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Author: Angie Warner, D.V.M.,D.Sc.

1. Learning Objectives

  • Be able to list 3 effects of histamine release on airway tissues.
  • Be able to list 3 effects of arachidonic acid metabolites (leukotrienes and prostaglandins) on airway tissues.
  • Be able to list 2 effects of substance P release on airway tissues.
  • Explain how host respiratory tissue can be injured by activated phagocytic cells.
  • Define respiratory hypersensitivity and explain how it occurs.
  • Explain the difference between equine allergic bronchiolitis and bovine hypersensitivity pneumonitis in terms of inciting cause, immunoglobulin class involved, and site within the respiratory tract.

2. The Effect of Inflammatory Mediators on Lung Function

2.1. Pulmonary Inflammation and Inflammatory Mediators

  • Pulmonary disease, except direct trauma, involves inflammatory processes. Inflammatory responses are important in bacterial and viral respiratory infections.
  • Immediate hypersensitivity reactions involve preformed mediators released from mast cells; late phase reactions also involve mast cell granule contents.
  • Membrane disruption generates lipid mediators with potent vascular and airway effects.
  • Phagocytic cell recruitment and activation initiates release of proteolytic enzymes, and reactive oxygen species.
  • Inflammatory cells release peptide cytokines, chemoattractants and reactive nitrogen species.

2.2. Pulmonary Cells Both Release and Metabolize Inflammatory Mediators

  • Pulmonary tissue contains many mast cells, a rich source of mediators.
  • PMN and eosinophils that are recruited into the alveolar space are a source of inflammatory mediators.
  • Macrophages in the alveolar spaces and interstitium and pulmonary intravascular macrophages in ruminants, swine, horses and cats are a potent source of mediators with local effects.
  • Pulmonary endothelial and epithelial cells are an important source of reactive nitrogen species, adhesion molecules and inflammatory mediators.
  • The lungs receive the entire cardiac output and consequently all circulating mediators.
  • The extensive pulmonary endothelial cell surface has great potential for synthesis and metabolism of large quantities of mediators.

2.3. Inflammatory Mediators with Important Effects on Pulmonary Function

  • Mast Cell Granule Preformed Mediator -- Histamine
    • Formed by decarboxylation of histidine and present complexed with heparin in mast cell granules. Mast cells are abundant in pulmonary tissue.
    • Released when IgE crosslinking causes mast cell degranulation.
    • Most species have airway smooth muscle H1 receptors that mediate contraction, and thus bronchoconstriction.
    • Capillary endothelial cells contract in response to histamine, resulting in transient gaps between endothelial cells and increased local vascular permeability with leakage of plasma proteins into the extravascular spaces.
    • H2 receptor stimulation mediates increased mucus secretion.
    • Histamine release leads to bronchial smooth muscle contraction, mucosal edema, inflammatory cell infiltrate, increased mucus in airways, epithelial loss, and goblet cell hyperplasia.
    • Histamine is rapidly metabolized, limiting duration of effect.
    • Histamine effects can be prevented by pharmacologic suppression of mast cell degranulation (cromolyn sodium, methylxanthines, glucocorticoids), or competitive inhibition of histamine binding to receptors (antihistamines: chlorpheniramine, chlorcyclizine, promethazine, diphenylhydramine).
    • Histamine effects can be counteracted by bronchodilators (epinephrine, B adrenergic agents), or suppression of inflammatory cell recruitment (glucocorticoids).
  • Arachidonic Acid Metabolites
    • Membrane perturbation of inflammatory cells causes release of arachidonic acid (AA), which is oxidatively metabolized by cyclooxygenase (COX) (prostaglandin formation) or lipoxygenase (leukotriene formation).
    • PGF2a causes bronchoconstriction, especially of small diameter airways, while PGE2 causes relaxation of airway smooth muscle.
    • PGF2a causes vasoconstriction; PGE2 induces prolonged vasodilation, thus potentiating effects of other mediators that affect capillary permeability.
    • Vascular endothelial cells produce prostacyclin (PGI2), which inhibits platelet aggregation, promotes vasodilation, and counteracts bronchoconstriction.
    • Platelets and pulmonary fibroblasts produce thromboxane A2, which promotes vasoconstriction and platelet aggregation.
    • LTC4, LTD4, and LTE4 (cysteinyl leukotrienes or slow reacting substance A) cause bronchoconstriction and vasoconstriction, especially of peripheral airways.
    • LTC4 and D4 also mediate general capillary vasodilation, and increases in capillary permeability, resulting in edema and protein extravasation.
    • LTC4 and D4 are potent mucus secretagogues.
    • LTB4 is a potent chemotactic mediator for PMN's and promotes leukocyte adherence to endothelium.
  • Inhibition of Arachidonic Acid Metabolism
    • Production of all AA metabolites can be inhibited by corticosteroids which suppress the activity of cellular phospholipase.
    • Nonsteroidal anti-inflammatory drugs (NSAID) inhibit both COX-1 (GI mucosa and renal autoregulation) or COX-2 (inflammatory prostaglandins). COXIBs are selective COX-2 inhibitory drugs (Deracoxib). Some NSAIDS have predominantly COX-2 vs. COX-1 inhibitory activity (etodolac).
    • Zileuton inhibits leukotriene systhesis, and Monteleukast is a leukotriene receptor antagonist.
  • Platelet Activation Factor (PAF)
    • PAF is a phospholipid released from membranes of leukocytes, macrophages, mast cells, platelets, and vascular endothelial cells. It induces bronchoconstriction in some species (baboon, human), but not others (rabbit, dog) and may cause sustained bronchial hyperreactivity.
    • PAF attracts and activates eosinophils and PMN, initiates platelet aggregation, and endothelial cell injury with consequent edema.
  • Toxic Metabolites of Oxygen (Reactive Oxygen Species-- ROS)
    • Phagocytic cells (PMN and macrophages) can produce a number of oxygen-derived free radicals during phagocytosis that are highly reactive and toxic to cells, although essential for host phagocyte microbicidal activity.
      • Superoxide 02-, peroxide H202, hydroxyl radical OH, and HOCl
    • Oxygen-derived free radicals can react with and damage major cellular constituents: proteins, nucleic acids, membrane lipids, and extracellular matrix.
    • Acute inflammation with release of toxic oxygen metabolites during phagocyte necrosis can cause alveolar epithelial, capillary and interstitial injury, resulting in healing with extensive fibrosis. Normal apoptotic cell death of phagocytes does not result in ROS release or tissue injury.
    • Cellular defenses against oxygen metabolites include free radical scavengers (glutathione peroxidase, superoxide dismutase, catalase and peroxidase, vitamin E).
    • Corticosteroids, which decrease neutrophil influx and metabolite release and superoxide dismutase show some promise for therapy.
  • Peptide Mediators (Cytokines)
    • Interleukin-1 and tumor necrosis factor (TNF) are peptides produced by phagocytic cells in response to endotoxin, immune complex phagocytosis, immune stimulation, toxins, and physical injury. They mediate acute phase response to infection or injury: fever, PMN release into the circulation, ACTH release, hypotension, increased heart rate.
    • IL-8 is a potent chemokine, or chemotactic cytokine, for neutropohils and play an important role in recruiting PMN into pulmonary tissue.
    • Macrophage chemotactic peptide (MCP-1) is important in monocyte recruitment, and RANTES in eosinophil attraction into lung tissue.
  • Neuropeptides: Neurotransmitters of the Noradrenergic Noncholinergic (NANC) Nerves
    • VIP (vasoactive intestinal peptide) is released by nerves and ganglia supplying airways and pulmonary vessels and is a potent endogenous bronchodilator but stimulates mucus secretion. Nitric oxide is also a mediator for the NANC inhibitory pathway.
    • Substance P and tachykinins are released from sensory nerves beneath airway epithelial cells and are potent bronchoconstrictors and stimuli for mucus secretion.
  • Nitric Oxide (NO)
    • A reactive gas produced normally in small amounts by endothelial cells through nitric oxide synthase (constitutive or cNOS). NO is important in maintaining normal vascular and bronchodilation.
    • Inducible NOS (iNOS) is increased during inflammation, and large amounts of NO during inflammation can inhibit viral replication and growth of some pathogens, in addition to other effects on the inflammatory process.

2.4. Immune-Mediated Injury of Host Tissue: the Hypersensitivity Reactions

  • Inflammation Initiated by Immune Responses Can Injure as Well as Protect Host Tissue
    • Immune responses can be directed at host tissue through cross-reacting antibodies.
    • Unregulated or prolonged inflammation can cause local tissue injury.
  • Type I: Immediate Hypersensitivity
    • Mediated by IgE bound to mast cells, causing mast cell degranulation with release of histamine and bradykinin.
    • Increased mucosal permeability allows greater access of inhaled allergens.
    • Increased mucus and altered mucus properties impair mucociliary clearance of inhaled particles, bacteria.
    • A late phase mast cell response has been recently recognized that begins 2-4 hours after stimulus and may last days.
      • also initiated by mast cell degranulation and granule matrix-derived mediators
      • additional component is recruitment of inflammatory cells -- PMN and eosinophils
      • non-specific airway hyper-responsiveness may persist for months due to inflammatory cells and their mediators
    • Allergic asthma is an example of air flow obstruction due to a combination of bronchial smooth muscle constriction and increased mucus secretion, airway edema, and mucosal inflammation in response to inhaled allergens.
    • Airway hyperresponsiveness (AHR) is an exaggerated narrowing of the airways in response to many different stimuli. Airways demonstrate increased sensitivity to excitatory neurotransmitters, inflammatory mediators, and nonspecific irritants. Hyperresponsiveness is due to facilitation of neurotransmission and of smooth muscle contraction by inflammatory mediators, and to thickening of the airway wall. It persists between acute attacks, although air flow obstruction is reversible.
  • Type II: Tissue-Specific Antibodies
    • Circulating antibody cross reacts with pulmonary and glomerular basement membrane and linear IgG deposits occur along these surfaces. (for example, Goodpasture's syndrome).
    • Sequelae are pulmonary hemorrhage and glomerulonephritis.
    • Injected or inhaled agents may initiate antibody formation through alteration in basement membrane antigens that allow cross-reactivity.
  • Type III: Immune Complex (Arthus) Reaction
    • Circulating immune complexes activate complement and recruit PMN to the site of complex deposition.
      • generally IgG is involved in immune complex formation and complement fixation
      • IgA from mucosal surfaces can form immune complexes, may fix complement via the alternative pathway, and activate macrophages
    • Recruited PMN are responsible for local damage to alveolar or interstitial tissue (IgG-mediated disease).
    • Example: Hypersensitivity pneumonitis, with parenchymal inflammation, tissue injury and resulting fibrosis -- restrictive disease.
  • Type IV: Delayed, or Cell-Mediated Hypersensitivity
    • Activation of T lymphocytes by antigen stimulates increased immunoglobulin secretion, and recruitment and activation of macrophages.
      • alveolitis, mononuclear cell infiltrate, granuloma formation and fibrosis

2.5. Clinical Examples of Immune-Mediated Pulmonary Disease in Animals

  • Equine Allergic Bronchiolitis / Chronic Obstructive Pulmonary Disease (COPD)
    • Obstructive airway disease characterized by bronchoconstriction (expiratory flow limitation), neutrophil infiltration, and excessive mucus production.
    • Pathologic changes: bronchitis, bronchiolitis, and occasionally emphysema (i.e., disease is concentrated in small airways).
    • Most common etiology is allergic and inflammatory response to barn and hay dust:
      • immediate hypersensitivity with a late phase component both develop after only very short exposure to barn environment in sensitized individuals
      • upper respiratory viral infection may predispose via a break in the mucosal barrier and penetration of sensitizing antigens
    • Both immediate and late phase type I responses are implicated, resulting in flow limitation, uneven ventilation, hypoxia, dyspnea, tachypnea (most similar to human asthma).
    • Clinical Signs: Dyspnea, forced expiratory effort, cough and increased mucopurulent exudate after exposure to barn environment:
      • management involves prevention of antigen exposure or treatment of the subsequent inflammatory response
  • Bovine Hypersensitivity Pneumonitis, Allergic Alveolitis
    • Hypersensitivity reaction (IgG-mediated) occurring at the level of the pulmonary parenchyma.
    • Etiologic agent is organic dust; i.e., spores or metabolites of thermophilic actinomycetes from moldy hay (Micropolyspora faeni or Thermoactinomyces vulgaris):
      • most similar to human occupational hypersensitivity pneumonitis (bovine farmer's lung)
    • Pathologic changes: Infiltration of alveolar septae by lymphocytes, plasma cells, macrophages, PMN, eosinophils, occasional granuloma formation.
    • Pathophysiology: Immune complex formation (type III):
      • antigen penetration deep in lung parenchyma, antibody interaction, immune complex formation and recruitment of inflammatory cells (initially PMN) and local inflammation
      • nflammation and tissue destruction cause fibrosis during healing -- restrictive disease with reduced lung compliance
    • Many individuals exposed to these common antigens develop antibodies and increased lymphocytes in lavage fluid, but are not symptomatic -- there is some degree of unique host susceptibility required.

3. References

  • Barnes P. New Concepts in chronic obstructive pulmonary disease. Ann Rev Med 54;113-129, 2003.
  • Breeze RM. Hypersensitivity disease. Vet Clin North Am Food An Pract 1: 324-332, 1985.
  • Forrester SD and Troy GC. Renal effects of nonsteroidal antiinflammatory drugs. Compend Cont Ed Pract Vet 21: 910-919, 1999.
  • Genetsky RM, Loparco FV. Chronic obstructive pulmonary disease in horses. Part I. Compend Cont Ed Pract Vet 7: S407-S414, 1985.
  • Kaliner MA. The late-phase reaction and its clinical application. Hosp Pract Oct 15, pp. 73-83, 1987.
  • Leff AR. Regulation of leukotrienes in the management of asthma. Ann Rev Med 52;1-14, 2001.
  • Peterson CA and Adler KB. Airways inflammation and COPD: Epithelial-neutrophil interactions. Chest 121;142S-150S, 2002.
  • Ricciardolo FL. Multiple roles of nitric oxide in the airways. Thorax 58;175-182, 2003.