3RD LEC PULMONARY SURFACTANT AND RDS

8/7/2019 3RD LEC PULMONARY SURFACTANT AND RDS

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Lecture 3

Metabolism of Pulmonary Surfactant& Respiratory Distress Syndrome

Nabil Bashir

Respiratory system2nd semester, 2011


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Specific objectives

1. Function of pulmonary surfactants

2. Stages of synthesis and degradation

3. Phospholipids synthesis as components:PC, PG, PI

4. Structure,function and clinical significance of protein components of

pulmonary surfactants: PS-A, PS-B, PS-C, and PS-D

5. What is RDS

6. The Laplace Relationship

7. Biochemical basis to prevent RDS


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What is RDS ?

Respiratory distress syndrome (RDS)

Hyaline membrane disease is a major cause of

respiratory distress in preterm infants.It is caused by surfactant deficiency.

Blood oxygen levels fall and carbon dioxide

rises, resulting in rising blood acid levels andhypoxia.


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Pulmonary Surfactant

Presents in the epithelial lining of alveoli.

Functions:

Lower the surface tension between air andalveolar fluid .

Pulmonary host defense

Consists of lipids (9095%) and four surfactantproteins (SP-A, SP-B, SP-C, and SP-D, 510%).


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Functional Properties of Surfactant

The hydrophobic and hydrophilic properties of

the phospholipids cause head to tail

orientation in the air-liquid interface inside

the alveolus, hence:

lower the surface tension of the liquid lining of

the alveoli

decrease the pressure needed to keep the

alveoli open and inflated.


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Surfactant Metabolism

Synthesized and secreted by type II alveolarepithelial cells.

Lamellar bodies, which serve as the intracellular

storage of surfactant. Secreted into the alveolar lumen by exocytosis.

Tubular myelin ,from which the phospholipidlayer .

Recycled into type II cells, where the majority arere-utilized or removed from the cycle byphagocytosis and degraded within alveolarmacrophages


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Surfactant lipids

The major lipid group in surfactant is

phospholipids (8090%).

1. Dipalmitoyl phosphatidylcholine (DPPC), -40%

2. Phosphaditylglycerol (PG)- 510%

3. Phosphaditylinositol (PI -


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Surfactant Proteins

Surfactant Protein SP-B

Surfactant Protein SP-C

Surfactant Protein SP-A

Surfactant Protein SP-D


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Surfactant Protein SP-B

Structure

1. High cysteine content .

2. The gene for SP-B is found on chromosome 2

and comprises 11 exons.3. SP-B mRNA is initially translated into a pre-

pro-protein of381 amino acid residues


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Summary of the putative functions of surfactant-

associated protein B (SP-B)

1. Promotion of phospholipid insertion into the

air-tissue (liquid) interface

2. Formation of tubular myelin-storage3. Influence on molecular ordering of

phospholipid monolayer- processing

4. Required in the proteolytic processing of SP-C


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Deficiency SP B causessevere respiratory distress.

Autosomal recessive

The most common allelicmutation of SP-B is the121ins2 mutation and

accounts for nearly twothirds of cases.

The mutation involvessubstitution of three basesby one in exon 4 of the geneand corresponds to codon121 of the SP-B mRNA .


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Surfactant Protein C (SP-C)

1. One of the most hydrophobic naturally

occurring polypeptides known .

2. The highly hydrophobic nature of SP-C is dueto the high content ofvaline residues , these

are present in two thirds of the molecule that

forms a regular -helix with the long axis of

this helix being orientated parallel to the acylchains of the phospholipids .


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STRUCTURE

1. SP-C is encoded by a single gene (referred toas SFTPC) on chromosome 8 ,autosomaldominant

2. SP-C is a small, hydrophobic 33- to 34-aminoacid polypeptide .

3. Synthesized as pro SP-C (see figure below)

and is subsequently palmitoylated.4. Processing of SP-C requires the presence of

SP-B;


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Summary of the functions of SP-C

1. Promotion ofphospholipid insertion into the

air-tissue (liquid) interface

2. Alteration ofproportion of phospholipidscomponents to alter surface tension lowering

properties at smaller volumes

3. Regulation ofphospholipid ordering


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Clinical significance

1. Unlike SP-B gene mutations, which lead to

respiratory distress very soon after birth, SP-

C deficiency usually presents at a few

months of age.

2. SP-C deficiency leads to progressive lung

fibrosis and surfactant dysfunction .


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Surfactant Protein A (SP-A)

SP-A is a large acidic glycoprotein of 250

amino acids.

It is a member of the family of proteins calledcollectins (collagenous lectins) because they

have both collagenous and lectin-binding

domains.

SP-A is the most abundant surfactant

associated protein .


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Structural features

1. 2(SP-A 3 chain) and 1(SP-A 2 chain) .

2. The primary structure of this basic sub-unit(monomer) of SP-A contains four major structural

domains: A short N-terminal segment containing two

intermolecular disulfide bonds

A collagen-like sequence of glycine-x-y repeats (where

x is proline and y is predominantly hydroxlated proline) An acidic and hydrophobic neck domain

A C-terminal carbohydrate recognition domain


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Summary of the functions of

surfactant-associated protein A (SP-A).

1. Formation oftubular myelin

2. Regulation of phospholipid insertion into

the surfactant monolayer3. Modulation of uptake and secretion of

phospholipids by type II pneumocytes

4. Activation of alveolar macrophages5. Binding and clearance ofbacteria

6. Binding and clearance ofviruses


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The basic structure of the

monomeric subunit of SP-A

In this structure, globular

heads form the flowers and

collagen helices the stalks

1. mutations in thecollagen domain.would affect the abilityof the sub-units tooligomerise.

2. mutations in mannose-binding lectin (astructurally similarcollectin) have beenassociated with anincreased risk of

infection in children .3. deletions of the SP-A

gene may be found innon-small cell lungcancer cells in adults .


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Surfactant Protein D (SP-D)

1. SP-D is the least abundant surfactant associated

protein.

2. It is encoded by a single gene (referred to as

SFTPD) on human chromosome 10, .

3. SP-D has a homogeneous quaternary structure

in the form of a cross .

4. Four identical rods of triple collagen-like helicesemanate from the central point and terminate in

the carbohydrate recognition domain


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It does not seem to have a role in the surfacetension lowering effect of surfactant and most of

its putative functions relate to lung defence

1. Activation of alveolar macrophages

2. Agglutination of bacteria

3. Protection again non-bacterial micro-organisms

and viruses4. Regulation of phospholipid homeostasis

5. Role in phosphatidylinositol metabolism


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Clinical significance

Certain SP-D (and SP-A) alleles have been

linked to possible susceptibilities to chronic

obstructive pulmonary disease .

Both SP-A and SP-D polymorphisms are

associated with increased severity of

childhood infection with respiratory virus

infection .


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The Laplace Relationship

Explains the relationship between intra-alveolar

pressure (P) needed to counteract the

tendency of the alveoli to collapse under the

force of surface (wall) tension (ST) and the

radius (r ).


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The Laplace

Relationship

The pressure (P)needed to

stabilize the respiratorysystem from within isdirectly proportional totwice the surface tension(ST)and inverselyproportional to the radius

(r)of the structure

P = 2 X ST

r


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The smaller the

alveolar radiusP 1 / r

The greater the

pressure needed


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The greater thesurface tension

P ST

The greater the

Pressure needed


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Larger alveoli need less pressure to open upand are less likely to collapse

Smaller alveoli need more pressure to open

and are more likely to collapse

Smaller alveoli are more likely to empty intothe larger alveoli

More Surfactant in the smaller alveoli willreduce the need for high pressure and reducesthe likelihood of collapse


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The Laplace

Relationship

S.Tension (ST) = 1 S.Tension(ST) = 1

Radius (r) = 1 Radius (r) = 2

P1 = 2 X ST/r P2= 2 XST/r

P1 = 2 X 1/1 P2= 2 X1/2

P1 = 2 P2= 2

P1> P2


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Prevention of RDS

Prevent premature delivery

Determine lung maturity to plan delivery by

Biochemical tests Biophysical tests


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Prevention of RDS

Biochemical tests to determine lung maturity:

Lecithin/sphingomyelin (L/S) ratio : the ratio is

1:1 until 32-33 weeks GA, then lecithinconcentration increase while sphingomyelin

concentration remain the same.

A ratio >2 indicates low risk for RDS.


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Prevention of RDS

Biochemical tests to determine lung maturity:

Phosphatidylglycerol (PG): concentration in amniotic fluid

rises several weeks after rise in lecithin concentration.

It indicates advanced lung maturity.Value >0.3 is associated with low risk for RDS.

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3RD LEC PULMONARY SURFACTANT AND RDS

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