Metabolism of Toxins in Pulmonary Tissue
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Questions and Answers

What role do P450 enzymes play in pulmonary tissue?

  • They directly convert oxygen into carbon dioxide.
  • They are responsible for the oxidative metabolism of most xenobiotics. (correct)
  • They facilitate the formation of phase II metabolites.
  • They catalyze the binding of glutathione to xenobiotics.

    • Which of the following is NOT a classic obstructive lung disease?

  • Emphysema
  • Chronic bronchitis
  • Asthma
  • Fibrosis (correct)

    • Which enzymes are involved in the elimination of metabolites formed during Phase I reactions in pulmonary tissue?

  • Glutathione S-transferases (correct)
  • P450 monooxygenases
  • NADPH-cytochrome P450 reductase
  • Cytochrome b5

    • What is primarily affected in obstructive lung diseases?

    <p>Airflow through the respiratory system</p> Signup and view all the answers

    Which of the following P450 enzymes is expressed in smokers?

    <p>CYP1A1</p> Signup and view all the answers

    Which condition is characterized by restriction of full lung expansion?

    <p>Restrictive lung disease</p> Signup and view all the answers

    What type of enzymes are involved in the conjugation of glutathione to electrophilic compounds?

    <p>Glutathione S-transferases</p> Signup and view all the answers

    Which tissues primarily express xenobiotic-metabolizing CYP enzymes in the human lung?

    <p>Bronchial and bronchiolar epithelium</p> Signup and view all the answers

    What characterizes the exudative phase of ARDS?

    <p>Release of pro-inflammatory cytokines</p> Signup and view all the answers

    Which of the following conditions is an example of a direct lung injury?

    <p>Severe injury to the chest</p> Signup and view all the answers

    Which symptom is not typically associated with the onset of ARDS?

    <p>Bluetooth skin discoloration</p> Signup and view all the answers

    Which phase of ARDS is characterized by increased collagen deposition?

    <p>Fibrotic Phase</p> Signup and view all the answers

    What typically happens to type II pneumocytes during the proliferative phase of ARDS?

    <p>They decrease in number</p> Signup and view all the answers

    What is a common cause of peripheral cyanosis?

    <p>Low oxygen levels in red blood cells</p> Signup and view all the answers

    What are the typical signs of hypoxemia in a patient?

    <p>Rapid breathing and confusion</p> Signup and view all the answers

    Which injury type is NOT an indirect lung injury associated with ARDS?

    <p>Pneumonia</p> Signup and view all the answers

    What is the primary characteristic of emphysema related to lung function?

    <p>Loss of elastic recoil</p> Signup and view all the answers

    Which type of emphysema is associated with α1-antitrypsin deficiency?

    <p>Panacinar emphysema</p> Signup and view all the answers

    What leads to the destruction of elastin in the lungs?

    <p>Increased activity of elastase</p> Signup and view all the answers

    Which of the following factors contributes mainly to centroacinar emphysema?

    <p>Cigarette smoke and nicotine</p> Signup and view all the answers

    Which receptor is involved in the attraction of neutrophils in the context of centroacinar emphysema?

    <p>Nuclear factor-kappa B</p> Signup and view all the answers

    What happens to the alveoli in emphysema?

    <p>They cluster together forming blebs</p> Signup and view all the answers

    Which type of emphysema is evident in newborns due to the overgrowth of a lung lobe?

    <p>Congenital lobar emphysema</p> Signup and view all the answers

    What is the group of irreversible lung diseases that includes emphysema called?

    <p>Chronic obstructive pulmonary disease (COPD)</p> Signup and view all the answers

    What is a primary consequence of the inflammation caused by lung injuries?

    <p>Damage to alveoli</p> Signup and view all the answers

    Cystic fibrosis is characterized by which of the following?

    <p>Mutations in the CFTR gene</p> Signup and view all the answers

    How does a reduction in pulmonary surfactant affect the lungs?

    <p>Promotes alveolar collapse</p> Signup and view all the answers

    What percentage of individuals with European ancestry are carriers of the cystic fibrosis gene?

    <p>1 in 25</p> Signup and view all the answers

    Which of the following is a common clinical feature of cystic fibrosis?

    <p>Chronic lung disease</p> Signup and view all the answers

    What happens to mucus in the airways when there is a dehydration of the surrounding water?

    <p>It thickens and flattens the cilia.</p> Signup and view all the answers

    How does normal CFTR protein affect sodium channels?

    <p>It inhibits sodium channels.</p> Signup and view all the answers

    What is the consequence of increased sodium absorption in relation to CFTR mutations?

    <p>Decrease in airway surface liquid volume.</p> Signup and view all the answers

    Why does thick mucus promote chronic infection in cystic fibrosis?

    <p>It provides a nutrient source for bacteria.</p> Signup and view all the answers

    What is the role of mucin secretion in airway clearance?

    <p>It traps bacteria for expulsion.</p> Signup and view all the answers

    What are the primary symptoms of Cystic Fibrosis related to lung function?

    <p>Cough, increased sputum production, and digital clubbing.</p> Signup and view all the answers

    Which of the following is a common bacterial pathogen associated with chronic lung infections in Cystic Fibrosis?

    <p>Pseudomonas aeruginosa.</p> Signup and view all the answers

    What physiological process is impaired due to the accumulation of thick mucus in the airways?

    <p>Gas exchange.</p> Signup and view all the answers

    How does a decrease in airway surface liquid volume affect ciliary function?

    <p>It causes them to beat poorly.</p> Signup and view all the answers

    What happens to the airway surface liquid when the CFTR protein is mutated?

    <p>Airway surface liquid volume decreases.</p> Signup and view all the answers

    What is the primary cause of acute bronchitis?

    <p>Infective agents or temporary environmental irritants</p> Signup and view all the answers

    Which condition is characterized by bronchospasm and airway obstruction?

    <p>Asthma</p> Signup and view all the answers

    What role does IgE play in asthma?

    <p>It causes bronchial smooth muscle constriction.</p> Signup and view all the answers

    Which of the following describes the immune response in asthma patients?

    <p>B-cell/helper T cell (Th2) response with antibody production</p> Signup and view all the answers

    What is a major symptom of acute bronchitis?

    <p>Cough with possible excessive mucus production</p> Signup and view all the answers

    What happens in very severe cases of asthma?

    <p>Wheezes become inaudible due to severe obstruction.</p> Signup and view all the answers

    What does the β-adrenergic theory of asthma explain?

    <p>The biochemical mechanism behind asthma and allergies</p> Signup and view all the answers

    Which of the following cells interacts with immature helper T cells during the immune response in asthma?

    <p>Antigen-presenting cells like macrophages</p> Signup and view all the answers

    Study Notes

    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.

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    Respiratory Biochemistry PDF

    Description

    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.

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