Biochem Emphysema
Transcript of Biochem Emphysema
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ALPHA
Jao Levina
Lopez, J. Kalaw
Liao Lopez, A.
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CASE
A severe form of obstructive lung disease was found in several
members of a family. One brother had died earlier of lung disease.
Blood plasma from his surviving brother and sister showed
abnormally low concentrations of antitrypsin (3 5 The
plasma fraction also moved abnormally on isoelectric focusing
gel electrophoresis.
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OBJECTIVES
To define emphysema
To define 1-antitrypsin and its effects on the lungs
To identify the signs and symptoms of emphysema
To enumerate the different methods of treating emphysema
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EMPHYSEMA
Long-term, progressive disease of the
lungs
Included in a group of diseases called
C
hronic Obstructive PulmonaryDiseases
Causes:
Smoking
Exposure to air pollution and second handsmoke
Heriditary
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Signs and Symptoms
Shortness of breath
Barrel chest
Fatigue
Coughing (with or withour sputum)
Wheezing
Cyanosis
Excess Mucus production
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Particulates become lodged into alveoli causing an inflammatory
response
Enzymes released during inflammatory response causes
disintegration of alveolar walls Deformation of lungs
Reduced surface area for gas exchange
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To accomodate for decreased surface area:
Expansion of thoracic cage (Barrel Chest)
Diaphragm contraction
Hyperventilation
Vasoconstriction of vessels = Pulmonary Hypertension
Familial Emphysema
Caused by 1-antitrypsin deficiency
Autosomal
Decreased production of 1-antitrypsin
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1-ANTITRYPSINA. Description
A1AT is a single-chain glycoprotein consisting of 394
amino acids in the mature form and exhibits a number
of glycoforms.
The three N-linked glycosylations sites are mainly
equipped with so-called diantennary N-glycans
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However, one particular site shows aconsiderable amount of heterogeneity since
tri- and even tetraantennary N-glycans can
be attached to the Asparagine 107 (ExPASy
amino acid nomenclature).
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These glycans carry different amounts of negatively-charged sialic acids, thiscauses the heterogeneity observed on normal A1AT when analysed by isoelectric
focussing.
In addition, the fucosylated triantennary N-glycans were shown to have the
fucose as part of a so-called Sialyl Lewis x epitope, which could confer this
protein particular protein-cell recognition properties.
The single cysteine residue of A1AT in position 256 (ExPASy nomenclature) is
found to be covalently linked to a free single cysteine by a disulfide bridge.
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A1AT has a characteristic secondary structure of beta sheets and alpha
helices.
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1-antitrypsin 1 is produced in the
liver and
released into the blood, ultimately to
protect the lungs from attack by an
enzyme called neutrophil elastase.
Neutrophil elastase is produced bywhite blood cells in response to
infection or irritants to digest damaged
tissue in the lungs.
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B. FUNCTION
Hepatocytes synthesize alpha1-antiprotease serine protease inhibitor
Its principle function in the lung is to inactivate
neutrophil elastase, to protect the lungs from
protease-mediated tissue destruction
The major biochemical activity is inhibition of
several neutrophil-derived proteases (eg,
trypsin, elastase, proteinase 3, cathepsin G).
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C. MUTATION
AAT deficiency is caused by mutations in the SERPINA1 gene, located
on chromosome 14
Mutation: Substitution of Lys residue for a glutamate at position 342
(Z-variant)
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Mutation cause a shortage (deficiency) of the protein
Z protein polymerizes in the liver
serum AAT
AAT to lungs
inhibition of elastase activity in lungs
neutrophil elastase destroys small air sacs in the lungs (alveoli)
emphysema
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D. Methionine and serine residues: Effect of smoking
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DIAGNOSIS
Serum 1 antitrypsin level (20-48 m)
Serum protein electrophoresis
90% of the serum 1 -globulin
Alpha-1 genotyping
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TREATMENT
1 Antitrypsin Replacement Therapy
Replacement of 1 antitrypsin in the blood and increase it to its protective
levels
recommended for symptomatic persons with the PiZZ phenotype given when 1 antitrypsin is less than 11 mol/L or 310 mg/L
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1 Antitrypsin
from pooled human plasma
administered intravenously every week
Dose: 60 mg/kg
Pitfalls:
Risk for disease transmission
Costly
Difficulty of administration
Recent Advancements: Inhalation Therapy
Transgenic production
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Synthetic Chaperones
Chaperones -auxiliary proteinsthat assist in the folding and
assembly of growing proteins
4-phenyl-butyriuc acid
Gene Technology
insertion of normal human 1antitrypsin gene that has been
done in muscle and liver cells
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CONCLUSION
Emphysema can be caused by a rare genetic predisposition called 1antitrypsin deficiency.
The deficiency in 1 antitrypsin causes an imbalance in the protease
and antiprotease activity resulting to alveolar destruction byneutrophil elastase.
Probable treatment of emphysema includes 1 antitrypsin
replacement therapy, use of synthetic chaperones and gene
technology.