Disease Asthma

Pathophysiology Reversible airway inflammation PMN, eosinophils, mononuclear cells, mast cells, T-lymphocytes, epithelial cell damage Increased sensitivity/hyperreactivity of bronchioles increased generation of IgE in response to external allergens Thickened bronchial basement MB Edema and inflammatory infiltrate in bronchial wall Increased size of submucosal glands Hypertrophy of bronchial wall muscle **See below for mechanism of the different types of asthmas

Clinical features Wheezing, SOB, severe dyspnea, coughing, bronchospasm that can last several hours Pulmonary fxn characteristic of obstructive disease results during acute attack, but NL findings prevail between attacks Status asthmaticus unremitting attacks that can last for days or weeks and can be fatal Airway mucous plugs Curschmann spirals mucous plugs that contain whorls of shed epithelium Charcot-Leyden crystals collections of crystalloid made up of eosinophil MB protein

Epidemiology 7-9% of population 70% are adults 50% have a positive family history risk when parents smoke Significant increase in incidence in the past 3 decades Death rates for African-Americans are 3x higher than Caucasians

Management Anti-inflam: glucocorticoids, Sodium cromoglycate, Nedocromil sodium, LT inhibitors [Zileuton, Zafirlukast], Monoclonal Abs [Omalizumab] Bronchodilators: Theophylline, 2agonists, Anticholinergics [Ipratropium] Th2 CK inhibitor Bronchoprovocational challenge to test for asthma give pt increasing dosages of methacholine, histamine or cold air asthmatics require a smaller concentration to reduce airflow rate by 20% Quit smoking Cigarette smoke effects: interferes w/ the ciliary action of the respiratory epithelium direct damage to epithelium inhs leukocyte ability to clear bacteria

Bronchitis

airway resistance Due to persistent irritants (smoking, air pollution, dust, fumes) and infections Hyperplasia of goblet cells and submucosal glands Excess mucus that can plug the lumen of the bronchioles Reid index [proportion of bronchial glands to bronchial wall thickness] Inflammatory infiltration and fibrosis of bronchiolar wall Can lead to dysplasia of the respiratory epithelium and possible cancer formation

Blue Bloater Prominent hypoxemia (cyanotic), leg swelling Productive cough for 3 consecutive mths over 2 consecutive yrs (definition) Mucopurulent secretions Hypercapnia early in course Greater increase in Hct

Smokers 4-10x more common Seen slight less often in women probably due to differences in smoking habits Usually presents at a younger age than emphysema Stocky, obese stature

Clustering of pigmented alv M Possible cor pulmonale Cor pulmonale early in course

Disease Bronchiectasis

Pathophysiology Irreversible bronchial dilation of medium-sized bronchi (> 2 mm) Chronic necrotizing infection leads to destruction of muscular and elastic components of the bronchial wall Commonly due to: obstruction tumor, foreign body, mucus plug Congenital conditions Cystic fibrosis Intralobular sequestration of the lung Immunodeficiency states Immobile cilia (Kartagener syndrome)

Clinical features Copious foul-smelling purulent sputum, cough, fever, dyspnea, orthopnea, cyanosis Paroxysmal cough particularly in the morning Hemoptysis Lung abscess Atelectasis distal to the obstruction Complications: cor pulmonale, metastatic brain abscess, amyloidosis Pink Puffer tachypnea, mild hypoxemia alv-capillary surface area [ DLCO] Can have airway collapse during expiration due to loss of tethering effect and reduced intraluminal pressure ( recoil)

Epidemiology

Management

Emphysema

Dilated alveoli due to destruction of alveolar wall which results in decreased elastic recoil Thought to be due to imbalance between proteases and anti-proteases alveolar M, PMN produce elastase 1-AT inhs PMN elastase [but not M elastase] PMNs rel oxygen radicals that inh 1-AT Nicotine is chemotactic for PMNs Smoking stims elastase rel from PMNs Smoking enhances M elastase activity Forms: - Centrilobular 95% of cases; proximal portion of terminal bronchioles affected w/ sparing of the distal alveoli; most severe in the upper lobes seen most in smokers - Panacinar affects entire respiratory bronchiole including alveoli affects the elderly and those w/ genetic 1-antitrypsin deficiency (inhs PMN elastase); most severe in the lower lobes (PMNs are concentrated in the lower lung) - Paraceptal involves the distal portion, but the proximal portion is spared; can form cyst-like structures that can lead to pneumothorax - Irregular associated w/ scarring

Most w/ emphysema are current or former smokers, but only 15% of smokers develop emphysema Older age Tall, thin stature Cor pulmonale late in course

Quit smoking Ipratropium bromide muscarine antagonist

Disease Cystic Fibrosis

Pathophysiology Autosomal recessive abnormality of ion transport across epithelial and exocrine cells CFTR gene (Chromosome 7, deletion of phenylalanine most common) binding of agonist increases cAMP which activates PK A which phosphorylates the chloride channel Epithelial cells are impermeable to chloride Viscous airway mucus w/ impaired mucociliary clearance due to increased Na+ reabsorption which in turn increases the water reabsorption Recurrent respiratory infections destroy airway architecture and causes irreversible airway obstruction Staph a. H. flu Pseudomonas aeruginosa Pseudomonas cepacia (common cause of death) Thin-walled (< 1mm) air-filled space in the lung > 1 mm when distended progressively enlarge over mths to yrs Walls may be formed by pleura, septa or compressed lung tissue No obstruction and NL parenchyma between the bullea (unlike emphysema)

Clinical features Sinusitis, nasal polyps, hyperglycemia High NaCl concentration in sweat Bronchiectasis, atelectasis Atrophy of exocrine glands Pancreatic insufficiency Nutritional def (esp in fat-soluble vitamins, A, D, E, K) and steatorrhea (fat in the feces) Meconium ileus in newborns small bowel obstruction Infertility in males absence of vas deferens (95%) Can become infected or form a pneumothorax Seen more in upper lobes

Epidemiology Most common genetic disease in Caucasians [affects 1:2000 and 1 in 20 are carriers] Rare in Asians and African Americans 550 known mutations. Tests can detect 70 of them which accounts for 90% of the mutations. Often associated w/ emphysema Familial occurrence Increased incidence w/ Marfans and Ehlers-Danlos

Management Control of infections Promotion of mucus clearance Improved nutrition Lung transplantation 70% survival rate Gene therapy Median life expectancy is 30 yrs

Congenital bullous lung disease

Surgical removal

Other types of emphysema o Compensatory emphysema dilation of alveoli w/o destruction of septal walls Hyperexpansion of residual lung parenchyma that follows surgical removal of diseased lung or lobe o Senile emphysema overdistended lungs found in the aged Larger alveolar ducts and smaller alveoli Without loss of elastic tissue o Obstructive overinflation expansion due to trapped air Due to tumor, foreign object or congenital abnormality o Bullous emphysema any form of emphysema that forms a large subpleural bullae o Interstitial emphysema entrance of air into the connective tissue stroma of lung, mediastinum or subcutaneous tissue

Due to alveolar tears

Types of Asthma o Atopic Asthma most common type, begins in childhood Triggering events = environmental antigens Dust, pollen, animal dander, foods Type I IgE-mediated hypersensitivity rxn Stimulates induction of Th2 T-cells which release IL-4 and IL-5 o IL-4 promote IgE production by B-cells and growth of mast cells o IL-5 promotes growth and activation of eosinophils Western lifestyle or Hygiene hypothesis o In asthma the Th2 cytokines predominate IL-4, IL-5 o Exposure in infancy to infection/Ags increases the predominance of Th1 and reduces the incidence of asthma Th1 cells produce IFN- and IL-2 which inhibit Th2 cells Mechanism: Exposure of presensitized IgE-coated mast cells on the mucosal surface to the same or a cross-reacting Ag results in the cross-linking of IgE Cross-linked IgE results in the release of the chemical mediators for the mast cell which causes Opens the mucosal intercellular tight junctions for enhanced penetration of the Ag for greater contact with more mast cells The Ag also directly stimulates the subepithelial vagal receptors that produce bronchoconstriction T-lymphocytes also release chemical mediators Acute phase occurs within minutes Bronchoconstriction, edema, mucus secretion, hypotension Late phase occurs 4-8 hours later and can last 12+ hrs Mediators released by mast cells and epithelial cells cause the influx of PMNs, monocytes, lymphocytes, basophils and especially eosinophils o Eosinophils release major basic protein which causes epithelial damage and airway constriction Mediators: LT C4, D4, E4 potent bronchoconstriction, mucus secretion, vascular permeability Acetylcholine potent bronchoconstriction Histamine bronchoconstriction Prostaglandin D2 bronchoconstriction, vasodilation PAF aggregation of platelets and release of histamine and serotonin from platelet granules o Nonatopic Asthma most often triggered by respiratory tract infection Especially due to viruses rhinovirus, parainfluenza virus Virus-induced inflammation of respiratory mucosa lowers the threshold of the subepithelial vagal receptors to irritants IgE levels are NL

Drug-Induced Asthma Aspirin-sensitive asthma Occurs in patients w/ recurrent rhinitis and nasal polyps w/ symptoms occurring 1 hr after ingestion of aspirin Symptoms of rhinorrhea, conjunctival irritation, scarlet flush of head and neck Typically in the 3rd-4th decade 2-5% of the population Experience asthma attacks and urticaria Thought to be due to the blocking of the COX pathway which results in an imbalance of the bronchoconstrictor LTs from the lipoxygenase route Occupational Asthma Due to: Fumes epoxy resins, plastics Organic and chemical dusts wood, cotton, platinum Gases toluene Other chemicals formaldehyde, penicillin products Type I IgG-mediated rxn 20-25% of adult-onset asthma is work-related Types: Aggravation of pre-existing asthma direct effect on the irritant receptors in the bronchi Without latency period Reactive Airway Disease Syndrome (RADS) acute bronchoconstriction due to exposure to high concentrations of irritants Allergic immune-medicated which develops after a variable period of symptomless exposure to a sensitizing agent Examples: High molecular weight compds Animal, fungal, bacterial, insect, plant Low molecular weight compds Chemical, metal Exercised Induced Asthma Symptoms associated w/ physical activity Mechanism related to the cooling and loss of water during rapid breathing Airway drying and dilation of blood vessels w/ edema Nerve gas Organophosphate pesticides Acetylcholine esterase inhibitors Ach concentration for smooth muscle contraction

Complicators and Aggravators of Asthma o Allergic bronchopulmonary aspergillosis (ABPA) Aspergillus fumigantus colonizes the sputum plugs in the bronchi Immune rxns to Ags released from the fungus o o Chronic sinusitis postnasal drainage Gastroesophageal reflux disease (GERD) Each can aggravate the other Asthma aggravates GERD by: Trapping air and flattening the diaphragm Creating a thoracoabdominal pressure gradient that favored reflux Bronchodilators decrease the esophageal sphincter tone GERD aggravates asthma by unknown mechanisms, but thought that gastric acid introduced into the distal esophagus decreases lung function and increases hyperreactivity Air pollution - in particulate levels and ozone Steroid-resistant asthma require higher doses Definition: failure to have a 15% increase in FEV1 after 7-14 days of oral prednisone Thought to be due to abnormalities in glucocorticoid receptor acquired after chronic inflammation and CK stimulation

o o

Cells

COPD PMNs Large in M in CD8+ T-lymphocytes LT B4 IL-8 TNF- Squamous metaplasia of epithelium Parenchymal destruction Mucus metaplasia Glandular enlargement Glucocorticoids have little to no effect

Mediators Consequences

Asthma Eosinophils Small in M in CD4+ T-lymphocytes Activation of mast cells LT D4 IL-4, IL-5 Fragile epithelium Thickening of basement MB Mucus metaplasia Glandular enlargement Glucocorticoids inhibit inflammation

Response to treatment