Metabolism of Toxins in Pulmonary Tissue

Metabolism and Bioactivation of Toxins in Pulmonary Tissue; α1-antitrypsin Deficiency Syndrome

• Alpha-1 antitrypsin protects lung tissue from proteases.
• Deficiency of alpha-1 antitrypsin leads to lung tissue damage.
• The liver releases alpha-1 antitrypsin into the blood.
• A buildup of abnormal alpha-1 antitrypsin can cause liver cirrhosis.

Biotransformation in Lungs

• Lungs metabolize foreign compounds through a process called biotransformation.
• Biotransformation is the modification of xenobiotics to facilitate their elimination.
• The goal of biotransformation is to eliminate lipophilic substances.
• This is achieved by enzymes capable of introducing new functional groups (Phase I reactions).
• Conjugating with internal cell molecules to increase water solubility (Phase II reactions).

Xenobiotic-Metabolizing Enzymes in Human Lung

• Phase I reactions involve oxidation, catalyzed by cytochrome P450-depending monooxygenases and flavin monooxygenases.
• Phase I also includes reductions catalyzed by P450 reductase.
• Phase II reactions are catalyzed by GSTs, UDP-glucuronyltransferase, EH, ST, and NAT.

Scheme of Xenobiotic Detoxification

• Phase I reactions convert xenobiotics into reactive electrophiles.
• Phase II reactions convert reactive electrophiles into less toxic hydrophilic products.
• Possible cleavage by enzymes in kidney or colon can produce mutagens and carcinogens.
• Final products are excreted from the body.

Metabolic Bioactivation

• Biotransformation reactions help eliminate foreign substances, but sometimes they activate harmless chemicals.
• This can cause cancer or other problems.
• Benzo(a)pyrene is a classic example of a substance activated into a reactive form capable of damaging DNA.
• CYP450 enzymes are involved in the bioactivation of benzo(a)pyrene.
• Important enzymes in the process of activating benzo(a)pyrene are CYP1A1, CYP450-1A2, and -1B1
• Reactive metabolite BPDE covalently interacts with DNA, leading to cancer formation.

Expression of P450 enzymes in Pulmonary Tissue

• CYP superfamily proteins (P450 monooxygenases) metabolize xenobiotics, drugs, pollutants, and endogenous compounds.
• P450 enzymes use molecular oxygen to oxidize compounds, and need NADPH-cytochrome P450 reductase to reduce oxygen.
• CYP enzymes are expressed in bronchial/bronchiolar epithelium, Clara cells, type II pneumocytes, and alveolar macrophages.

Expression of Phase II Enzymes in Pulmonary Tissue

• Phase II enzymes, GSTs, UGTs, and epoxide hydrolases, play a role in eliminating metabolites produced during Phase I reactions.
• Glutathione S-transferases (GSTs) catalyze the conjugation of glutathione to electrophilic compounds.

Diseases of Respiratory System

• Non-infectious respiratory diseases are categorized as obstructive or restrictive.
• Obstructive diseases (e.g., emphysema, chronic bronchitis, bronchiectasis, and asthma) hinder airflow.
• Restrictive lung diseases (e.g., pulmonary fibrosis and scarring from other diseases) impede lung expansion.

What is Emphysema?

• Emphysema is a loss of elastic recoil in the lungs, making it difficult to exhale.
• Trapped air in the alveoli causes them to enlarge (blebs).
• Chronic obstructive pulmonary disease (COPD) is a group of diseases with diminished exhalation.
• Emphysema and chronic bronchitis often occur together.

Causes of COPD

• Smoking is a major cause of COPD, including emphysema.
• α1-antitrypsin deficiency compromises lung protection from elastase.
• Other potential factors include hypocomplementemic urticarial vasculitis, intravenous Ritalin abuse, Ehlers-Danlos syndrome/Marfan syndrome, and Salla disease.

Classification of Emphysema

• Emphysema is categorized into panacinar and centroacinar types based upon the distribution of the damage.
• Panacinar emphysema involves all portions of the acinus and secondary pulmonary lobule uniformly.
• Centroacinar emphysema primarily affects the respiratory bronchioles.

Emphysema and α1-antitrypsin

• Elastin is a protein in the lungs, degraded by neutrophils' elastase.
• α1-antitrypsin inhibits elastase, preventing lung damage.
• α1-antitrypsin deficiency in smokers can lead to degradation of the lung tissue (emphysema).

Alpha-1 Antitrypsin Deficiency

• Sufficient alpha-1 antitrypsin coats the lungs.
• This coating protects the lungs from neutrophil elastase.
• Deficiencies of alpha-1 antitrypsin can cause destruction of the lungs.
• Trapped alpha-1 antitrypsin in the liver causes liver damage.

Centroacinar Emphysema

• Centroacinar emphysema primarily affects the respiratory bronchioles.
• Nicotine, through its metabolites, can attract neutrophils, activating neutrophil elastase.

Bronchitis

• Bronchitis involves inflammation of the bronchial mucus membranes, categorized as acute or chronic.
• Acute bronchitis is commonly caused by viruses or bacteria, often accompanied by cough, mucus production.
• Chronic bronchitis affects the airways over time.

Asthma

• Asthma is a chronic inflammatory condition affecting the bronchi.
• Obstruction occurs with bronchospasm, and there can be varying degrees of severity.
• Pathological growth and enlargement of smooth muscles occurs.
• Pathogenic cytokines, and elevated Immunoglobulin (Ig)E are associated with asthma.

What is ARDS? Acute Respiratory Distress Syndrome

• ARDS is a severe lung condition characterized by hypoxemia (low oxygen levels in the blood) and stiff lungs.
• It's a response to multiple types of insults and injuries to the body.
• ARDS develops in three stages, exudative, proliferative, and fibrotic.

Phases of ARDS

• Exudative phase: Initial inflammatory stage, and increased vascular permeability.
• Proliferative phase: Type II pneumocytes decrease, fibrotic changes, and alveolar capillary thickening.
• Fibrotic phase: Increased collagen, and decreased compliance.

Lung Injuries and their Symptoms

• Direct injuries include breathing in smoke, harmful irritants, and ventilators.
• Indirect injuries include sepsis, blood transfusions, injuries to the chest, severe bleeding, pancreatitis, fat embolism, and drug reactions.
• Early symptoms include dyspnea, tachypnea, and hypoxemia (low oxygen content in the blood)

Cyanosis

• Cyanosis is a bluish tint of the skin and mucous membranes caused by oxygen depletion in blood.
• It's usually a sign of low oxygen levels in the blood, due to lung or heart diseases.

Biochemical Basis of Lung Injuries

• Inflammation, with neutrophils, monocytes, and macrophages present, is initially triggered.
• Inflammation damages alveoli, enlarging the space between alveolar membranes and capillaries.
• Acidosis, shortness of breath, increased breathing rate, and decreased oxygenation follow.
• Continued inflammation leads to the deposition of hyaline membranes in the alveoli and alveolar collapse, hindering breathing.

Cystic Fibrosis (CF)

• CF is a multisystem disorder caused by mutations in the CFTR gene.
• CF is inherited in an autosomal recessive manner; characterized by chronic sinopulmonary disease, nutritional/GI abnormalities, and electrolyte abnormalities.

Who is Affected by CF?

• CF affects approximately 1 in 2500 people of European ancestry.
• Median survival is 25 years, with an increasing number of patients surviving past 30.

Autosomal Recessive Inheritance in CF

• A 50% chance of a carrier child if one parent is a carrier.
• A 25% chance of an affected child if both parents are carriers.
• A 25% chance of a child with no mutant copies of the CFTR gene if both parents are carriers.

Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Gene

• The CFTR gene is located on chromosome 7.
• There are over 1,500 mutations in the CFTR gene, the most common being ΔF508, present in up to 70% of CF alleles in Caucasians.

The Cystic Fibrosis Transmembrane Conductance Regulator (CFTR)

• CFTR protein is composed of 1480 amino acids, folded into a specific 3-D shape.
• CFTR protein is shaped like a tube, spanning the cell membrane.
• CFTR is a member of the ATP binding cassette (ABC) superfamily of proteins.

What Does the CFTR Protein Do?

• CFTR is an ion channel that allows chloride ions to move across cell membranes.
• Inside the lung, this process influences the water content and consistency of mucus.
• The movement of chloride ions is essential for the proper functioning of cilia, which remove mucus.

Disease-Causing Mutation Subclasses in Cystic Fibrosis

• Over 1700 CF mutations are characterized into 5 classes based on how they affect the CFTR protein.
• The classes reflect the degree of functional loss of the CFTR protein.

How Do Problems With the CFTR Protein Cause CF?

• Dysfunction of the CFTR protein disrupts the normal chloride and water balance in the airways.
• This leads to thickening and buildup of mucus, hindering clearance by cilia.

Airway Surface Liquid Low Volume Hypothesis

• Adequate airway surface liquid (ASL) volume is necessary for healthy airway clearance.
• The hypothesis suggests that mutations in the CFTR gene lower the ASL volume, which then impacts ciliary action.
• Reduced ASL volume results in inefficient mucus clearance.
• This reduces bacterial removal and increases bacterial buildup within the airways.

CF Lung Pathophysiology

• Diminished host defense creates susceptibility to chronic bacterial infections.
• The common infections include Pseudomonas aeruginosa, Staphylococcus aureus, Haemophilus influenzae, and Burkholderia cepacia.

CF Symptoms

• Pulmonary symptoms include cough, increased sputum, recurring pneumonia, and clubbed fingers.
• Gastrointestinal symptoms include pancreatic enzyme insufficiency, vitamin deficiencies, and malnutrition.

Diagnosis-Sweat Chloride

• Sweat chloride test is a diagnostic tool for CF.
• A chemical stimulant is used to increase sweating. Electrodes are used to measure the chloride level in the sweat.

Prenatal Screening

• The American College of Obstetricians and Gynecologists recommends prenatal screening for cystic fibrosis susceptibility.
• This is done by testing for carrier status of the 23 most common mutations in the population.
• Prenatal screening sensitivity for CF among the white population is less than 78% and lower for non-white populations.

Cystic Fibrosis- Treatment is Multidisciplinary

• Managing CF patients requires a collaborative approach (multidisciplinary approach) involving airway clearance therapies, infectious disease management, nutrition, and gastroenterological care.

This quiz covers the metabolism and bioactivation of toxins within pulmonary tissue, specifically focusing on α1-antitrypsin deficiency syndrome. It includes the biotransformation processes in the lungs and the role of xenobiotic-metabolizing enzymes. Test your understanding of these critical respiratory and liver functions.