11respiratory system (2) pathology


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  • The “space” between the endothelium and the type-1 pneumocyte, is the blood air interface
  • Viral pneumonias, generally interstitial, bacterial pneumonias generally alveolar!!!
  • Corona viruses are RNA, “enveloped”, i.e., “crowned” viruses
  • “Chronic” by classification, but “granulomatous” by histology.
  • 11respiratory system (2) pathology

    1. 1. Respiratory system
    2. 2. Normal Anatomy  Trachea divides into right and left mainstem bronchi.  Each main bronchus divides into lobar bronchi, then into segmental bronchi  Lobar bronchi are usually called secondary bronchi and segmental bronchi are called tertiary bronchi.  Bronchioles lack cartilage and submucosal glands  Right bronchus more vertical than left, thus aspirated material tends to enter right lung  Lung has double arterial supply - pulmonary and bronchial
    3. 3. Normal histology  Alveolar capillary basement membrane fuses with alveolar epithelium to form a single membrane for oxygen and carbon dioxide diffusion.  Acinus contains 3-5 terminal bronchioles, alveolar ducts and alveoli  Alveoli are lined by pseudostratified, columnar epithelium  Alveoli contain type I and II pneumocytes  Type I pneumocytes: 95%, flattened  Type II pneumocytes: 5%, produce surfactant, involved in repair if type I destroyed  Bronchial-bronchiolar epithelium contains goblet cells, neuroendocrine (Kultschitsky’s) cells, serous cells, basal cells, Clara cells and ciliated cells
    4. 4. CONGENITAL  Agenesis/Hypoplasia  Tracheal/bronchial anomalies, i.e., Tracheo-Esophageal (TE) fistula  Vascular anomalies  Congenital Emphysema  Foregut cysts  Pulmonary Artery Malformations (CPAM)  Sequestration (no connection to airways)
    6. 6. PULMONARY INFECTIONS  Pulmonary infections in the form of pneumonia are one of the leading causes of death all around the world.  This – – – is due to (1) the epithelial surfaces of the lung are constantly exposed to liters of variously contaminated air (2) nasopharyngeal flora are regularly aspirated during sleep, even by healthy persons; and (3) other common lung diseases render the lung parenchyma vulnerable to virulent organisms.
    7. 7. PNEUMONIA  Definition – Broadly defined as any infection in the lung parenchyma.  It may present as acute, fulminant clinical disease or as chronic disease.  Pathogenesis : Inflammation caused by organisms.
    8. 8. PNEUMONIA  The histologic spectrum of pneumonia may vary from a  Fibrinopurulent alveolar exudate seen in acute bacterial pneumonias.  Mononuclear interstitial infiltrates in viral and other atypical pneumonias.  Granulomas and cavitation seen in many of the chronic pneumonias.
    9. 9. PNEUMONIA Classification – Anatomical Acute bacterial pneumonias can present as one of two anatomic and radiographic patterns, - Bronchopneumonia and - Lobar pneumonia.
    10. 10. – Aetiological or according to clinical setting  Community-Acquired Acute Pneumonia  Community-Acquired Atypical Pneumonia  Nosocomial Pneumonia  Aspiration Pneumonia  Chronic Pneumonia  Necrotizing Pneumonia and Lung Abscess  Pneumonia in the Immunocompromised Host
    11. 11. PNEUMONIA Community-Acquired Acute Pneumonias – Community-acquired acute pneumonias are bacterial in origin. – Onset is usually abrupt, with high fever, shaking chills, pleuritic chest pain, and a productive mucopurulent cough; occasional patients may have haemoptysis. – S. pneumoniae (or pneumococcus) is the most common cause of community-acquired acute pneumonia.
    12. 12. PNEUMONIA Pneumococcal pneumonia – Caused by Streptococcus pneumoniae – Is responsible for more than 90% of lobar pneumonias. – Can present as  Lobar pneumonia  Bronchopneumonia
    13. 13. PNEUMONIA
    14. 14. PNEUMONIA Pneumococcal  pneumonia Lobar pneumonia – In lobar pneumonia the contiguous airspaces of part or all of a lobe are homogeneously filled with an exudate that can be visualized on radiographs as a lobar or segmental consolidation.
    15. 15. Bronchopneumonia – Implies a patchy distribution of inflammation that generally involves more than one lobe. – This pattern results from an initial infection of the bronchi and bronchioles with extension into the adjacent alveoli.
    16. 16. PNEUMONIA Lobar pneumonia – Inflammation involves a lobe diffusely. – 4 pathological stages identified in the progress of untreated infection. 1. Stage I- Acute congestion 2. Stage II- Red hepatization 3. Stage III- Gray hepatization 4. Stage IV- Resolution
    17. 17. PNEUMONIA Acute congestion Lasts for 1-2 days Acute congestion and oedema Macroscopy – – – Lung is heavy and firm Dark red Abundant frothy red fluid can be squeezed from it
    18. 18. PNEUMONIA Acute congestion Microscopy – Alveolar spaces filled with inflammatory exudates and organisms – Neutrophils are abundant – Fibrin will be present – Gram stained smear show large number of gram positive diplococci
    19. 19. PNEUMONIA Red hepatization  Lasts for 2-4 days Macroscopy – Pleural surface have fibrinous tags of fibrin. – Cut surface appear dry, firm red granules , feel like liver ( liver-like consistency). – Affected lung tissue airless and sink in water.
    20. 20. PNEUMONIA Red hepatization Microscopy – Capillary engorgement persists. – Alveolar spaces are packed with neutrophils, red cells, and fibrin – Organisms are almost disappeared, if present only few
    22. 22. PNEUMONIA  Gray hepatization  Lasts for 4-8 days  Macroscopy – Cut surface is dry, granules and gray. – Fibrinosuppurative exudate persist within the alveoli.  Microscopy – Capillary engorgement resolved – Alveolar spaces are distended and filled with dense fibrin and with dead and dying polymorphs. – Occasional degenerating red cells are seen.
    23. 23. PNEUMONIA  Resolution  8th day onwards  Macroscopy – – Fibrinous or fibrinopurulent pleuritis (pleural exudate) may resolve or undergo organization, leaving fibrous thickening or permanent adhesions. Lung parenchyma appear normal
    24. 24. Resolution Transformation of exudates to mucoid masses richly infiltrated by macrophages and fibroblasts
    25. 25. PNEUMONIA  Resolution Microscopy – Capillaries will be normal – Alveolar space will have macrophages. Exudates within the alveoli are enzymatically digested to produce granular, semifluid debris that is resorbed, ingested by macrophages, coughed up, or organized by fibroblasts growing into it.
    26. 26. PNEUMONIA Bronchopneumonia Commonly seen among infancy, old age , patients with debilitating diseases and patients with prolonged bed rest. Organisms colonize the bronchiole and extend through the walls into surrounding alveoli.
    27. 27. PNEUMONIA  Bronchopneumonia  Macroscopy – Foci of inflammatory consolidation are distributed in patches throughout one or several lobes, most frequently bilateral and basal. – Well-developed lesions up to 3 or 4 cm in diameter are slightly elevated and are gray-red to yellow . – The lung substance immediately surrounding areas of consolidation is usually hyperemic and edematous. – Confluence of these foci may occur in severe cases, producing the appearance of a lobar consolidation.
    28. 28. PNEUMONIA Bronchopneumonia Pleural involvement is less common than in lobar pneumonia.  Microscopy – The reaction consists of focal suppurative exudate that fills the bronchi, bronchioles, and adjacent alveolar spaces. – Ciliated epithelium is destroyed. – Vascular congestion
    29. 29. Clinical Course  High grade fever, and productive cough.  (Interleukin (IL) 1 and tumor necrosis factor (TNF), results in fever. IL-8 and granulocyte CSF, stimulate the release of neutrophils and their attraction to the lung)  Pleuritic pain and pleural friction rub.  The whole lobe is radiopaque in lobar pneumonia, whereas there are focal opacities in bronchopneumonia.
    30. 30. PNEUMONIA  Sequalae and complications – Complete restitution of the lung is the rule for both forms. – Complications may occur – (1) Tissue destruction and necrosis may lead to abscess formation; (2) Suppurative material may accumulate in the pleural cavity, producing an empyema; – – – (3) Organization of the intra-alveolar exudate may convert areas of the lung into solid fibrous tissue; (4) Bacteremic dissemination may lead to meningitis, arthritis, or infective endocarditis.
    31. 31. Community-acquired atypical pneumonias  The term atypical denotes the moderate amount of sputum, no physical findings of consolidation, only moderate elevation of white cell count, and lack of alveolar exudate.  Mycoplasma pneumoniae  Viruses: Influenza virus, the RSV, adenovirus, rhinoviruses, rubeola, and varicella  Chlamydia pneumoniae; and Coxiella burnetii
    32. 32. Morphology  All causal agents produce essentially similar morphologic patterns.  The lung involvement may be quite patchy or may involve laterally or unilaterally.  The affected areas are congested. The pleura is smooth, and pleuritis or pleural effusions are infrequent.
    33. 33. Morphology  Microscopically  The : alveolar septa are widened and edematous and usually have a mononuclear inflammatory infiltrate of lymphocytes, macrophages, and occasionally plasma cells.
    34. 34.  Frequently “interstitial”, NOT alveolar
    35. 35. Severe Acute Respiratory Syndrome (SARS)  CORONA-VIRUS  SARS first appeared in November 2002 in the Guangdong Province of China  Like most other NON-bacterial pneumonias confirmed by PCR  Like most viral pneumonias, interstitium infiltrated, some giant cells often present.
    36. 36. S A R S
    37. 37. HOSPITAL-ACQUIRED PNEUMONIA  Pulmonary infections acquired in the course of a hospital stay.  They are common in patients with – DEBILITATION – CATHETERS, VENTILATORS – Enterobacteriaceae, pseudomonas – staph (MRSA) – MRSA (MR=Methicillin Resistant)  Hospital-acquired infections are serious and often lifethreatening complications.
    38. 38. ASPIRATION PNEUMONIA  Occurs in markedly debilitated patients or UNCONSCIOUS PATIENTS.  These patients have abnormal gag and swallowing reflexes that predispose to aspiration.  The resultant pneumonia is partly chemical because of the extremely irritating effects of the gastric content/acid.  This type of pneumonia is often necrotizing.  In those who survive, Often lead to lung ABSCESSES
    39. 39. CHRONIC PNEUMONIA  USUALLY NOT persistences of the community or nosocomial bacterial infections.  Often SYNONYMOUS with the 4 classic systemic fungal or granulomatous pulmonary infections, i.e., TB, Histo-, Blasto-, Coccidio-  If you see pulmonary granulomas, think of a CHRONIC process, often years
    41. 41. LUNG ABSCESS  The term “pulmonary abscess” describes a local suppurative process within the lung, characterized by necrosis of lung tissue.  Oropharyngeal surgical procedures, sinobronchial infections, dental sepsis, and bronchiectasis play important roles in their development
    42. 42. Etiology and Pathogenesis     ASPIRATION of infective material SEPTIC EMBOLIZATION NEOPLASIA, sec. infection is common From NEIGHBORING structures: – – – – ESOPHAGUS SPINE PLEURA DIAPHRAGM ANY pneumonia which is severe and destructive, and inadequate treatment
    43. 43. Morphology     Abscesses: a few millimeters to large cavities of 5 to 6 cm, single or multiple. Pulmonary abscesses due to aspiration are more common on the right and are most often single. Abscesses that develop in the course of pneumonia or bronchiectasis are usually multiple, basal, and diffusely scattered. Septic emboli and pyemic abscesses are multiple and may affect any region of the lungs.
    44. 44. Morphology  The cardinal histologic change in all abscesses is suppurative destruction of the lung parenchyma within the central area of cavitation.  In chronic cases considerable fibroblastic proliferation produces a fibrous wall.
    45. 45. Pneumonia in the immunocompromised host
    46. 46. Haemophilus influenzae  Major cause of life-threatening acute LRT infections, otitis media, and meningitis in young children.  In adults- Most common cause of acute exacerbation of COPD in adults  Exists in two forms: encapsulated (5%) and unencapsulated (95%).
    47. 47. Staphylococcus aureus     Cause of secondary bacterial pneumonia in children and healthy adults following viral respiratory illnesses MRSA, of course, is usually NOT “community” acquired Complications: lung abscess and empyema. I/V drug abusers are at high risk of developing staphylococcal pneumonia in association with endocarditis.
    48. 48. Klebsiella pneumoniae    Afflicts debilitated and malnourished people, particularly chronic alcoholics. ALCOHOLICS with pneumonia are often thought of as having Klebsiella until proven otherwise Thick and gelatinous sputum is characteristic, because the organism produces an abundant viscid capsular polysaccharide, which the patient may have difficulty expectorating.
    50. 50. OBSTRUCTIVE vs. RESTRICTIVE AIRWAY DISEASE   Obstructive airway disease: increase in resistance to airflow due to obstruction at any level; includes emphysema, chronic bronchitis, bronchiectasis, asthma; reduced maximal airflow rates (FEV1) Restrictive airway disease: reduced expansion of lung parenchyma with decrease in total lung capacity; normal FEV1; due to chest wall disorders (polio, obesity, pleural disease, kyphoscoliosis), interstitial / infiltrative diseases
    51. 51. Common abstructive and restrictive diseases           Obstructive Asthma COPD (Chronic bronchitis+emphysema) Bronchiectasis Cystic fibrosis Bronchiolitis Restrictive—Parenchymal Sarcoidosis Idiopathic or drug induced pulmonary fibrosis Pneumoconiosis
    52. 52.           Restrictive—Extraparenchymal Neuromuscular Diaphragmatic weakness/paralysis Myasthenia gravis Guillain-Barré syndrome Muscular dystrophies Cervical spine injury Chest wall Kyphoscoliosis Ankylosing spondylitis
    53. 53. Patterns of Abnormal Function
    54. 54. Overlap between chronic obstructive lung diseases
    55. 55. Site of disease  Bronchi-chronic bronchitis, bronchiectasis, asthma  Bronchioles-bronchiolitis  Acini-emphysema
    56. 56. Chronic obstructive pulmonary disease (COPD)     Also called chronic obstructive lung disease (COLD) Two sub types: Chronic bronchitis and emphysema, coexist to variable degree in most patients Characterized by gradual decrease in FEV1 over a period of time with a acute episode of acute exacerbation. Risk factors: smoking, air pollution, respiratory infection, positive family history
    57. 57. Natural progression of COPD  40s: chronic productive cough, wheeze occasionally  50s: 1st acute chest illness  60s: Dyspnea on exertion, increasing cough/sputum production, frequent exacerbation  Late stage: Hypoxemia with cyanosis, corpulmonale
    58. 58. Chronic bronchitis  Definition: defined clinically as persistent cough with sputum for at least 3 months for at least 2 consecutive years
    59. 59. Pathogenesis    Tobacco smoke (90%) and dust from grain, cotton, and silica. Hypersecretion of mucus in the large airways, associated with hypertrophy of the submucosal glands in the trachea and bronchi. Proteases released from neutrophils, and matrix metalloproteinases, stimulate mucus hypersecretion.
    60. 60. Pathogenesis  Secondary infection- producing acute exacerbations.  (Cigarette smoke interferes with ciliary action of the respiratory epithelium, it may cause direct damage to airway epithelium, and it inhibits the ability of bronchial and alveolar leukocytes to clear bacteria).
    61. 61. Morphology  Gross: hyperemia, swelling, and edema of the mucous membranes, frequently accompanied by excessive mucinous or mucopurulent secretions.  Microscopic: chronic inflammation of the airways and enlargement of the mucus-secreting glands of the trachea and bronchi, mucous gland hyperplasia.
    62. 62. Morphology  Reid index: ratio of thickness of mucus gland layer to thickness of wall between epithelium and cartilage ( normal is 0.4), increased in chronic bronchitis.  The bronchial epithelium may exhibit squamous metaplasia and dysplasia
    63. 63. Chronic bronchitis
    64. 64. Clinical Features       Persistent productive cough Dyspnea on exertion Hypercapnia, hypoxemia, and cyanosis (“blue bloaters”), polycythemia CXR: Increased bronchovascular marking Longstanding cases- leads to cor pulmonale with cardiac failure. Death may also result from further impairment of respiratory function due to superimposed acute infections
    65. 65. Emphysema  Definition: Abnormal permanent enlargement and destruction of air spaces distal to terminal bronchiole without obvious fibrosis  Differs from overinflation, which is not due to wall destruction (example: due to loss of opposite lung)  Acinar and airspace enlargement is usually due to tobacco related wall destruction.
    66. 66. Type of emphysema        Emphysema is classified according to its anatomic distribution within the lobule. There are four major types: (1) centriacinar (> 95% of cases) (2) panacinar (3) paraseptal (distal), and (4) irregular. The first two cause clinically significant airflow obstruction.
    67. 67. Pattern of emphysema
    68. 68. Type of emphysema  Centriacinar emphysema: affects proximal (central) part of acini, sparing distal alveoli; worse in upper lobes, particularly apices  Seen in heavy smokers, coal worker pneumoconiosis  Clinically significant at age 40+ in smokers, although ventilatory deficits seen earlier
    69. 69. Type of emphysema    Panacinar emphysema: acini uniformly enlarged from respiratory bronchiole to terminal alveoli; usually lower lungs; associated with alpha-1-antitrypsin deficiency Paraseptal (distal acinar) emphysema: distal acini affected, multiple continuous airspaces are affected; may be source of spontaneous pneumothorax Irregular emphysema: minor clinically; invariably associated with scarring, irregular involvement of acini
    70. 70. Pathogenesis  Macrophages, CD8+ and CD4+ T lymphocytes, and neutrophils are increased in lung.  Activated inflammatory cells release a variety of mediators, including leukotriene B4, IL-8, TNF, that are capable of damaging lung structures or sustaining neutrophilic inflammation. Protease-antiprotease imbalance, aided abetted by imbalance of oxidants and antioxidants 
    71. 71. Pathogenesis    The protease-antiprotease imbalance hypothesis is based on the observation that patients with a genetic deficiency of the α1-antitrypsin have a markedly enhanced tendency to develop pulmonary emphysema. α1-antitrypsin, normally present in serum, tissue fluids, and macrophages, is a major inhibitor of proteases. α1-antitrypsin is encoded by codominantly expressed genes on the proteinase inhibitor (Pi) locus on chromosome 14.
    72. 72. Pathogenesis     The following sequence is postulated: 1. Neutrophils are normally sequestered in peripheral capillaries, and a few gain access to the alveolar spaces. 2. Any stimulus that increases either the number neutrophils and macrophages in the lung or the release of their protease-containing granules increases proteolytic activity. 3. With low levels of serum α1-antitrypsin, elastic tissue destruction is unchecked and emphysema results.
    73. 73. Pathogenesis    In smokers, neutrophils and macrophages accumulate in alveoli. Direct chemoattractant effects of nicotine as well as the effects of reactive oxygen species (ROS) contained in smoke. These activate the transcription factor NF-κB, which switches on genes that encode TNF and chemokines, including IL-8. These, in turn, attract and activate neutrophils
    74. 74. Pathogenesis  Accumulated neutrophils are activated and release their granules, rich in a variety of cellular proteases (neutrophil elastase, proteinase 3, and cathepsin G), resulting in tissue damage.  In addition to elastase, matrix metalloproteinases derived from macrophages and neutrophils have a role in tissue destruction
    75. 75. Pathogenesis
    76. 76. Morphology  Gross: voluminous lungs, generally, the upper two thirds of the lungs.  Large apical blebs or bullae are more characteristic of irregular emphysema secondary to scarring and of distal acinar emphysema.
    77. 77. Centriacinar Panacinar
    78. 78. Bullae, or “peripheral blebs”
    79. 79. Morphology     Microscopic: abnormally large alveoli separated by thin septa with only focal centriacinar fibrosis. The pores of Kohn are so large that septa appear to be floating or protrude blindly into alveolar spaces with a club-shaped end. Destruction of alveolar walls With advanced disease, larger abnormal airspaces, blebs or bullae, which often deform and compress the respiratory bronchioles and vasculature of the lung.
    80. 80. The loss of alveolar walls with emphysema
    81. 81. Clinical Course       The clinical manifestations of emphysema do not appear until at least one third of the functioning pulmonary parenchyma is damaged. Dyspnea Cough or wheezing is the chief complaint. Weight loss Barrel-shaped chest, dyspnea, sits forward in a hunched-over position, and breathes through pursed lips. Pink puffers
    82. 82. Complication     Cor pulmonale and eventually CCF, related to secondary pulmonary vascular hypertension. Death is due to – respiratory acidosis and coma, right-sided heart failure, and massive collapse of the lungs secondary to pneumothorax. Treatment: bronchodilators, steroids, bullectomy, and, in selected patients, lung volume reduction surgery and lung transplantation. Substitution therapy with α1-AT is being evaluated.
    83. 83. Summary
    84. 84. Asthma
    85. 85. Asthma  Definition: Asthma is a chronic but reversible inflammatory disorder of the airways characterized by recurrent episodes of wheezing, breathlessness, chest tightness, and coughing.
    86. 86. Asthma  The hallmarks of the disease are hyperresponsiveness of airway to a variety of stimuli, resulting in – – – episodic bronchoconstriction inflammation of the bronchial walls and increased mucus secretion
    87. 87. Asthma, type     Atopic Asthma Type I IgE-mediated hypersensitivity reaction . The disease usually begins in childhood and is triggered by environmental allergens (dust, pollens, animal dander and food). A positive family history of asthma is common. Serum radioallergosorbent tests (called RAST) identify the presence of IgE specific for a panel of allergens.
    88. 88. Asthma, type  Non-Atopic Asthma : Non-immune, respiratory infections due to viruses (e.g., rhinovirus, parainfluenza virus) are common triggers.  IgE-normal, no positive family history  It is thought that virus-induced inflammation of the respiratory mucosa lowers the threshold of the subepithelial vagal receptors to irritants.
    89. 89. Asthma, type     Drug-Induced Asthma Aspirin-sensitive asthma occurs in individuals with recurrent rhinitis and nasal polyps. Occupational Asthma This form of asthma is stimulated by fumes, organic and chemical dusts (wood, cotton, platinum), gases (toluene), and other chemicals (formaldehyde, penicillin products).
    90. 90. Pathogenesis (atopic asthma)  The major etiologic factors in atopic asthma are a genetic predisposition to type I IgE mediated hypersensitivity reaction    Initial sensitization affects T helper 2 cells, which release IL-4/5, which promote IgE release by B cells, that binds to mucosal mast cells and eosinophils. Reexposure to allergen leads to mediator release from mucosal mast cells IL-4-production of IgE, Il-5-activates locally recruited eosinophils, IL-13-mucus secretion
    91. 91. Pathogenesis  Acute/immediate phase response (minutes): release of preformed mediators-bronchoconstriction, edema, mucus secretion  Late phase reaction (hours): due to release of major basic protein from eosinophils, which causes epithelial damage and airway constriction.
    92. 92. Mediators    Potent mediators: leukotrienes C4, D4, E4 (bronchoconstriction, increased vascular permeability, increased mucus secretion) and acetylcholine (cause airway smooth muscle constriction by directly stimulating muscarinic receptors) Minor mediators: histamine, prostaglandin D2 (bronchoconstrictor) Others: IL-1, TNF, and IL-6, chemokines (e.g., eotaxin), neuropeptides, nitric oxide, bradykinin, and endothelins.
    93. 93. Morphology    Gross: overdistended lung, with small areas of atelectasis, occlusion of bronchi and bronchioles by thick, tenacious mucus plugs. Micro: the mucus plugs contain whorls of shed epithelium, which give rise to the well-known spiral shaped mucus plugs called Curschmann spirals Numerous eosinophils and Charcot-Leyden crystals (crystalloid mad up of galactin-10)
    94. 94. Morphology,microscopic     Overall thickening of airway wall Sub-basement membrane fibrosis (deposition of type 1 and III collagen beneath the classic BM composed of type IV collagen and laminin) An increase in size of the submucosal glands and mucous metaplasia of airway epithelial cells Bronchial smooth muscle hyperplasia and hypertrophy
    95. 95. Microscopic
    96. 96. Eosinophils
    97. 97. Charcot-Leyden crystals
    98. 98. Clinical Course  Acute asthmatic attack lasts up to several hours.  Chest tightness, dyspnea, wheezing, and cough with or without sputum production  Cyanosis and even death.  With appropriate therapy to relieve the attacks, most individuals with asthma are able to maintain a productive life.
    99. 99. Summary     Begins in childhood, triggered by environmental allergens , often positive family history (atopic) Skin test causes wheel and flare reaction Classic example of Type I IgE mediated hypersensitivity reaction Initial sensitization affects T helper 2 cells, which release IL-4/5, which promote IgE release by B cells, mast cells and eosinophils
    100. 100. Summary      Reexposure to allergen-mediator release from mucosal mast cells Acute response: bronchoconstriction, edema, mucus secretion, hypotension Late phase reaction: epithelial damage and airway constriction Putative mediators: leukotrienes C4, D4, E4 and acetylcholine; minor mediators: histamine, prostaglandin D2 Blood eosinophilia, sputum eosinophils