Question

In the chronic lung disease emphysema, the lung's air sacs (alveoli), where oxygen from the air is exchanged for carbon dioxide in the blood, degenerate. \(\alpha\) 1-Proteinase inhibitor deficiency is a genetic condition that runs in certain families and results from mutations in critical amino acids in the sequence of \(\alpha 1\)-proteinase inhibitor. The individuals with mutations are more likely to develop emphysema. \(\alpha\) 1-Proteinase inhibitor is produced by the liver and then circulates in the blood. \(\alpha 1\)-Proteinase inhibitor is a protein that serves as the major inhibitor of neutrophil elastase, a serine protease present in the lung. Neutrophil elastase cleaves the protein elastin, which is an important component for lung function. The increased rate of elastin breakdown in lung tissue is believed to cause emphysema. One treatment for \(\alpha 1\)-proteinase inhibitor deficiency is to give the patient human wild type \(\alpha 1\)-proteinase inhibitor (derived from large pools of human plasma) intravenously by injecting the protein directly into the bloodstream. (a) Explain the rational for the treatment with wild-type \(\alpha 1\)-proteinase inhibitor. (b) This treatment involves the intravenous administration of the wild-type \(\alpha 1\)-proteinase inhibitor. Explain why \(\alpha 1\)-proteinase inhibitor can not be taken orally.

Short answer

Wild-type alpha 1-proteinase inhibitor is used in treatment because it inhibits neutrophil elastase, preventing elastin breakdown in the lungs. It's given intravenously because ingesting orally would lead to the protein breaking down in the digestive process and not provide the needed effect.

Step-by-step solution

Understand the role of Alpha 1-Proteinase Inhibitor

Alpha 1-Proteinase Inhibitor is a protein produced by the liver which serves as the major inhibitor of neutrophil elastase, an enzyme that breaks down elastin in the lungs. The deficiency of this protein leads to an increased rate of elastin breakdown, which subsequently causes emphysema. Mutations in the sequence can make individuals more prone to developing the disease.

Explain the rationale for treatment with Wild-Type Alpha 1-Proteinase Inhibitor

Wild type Alpha 1-Proteinase Inhibitor derived from human plasma is given intravenously because it allows the protein to directly enter the bloodstream, bypassing the liver where mutations that lead to the disease may occur. Once in the bloodstream, it inhibits neutrophil elastase, preventing the breakdown of elastin in the lungs and conserving lung function.

Explain why Alpha 1-Proteinase Inhibitor cannot be taken orally

The Alpha 1-Proteinase Inhibitor cannot be taken orally because proteins are broken down during digestion. If the inhibitor is taken orally, the stomach would break it down into its amino acid components as part of the normal digestive process. These smaller components wouldn't provide the desired effect. Hence, it is given intravenously to bypass digestion.

Key concepts

Understanding Emphysema and Its Impact on Lung Function

Emphysema is a chronic lung condition characterized by the damage and destruction of the alveoli, the tiny air sacs in the lungs responsible for gas exchange. In a healthy lung, oxygen from the air we breathe is transferred to the blood in exchange for carbon dioxide. However, in emphysema, the alveoli walls break down, leading to larger but fewer and less efficient air sacs. This impairs the lung's ability to oxygenate the blood, resulting in shortness of breath and reduced overall lung capacity.

The progression of emphysema is closely associated with the destructive action of enzymes such as neutrophil elastase. Elastin, a key protein that provides the necessary elasticity and structure to the lung tissue, is degraded by neutrophil elastase when it's not adequately controlled. Over time, this enzyme-mediated damage contributes to the loss of lung elasticity, which is a hallmark of emphysema.

Neutrophil Elastase Inhibition as a Therapeutic Strategy

Neutrophil elastase is a type of enzyme known as a serine protease and is primarily produced by neutrophils, a type of white blood cell. Under normal circumstances, neutrophil elastase plays a role in fighting infections by breaking down proteins of invading organisms. However, when its activity is not properly regulated, it also breaks down elastin and other important structural proteins within the lung tissue. To prevent such damage, our bodies produce Alpha 1-Proteinase Inhibitor (A1PI), which is a natural inhibitor of neutrophil elastase.

Inhibiting neutrophil elastase is crucial for those with a predisposition to emphysema, particularly in cases of genetic A1PI deficiency. Therapeutically boosting the levels of A1PI can help maintain the integrity of the lungs by keeping the destructive tendencies of neutrophil elastase in check. Without this inhibition, unchecked neutrophil elastase activity would lead to accelerated lung tissue degradation and the progression of emphysema.

Genetic Mutations Affecting Alpha 1-Proteinase Inhibitor

Genetic mutations can significantly alter the structure and function of proteins. In the case of A1PI, mutations can lead to a deficiency or complete lack of functional inhibitor. This genetic condition is inherited and affects the body's ability to regulate the activity of neutrophil elastase.

These mutations typically occur in the SERPINA1 gene, which instructs the body on how to produce A1PI. When mutations in critical amino acids occur, they can alter the shape of the A1PI protein. This can prevent it from effectively inhibiting neutrophil elastase, leaving the enzyme free to break down elastin and other lung proteins. Over time, this can lead to the development of emphysema even in individuals who do not have other risk factors such as a history of smoking.

Intravenous Protein Therapy for Deficiency Management

When patients have a deficiency in A1PI due to genetic mutations, intravenous protein therapy can be administered to supplement the body's levels of this vital inhibitor. This treatment involves the infusion of plasma-derived, wild-type A1PI directly into the bloodstream. The wild-type refers to the normal, non-mutated form of the protein. By bypassing the digestive system, IV therapy ensures that the protein remains intact and functional, ready to inhibit neutrophil elastase activity.

IV therapy for A1PI deficiency is typically administered on a regular basis to maintain sufficient inhibitory levels within the blood. It's important to note that this treatment doesn't cure emphysema; rather, it aims to slow the progression of lung damage by restoring the balance between A1PI and neutrophil elastase. By addressing the underlying deficiency, IV protein therapy can improve quality of life and respiratory function for individuals affected by genetic mutations leading to emphysema.