboidal epithelial cell
hyperplasia,interstitial thickening and loss of normal
alveolar structures.
21
22. Functions Of Surfactant
• The main function of the surfactant is to reduce the
surface tension at the alveoli and prevents its
collapse.
• To maintain the stability of alveoli.
22
25. Physical Forces At Air Liquid
Interface
• Arises because the attractive forces between
adjacent molecules of liquid are much stronger than
those between the liquid and gas.
• Liquid surface area becomes as small as possible.
25
28. Effect Of Surface Tension
Surface tension at air- liquid interfaces
Alveolar collapse at low lung volumes
Ventilation perfusion mismatch
Impairs normal gas exchange
28
32. Functions Of Surfactant
BIOPHYSICAL FUNCTIONS:
• Reduces surface tension and prevents collapse of alveoli
during expiration
• Increases lung compliance and decreases work of
breathing
• Maintain gas exchange area of lung
32
34. Host Defense Functions
• Opsonization of bacteria,virus,fungi,allergens.
• Facilitate phagocytosis of pathogens.
• Direct microbicidal activity.
• Promote and modulate phagocytosis of apoptotic cells.
34
35. Phospholipids
• The critical lipid component of surfactant is
dipalmitoylphosphatidylcholine(DPPC) 50-60%,an
atypical phospholipid species of phosphatidylcholine.
• Along with unsaturated phosphatidylcholine and
phosphatidylglycerol.
• Amphophilic,spontaneously form a monolayer film at
air-liquid interfaces to stabilize the surface film at
low lung volumes.
35
37. Phospholipids Composition–
Clinical Correlation
• Composition of surfactant lipid is important for optimal
lung function and changes are associated with disease.
• In ARDS, reduction in the percentage of
phosphatidylglycerol is the earliest alteration detected
in the composition of surfactant.
37
38. Surfactant Proteins
• SURFACTANT PROTEIN A (SP-A)
• SURFACTANT PROTEIN B (SP-B)
• SURFACTANT PROTEIN C (SP-C)
• SURFACTANT PROTEIN D (SP-D)
38
39. Functions Of Surfactant Proteins
SP A AND SP D
• Hydrophilic
• No primary role in
modulating surfactant
biophysics
• Host defense functions-
innate immunity
• Homeostasis of surfactant
SP B AND SP C
• Hydrophobic proteins
• Improve rate of delivery of
DPPC at air- liquid interface
• Improves surfactant like
properties of phospholipids
39
40. Surfactant Protein A
STRUCTURE
• First surfactant protein identified and most abundant of the surface
protein.
• Secreted octadecameric collagenous glycoprotein with a complex
tertiary structure
• Forms a polarized bouquet like structure composed of 18 monomers
organised as six trimeric units
40
41. Surfactant Protein A
SYNTHESIS:
• Two SP-A genes, SFTPA1 and SFTPA2, located on
chromosome 10.
• Most SP A is found in the alveoli (AT2 organelles &
intra alveolar surfactant) with less prominent
expression in tracheal submucosal glands.
41
42. Surfactant Protein A
FUNCTIONS:
• Capable of binding both the surfactant lipid and
inhaled organisms or particles.
• Suppress the secretion of inflammatory cytokines by
macrophages.
• Surfactant recycling and clearance.
42
43. Mutations In SFTPA Gene
• Inherited as autosomal dominant missense mutation in the gene
encoding SP-A.
• Disturbed oligomerization and intracellular trafficking of SPA ,
unfolded protein response and chronic alveolar cell injury.
• Pathologically diagnosed as usual interstitial pneumonitis presenting
as ILD in the 4th and 5th decades of life.
• Increased risk of pulmonary adenocarcinoma at more advanced ages.
43
44. Surfactant Protein D
SYNTHESIS AND STRUCTURE:
• Encoded by a single gene SFTPD located on chromosome 10
near SFPTA gene.
• Synthesised by AT2 cells and non ciliated bronchiolar cells in
the lung.
• Collageneous glycoprotein with a complex but highly
ordered tertiary structure.
44
46. Surfactant Protein D
CLINICAL CORRELATION:
• SP-D is up-regulated in a variety of infectious and
inflammatory disease states,including allergic
asthma,hyperoxic lung injury,bleomycin injury and
pneumocystis pneumonia.
• Elevation of SP-D proposed as a diagnostic and /or predictive
biomarker in COPD, IPF, post lung transplant recipients.
46
48. Functions Of SP-D
• Binds to variety of micro-organisms to promote clearance
from the alveolar space.
• Pro-inflammatory and anti-inflammatory signalling
functions.
• Important function in the clearance of apoptotic cells.
48
49. Surfactant Protein B
STRUCTURE
• Hydrophobic surfactant.
• Homodimer composed of two 79 aminoacid polypeptide
chains linked by disulphide bonds.
• Each monomer has 5 amphipathic helices that interact with
surfactant monolayer.
49
50. Surfactant Protein B
SYNTHESIS:
• SP-B gene is located on short arm of chromosome 2.
• Gene is expressed in AT2 cells and non ciliated
bronchiolar epithelial cells
50
51. Surfactant Protein B
FUNCTIONS:
• In the alveoli,the positively charged amino acid residues of SP-B
interacts with negatively charged DPPG.
• Purify the DPPC monolayer by removal of DPPG.
• Reconstitutes the characteristic ultrastructural features of
tubular myelin,producing multilamellar aggregates and
square lattice configuration.
51
52. SP-B Deficiency
• Inherited as autosomal recessive pattern.
• SP-B deficiency distrupts the formation of lamellar
bodies and tubular myelin,interferes with the
processing of proSP-C to the active peptide.
• Lack both SP-B and SP-C proteins in the alveoli.
52
53. Clinical Features Of SP-B Deficiency
• Pro-SPC accumulates in air spaces alveolar proteinosis like
syndrome.
• Desquamative interstitial pneumonitis,chronic pneumonitis of
infancy or infantile alveolar proteinosis.
• Acute atelectasis and respiratory distress.
• Presenting as full term infants with signs and symptoms of
diffuse alveolar collapse soon after birth.
• Refractory to surfactant replacement therapy .
53
54. Surfactant Protein C
SYNTHESIS:
• Encoded by a single gene located on
chromosome 10.
• Exclusively in type 2 alveolar cells.
• Hydrophobic peptide of 35 aminoacids stored in
lamellar bodies.
54
55. Surfactant Protein C
FUNCTIONS:
• Cooperates with SP-B to enhance the surfactant
properties of lipid bilayer.
• Stabilize the surface film and minimize film collapse via
insertion into the surface monolayer to organize
surfactant phospholipids during respiratory cycle.
55
56. SP-C Gene Mutation
• Inherited as autosomal dominant gene.
• Misfolded mutant pro-spc protein is misrouted
resulting in intracellular accumulation.
• Interstitial lung disease in both children and adults.
• Including RDS in newborns,CPI,NSIP and other forms
of interstitial pneumonitis.
56
57. Recycling And Catabolism Of Surfactant
• Reuptake by AT2 cells(85%) for reprocessing and phagocytosis
by alveolar macrophages(15%) for catabolism.
• Reuptake is increased in response to surfactant
secretagogues,such as ATP and phorbol myristate acetate.
• Catabolism of extracellular surfactant is regulated by GM-CSF
and its ability to activate macrophages.
57
63. Regulation Of Surfactant Production
• Subjected to precise regulatory controls both during
development and postnatally.
• Phospholipid synthesis increases markedly in late
gestation and is enhanced by hormones like
glucocorticoids.
63
64. Regulation Of Surfactant Production
• Surfactant proteins synthesis is also highly regulated.
• Increased levels of SP mRNA increase in perinatal
period.
• Surfactant production is enhanced by
glucocorticoids,EGF,cAMP but inhibited by TNF
alpha,TGF beta and insulin.
64
70. Adult Respiratory Distress Syndrome
• Occurs in association with trauma,sepsis,long bone
fractures,thermal burns,aspiration of gastric
contents,pneumonia,infection.
• Deficiency in pulmonary surfactant as well as
inhibition of the remaining surfactant.
70
72. Adult Respiratory Distress Syndrome
Mechanism include:
1.Competition of the proteins for air-liquid interface.
2.Sequestration and dilution of surfactant in non
surface active particles.
3.Inhibition of SP and lipid synthesis and secretion.
72
74. MECONIUM ASPIRATION
SYNDROME
Meconium causes surfactant
inactivation by destroying its
fibrillary structure.
PLA2 induces hydrolysis of
DPPC ,releasing free FAs and
lyso-PC
Damage the alveolar capillary
membrane and cause
neutrophil seqestration.
PULMONARY
HEMORRHAGE
Plasma proteins and neutrophils
are released, which in turn
expresses proteases,free
radicals and cytokines
Free radicals damage type 2
pneumocytes and elastases
degrades SP A
Plasma proteins reduces the
rate of absorption and also
competes with surfactant for
the interface
74
76. Surfactant Replacement Therapy
INDICATIONS:
• Done mainly for IRDS.
• Also used in other conditions like meconium
aspiration syndrome,pneumonia,pulmonary
hemorrhage,congenital diaphragmmatic hernia and
acute respiratory distress syndrome.
76
78. Methods Of Surfactant Administration
• Slow infusion versus rapid bolus administration.
• Less invasive surfactant administration(LISA).
• Minimally invasive surfactant therapy(MIST).
• Through laryngeal mask airway.
• Nebulized surfactant delivery.
78
79. Common Brands Of Surfactant
• Survanta
• Curosurf
• Neosurf
• Dose 100mg/kg to 200mg/kg of surfactant to preterm
infants.
• Cost ranges between 5K to 20K.
79
80. References
• Fishman’s Pulmonary Diseases and Disorders –fifth
edition.
• Crofton and Dougla’s Respiratory diseases –fifth
edition volume1.
• Murray and Nadel’s Textbook of Respiratory Medicine
–seventh edition.
• Textbook of pulmonary and critical care medicine by
S K Jindal second edition volume 1.
• West’s Respiratory Physiology ,The Essentials- tenth
edition
• AIIMS protocols in Neonatology.
80
