Respiratory_Biochemistry_II_FA23_updated.pptx

RESPIRATORY BIOCHEMISTRY II Vanessa De La Rosa, PhD • Outline the biochemistry of airway mucus structure, function and secretion. • Introduce clinical biochemical markers of the respiratory system. SESSION OBJECTIV ES • Review the structure and function of hemoglobin. • Review the exchange of c...

RESPIRATORY BIOCHEMISTRY II Vanessa De La Rosa, PhD • Outline the biochemistry of airway mucus structure, function and secretion. • Introduce clinical biochemical markers of the respiratory system. SESSION OBJECTIV ES • Review the structure and function of hemoglobin. • Review the exchange of carbon dioxide and oxygen at the capillary and how major shifts to either side of this reaction can lead to respiratory acidosis or respiratory alkalosis. • Discuss examples of restrictive lung diseases resulting from chronic occupational or environmental exposures. • Protects respiratory tract from chemical, microbiological, and physical noxious environmental insults • Mucus layer is continuously renewed • Normally thin and mobile • Comprised of water and mucins (proteins) • Excessive mucus or impaired clearance contributes to pathogenesis of all common pulmonary diseases AIRWAY MUCUS • A deficient mucous barrier leaves lungs vulnerable to injury MUCINS: THE PRINCIPAL PROTEIN COMPONENT OF MUCUS • Mucin expression varies in upper and lower respiratory tract • Major mucins produced in the airways are soluble mucins MUC5AC and MUC5B and the transmembrane mucins MUC1, MUC4, and MUC16 • MUC5AC (upper and lower); MUC5B (lower only) MUCIN STRUCTURE •Mucin structures can be soluble or transmembrane •Large glycoproteins reminiscent of a bottle brush •PTS domains •O-linked glycosylation •Cysteine-rich regions involved in cross-linking via disulfide bonds Nat Commun 13, 3542 (2022) MUCIN SECRETION • Continuously synthesized • Secreted by surface goblet cells and submucosal glands • Glycan side chains bind large amounts of liquid (100X>weight) • Hydration status dramatically affects viscosity & elasticity • Secretion regulated by extracellular ATP via apical membrane P2Y 2 (purinergic) receptors • Presence of ATP at low levels in airway-surface liquid results in steady release of mucins Disulfide crosslinks form linear interwoven polymeric network 6 MUCIN FUNCTION • Regulates permeability to molecules and particles • Mucus properties can differ as a function of disease state • Excessive disulfide bridging may play a role in the pathophysiology of mucoobstructive diseases International Journal of MUCUS FUNCTION •Changes in hydration, pH, and oxidative stress can introduce additional ionic, hydrogen, hydrophobic, and disulfide bonds •Water hyperabsorption and subsequent dehydration of the mucus layer •Mucus more viscous Altered fluid and ion MYELOPEROXIDASE AND MUCUS •Myeloperoxidase is a heme containing enzyme •Released into the extracellular environment from neutrophils •Mucus rich in neutrophils •Heme degradation results in color change Journal of Immunology Research, 2016 ELASTIN STRUCTURE AND LUNG FUNCTION •Protein with rubber-like properties •Composed primarily of small non-polar amino acids (G, A, V) •Hydrophobic segments are responsible for the elastic properties of the molecule •Also rich in proline and lysine, but contains little hydroxyproline and hydroxylysine •Interchain cross-links form desmosine residues •Degraded by elastase 10 CLINICAL BIOCHEMISTRY: AAT • α1-antitrypsin (AAT) protease inhibitor is produced & secreted by liver • inhibits elastase (degrades elastin) produced and secreted by neutrophils • reduced/deficient plasma levels a risk factor for early-onset chronic obstructive pulmonary disease (COPD) • due to variations in α1-antitrypsin gene • M allele (normal) • Z allele (mutant); K342E substitution • S allele (mutant); V264E substitution • mutant alleles cause α1-antitrypsin to aggregate (Z>S) in hepatocyte ER • reduced plasma levels (<≈60% of normal) allow elastase to destroy lung tissue REVIEW OF HEMOGLOBIN AND GAS EXCHANGE RESPIRATORY ACIDOSIS/ALKALOSIS RESTRICTIVE LUNG DISEASE • Several restrictive lung diseases result from the continued exposure to irritants • Pneumoconiosis = restrictive lung disease caused by the chronic exposure and inhalation of particles small enough to bypass the defense mechanism of the upper airway. • Chronic inflammation stimulates lung fibroblasts to deposit fibrous connective tissue leading to permanent scarring. • Scarring distorts airways and thickens the walls of the smaller bronchioles and alveoli • Reduced pulmonary compliance and lung function • O2–CO2 exchange can be markedly reduced. TOBACCO SMOKE TOBACCO SMOKE •Leading cause of lung cancer •>7000 chemicals when burned •70 suspected/known carcinogens • Arsenic • Cadmium • Formaldehyde • PAHs • Benzene OCCUPATIONAL EXPOSURES TO PARTICLES Disease Causative Agent Anthracosis Coal dust Asbestosis Asbestos fibers Baritosis Barium dust Bauxite fibrosis Bauxite dust Berylliosis Beryllium dust Byssinosis Cotton dust Chalicosis (flint or Stonecutters’ disease) Stone dust Coal worker’s pneumoconiosis (“black lung”) Coal dust Farmer’s lung Hay, mold, and other agricultural dusts Labrador lung Mixed dust (iron, silica, and anthophyllite) Siderosis Iron dust Silicosis Silica dust Silicosiderosis Mixed dust (silica and iron) RADON •2nd leading cause of lung cancer •Respiratory damage depending on particle size •Naturally occurring in environment at low levels •Generated from the decay of Uranium