PULMONARY SURFACTANT, ALPHA 1 ANTITRYPSIN INHIBITOR DEFICIENCY,

AND CYSTIC FIBROSIS

DR. NABIL BASHIR

BIOCHEMISTRY/RESPIRATORY SYSTEM

Pulmonary surfactant

• Pulmonary surfactant is (phospholipoprotein) complex

• The proteins and lipids that make up the surfactant have both hydrophilic and hydrophobic regions.

• By adsorbing to the air-water interface of alveoli, with hydrophilic head groups in the water and the hydrophobic tails facing towards the air, the main lipid component of surfactant, dipalmitoylphosphatidylcholine (DPPC), reduces surface tension.

Composition

-40% dipalmitoylphosphatidylcholine (DPPC);

-40% other phospholipids (PCs);

-5% surfactant proteins (SP-A, SP-B, SP-C and SP-D);

-Cholesterol (neutral lipids)

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Proteins

• Proteins make up the remaining 10% of the surfactant.

• Half of this 10% is plasma proteins

• the rest is formed by the apolipoproteins, surfactant proteins SP-A, SP-B, SP-C, and SP-D.

SP-A and SP-D confer innate immunity

SP-A is involved in a negative feedback mechanism to control the production of surfactant.

• SP-B and SP-C are hydrophobic membrane proteins that increase the rate that surfactant spreads over the surface--lower surface tension.

• congenital absence of SP-B -----respiratory failure

• congenital absence of SP-C -----progressive interstitial pneumonitis.

Infant respiratory distress syndrome (IRDS)

• Infant respiratory distress syndrome (IRDS), also called neonatal respiratory distress syndrome (NRDS), respiratory distress syndrome of newborn.

• developmental insufficiency of pulmonary surfactant production and structural immaturity in the lungs.

• It can also be a consequence of neonatal infection.

• It can also result from a genetic problem with the production of surfactant associated proteins

Surfactant metabolism dysfunction

SFTPB mutations .:

• complete lack of mature SP-B protein .

• autosomal recessive manner.

SFTPC mutations :

• autosomal dominant pattern, although the onset and severity of lung disease are highly variable, even within the same family.

Lecithins

• Lecithins are mixtures of glycerophospholipids including:

- phosphatidylcholine,

- phosphatidylethanolamine,

- phosphatidylinositol,

- phosphatidic acid.

Biochemical tests to determine

lung maturity 1. Lecithin/sphingomyelin (L/S) ratio :

A ratio >2 indicates low risk for RDS.

2. Phosphatidylglycerol (PG):

Value >0.3 is associated with low risk for

RDS.

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Alpha-1 Antitrypsin Deficiency

• Alpha-1 antitrypsin deficiency is an inherited disorder that may cause lung disease and liver disease.

• Affected individuals often develop emphysema, damage to alveoli.

• Smoking or exposure to tobacco smoke accelerates the appearance of emphysema symptoms and damage to the lungs.

Genetic changes

• Mutations in the SERPINA1 gene cause alpha-1 antitrypsin deficiency.

• alpha-1 antitrypsin protects the body from a powerful enzyme called neutrophil elastase.

• Neutrophil elastase is released from white blood cells to fight infection, but it can attack normal tissues (especially the lungs) if not tightly controlled by alpha-1 antitrypsin.

• More than 120 mutations in the SERPINA1 gene have been identified.

• The most common mutation replaces the amino acid glutamic acid - lysine at protein position 342 (written as Glu342Lys or E342K).

• This mutation results in a version of the SERPINA1 gene called the Z allele that produces very little alpha-1 antitrypsin.

Inheritance patterns

• This condition is inherited in an autosomal codominant pattern.

• Codominance means that two different versions of the gene may be active (expressed), and both versions contribute to the genetic trait.

• The most common version (allele) of the SERPINA1 gene, called M, produces normal levels of alpha-1 antitrypsin.

• Most people in the general population have two copies of the M allele (MM) in each cell.

• M--- normal

• S --- low levels alpha-1 antitrypsin

• Z --- very little alpha-1 antitrypsin.

• ZZ ---have alpha-1 antitrypsin deficiency.

• SZ ---increased risk of developing lung diseases (such as emphysema), particularly if they smoke.

Cystic Fibrosis

• Cystic fibrosis : recessive genetic mutations in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene.

• Classic cystic fibrosis is characterized by chronic bacterial infection of the airways ,fat maldigestion due to pancreatic exocrine insufficiency, infertility in males due to obstructive azoospermia, and elevated concentrations of chloride in sweat.

Molecular Genetics and Gene Function

• Gene Structure: 250,000 bp long and contains 27 exons.

• mRNA: 6129 bp long.

• Protein Size: The CFTR protein is 1480 amino acids long and has a molecular weight of 168,173 Da.

• Protein Function: chloride channel protein found in membranes of cells that line passageways of the lungs, liver, pancreas, intestines, reproductive tract, and skin.

CFTR FUNCTION

CFTR controls

chloride ion

movement in and

out of the cell.

CFTR FUNCTION…….

Protein Structure and Function • CFTR transports chloride ions (Cl-) ions across

the membranes of cells in the lungs, liver, pancreas, digestive tract, reproductive tract, and skin.

• CFTR is made up of five domains:

• two membrane-spanning domains (MSD1 and MSD2) that form the chloride ion channel

• two nucleotide-binding domains (NBD1 and NBD2) that bind and hydrolyze ATP (adenosine triphosphate)

• and a regulatory (R) domain.

• Delta F508, the most common CF-causing mutation, occurs in the DNA sequence that codes for the first nucleotide-binding domain (NBD1).

delta F508 mutation

• Incorrect folding- degradation. - never reaches the cell membrane.

• homozygous for delta F508 mutation --critical loss of chloride ion transport.

• This upsets the sodium and chloride ion balance needed to maintain the normal, thin mucus layer that is easily removed by cilia lining the lungs and other organs.

• The sodium and chloride ion imbalance creates a thick, sticky mucus layer that cannot be removed by cilia and traps bacteria, resulting in chronic infections.

Presentation of Disease

Gene Therapy

• In the case of CF, gene therapy involves inhaling a spray that delivers normal DNA to the lungs.