Chronic Obstructive Pulmonary Diseases Chronic Bronchitis Emphysema Bronchiectasis Bronchial Asthma Small Air way disease Bronchiolitis

Pathogenesis Prolonged exposure to cigarette smoke and/or other air pollutants. Airway obstruction at times may result in a check-valve mechanism leading to overdistension and rupture of alveolar septa, especially if the latter are inflamed and exposed to high positive pressure (i.e. barotrauma). With loss of alveolar surface in emphysema, there is a decrease in surface tension, resulting in expiratory airway collapse. Additional investigative work continues in an effort to link disease states to pathogenesis

Etiology By far the most common etiological cause of COPD remains smoking. Even after the client quits smoking, the disease process continues to worsen. Air pollution and occupation also play an important role in COPD. Smog and second-hand smoke contribute to worsening of the disease.

Cont. Occupational exposure to irritating fumes and dusts may aggravate COPD. Silicosis and other pneumonoconioses may bring about lung fibrosis and focal emphysema. Exposure to certain vegetable dusts, such as cotton fiber, molds and fungi in grain dust, may increase airway resistance and sometimes produce permanent respiratory impairment.

Cont. Exposures to irritating gases, produce pulmonary edema, bronchiolitis and at times permanent parenchymal damage. Chlorine Oxides of nitrogen and sulfur, Repeated bronchopulmonary infections can also intensify the existing pathological changes, playing a role in destruction of lung parenchyma and the progression of COPD.

Chronic Bronchitis Definition: Chronic bronchitis is a clinical syndrome defined by chronic sputum production Persistent cough with sputum production for at least 3 months in at least 2 consecutive years Anatomic site Bronchus

Morphology Hyperemia and edema of mm of lungs Mucinous secretions or casts filling in the air ways Increase in the size and numbers of mucous secreting glands Bronchial or bronciolar mucous plugging, fibrosis, inflammation and fibrosis Squamous metaplaisa or dysplasia of bronchial epithelium

Chronic Bronchitis Pathophysiology Cilia Damaged Chronic inflammation Hypertrophy & hyperplasia of bronchial glands that secrete mucus Increase number of goblet cells Cilia are destroyed

Chronic Bronchitis Pathophysiology Narrowing of airway Starting w/ bronchi  smaller airways airflow resistance work of breathing Hypoventilation & CO2 retention  hypoxemia & hypercapnea

Chronic Bronchitis Pathophysiology Bronchospasm often occurs End result Hypoxemia Hypercapnea Polycythemia (increase RBCs) Cyanosis Cor pulmonale (enlargement of right side of heart

Cartilage damage in long standing cases Degenerative changes, atrophy and loss of bronchial cartilage were common features of most chronic bronchitic specimens This usually being related to intrinsic changes in the chondrocyte phenotype, including proliferative and matrix-degrading properties. Mast cells and macrophages were often observed in close association with the bronchial cartilage, suggesting that inflammatory cells may also contribute to the mechanisms of bronchial cartilage degradation and loss

Inflammatory Cells Studies show that smokers with symptoms of chronic bronchitis have an increased number of inflammatory cells in their bronchial glands when compared with asymptomatic smokers. This inflammatory process consists predominantly of neutrophils and macrophages, and of an increased proportion of CD8+ T-lymphocytes Mast cells

Mast cells Lymphocytes Neutrophils Macrophages Macrophages, Mast cells, Lymphocytes and Neutrophils

Neutrophils Lymphocytes Mast cells Macrophages

This inflammatory process consists predominantly of neutrophils and macrophages, and of an increased proportion of CD8+ T-lymphocytes and Mast Cells                                                              

Pathogenesis Chronic irritation of airways Smoking Dust Air pollutants etc The major risk factor for the development of chronic bronchitis is cigarette smoking Infective agents Secondary factor These irritants cause Hypersecretions of mucous Subsequent hypertrophy of mucous glands Metaplasia inflammation

Emphysema Pulmonary emphysema is described in clinical, radiological and physiologic terms, but the condition is best defined morphologically Definition:Abnormal enlargement of airspaces distal to the terminal bronchioles with destruction of their wall It is characterized by destruction and enlargement of alveoli

Cont. Although the normal lung has about 35,000 terminal bronchioles and their total internal cross-sectional area is at least 40 times as great as that of the lobar bronchi but the bronchioles are more delicate and vulnerable.

Cont Bronchioles may be obstructed partially or completely, temporarily or permanently, by thickening of their walls, by collapse due to loss of elasticity of the surrounding parenchyma, or by influx of exudates.

Cont In advanced emphysema, the lungs are large, pale, and relatively bloodless. They do not readily collapse. They many contain many superficial blebs or bullae, which occasionally are huge. The right ventricle of the heart is often enlarged (cor pulmonale), reflecting pulmonary arterial hypertension.

Emphysema: Pathophysiology Structural changes Hyperinflation of alveoli Destruction of alveolar & alveolar-capillary walls Small airways narrow Lung elasticity decreases

Emphysema Loss of Lung Surface Area for Gas Exchange and Oxygen Transport Loss of Lung Surface area is due to death of Lung Endothelial Cells Polycyclic aromatic hydrocarbons (PAHs) in Cigarette Smoke and in Environmental Pollution may cause endothelial cell death

Emphysema: Pathophysiology Mechanisms of structural change Obstruction of small bronchioles Proteolytic enzymes destroy alveolar tissue Elastin & collagen are destroyed Support structure is destroyed “paper bag” lungs

Emphysema: Pathophysiology The end result: Alveoli lose elastic recoil, then distend, & eventually blow out. Small airways collapse or narrow Air trapping Hyperinflation Decreased surface area for ventilation

Emphysema: Clinical Manifestations Early stages Dyspnea Non productive cough Diaphragm flattens A-P diameter increases “Barrel chest” Hypoxemia may occur Increased respiratory rate Respiratory alkalosis Prolonged expiratory phase Tripod position

Emphysema: Clinical Manifestations Later stages Hypercapnea Purse-lip breathing Muscle retraction Use of accessory muscles to breathe Underweight No appetite & increase breathing workload Loss of subcutaneous fat Lung sounds diminished

Clinical Manifestations Pulmonary function  residual volume,  lung capacity, DECREASED FEV1, vital capacity maybe normal Arterial blood gases Normal in moderate disease May develop respiratory alkalosis Later: hypercapnia and respiratory acidosis Chest x-ray Flattened diaphragm hyperinflation

Classification Anatomical Distribution Cetriacinar Panacinar Paraseptal Irregular

Pathogenesis Protease anti Protease Theory Pollutants in environment Hereditary deficiency of the major protease inhibitors Laurell and Eriksson –1963 – deficiency of α1-antitrypsin and emphysema Pollutants in environment smoking of cigarettes exhalations from cars, dust from grain Recruitment of neutrophils stimulation of macrophages and epithelial cells to produce TNF- α, IL-8 and LTB4 Elastase release from leukocytes and tissue macrophages Inactivation of α1-antitrypsin by oxidants in tobacco smoke or free radicals released from the neutrophils

Diseases in which misfolding of a given protein results in improper trafficking

Diseases in which misfolding of a given protein results in improper trafficking polymers of alpha1 antitrypsin molecules will form. These will be retained in the liver (where alpha1 antitrypsin is produced) and will not reach the lungs

increased lung lucency hyper aeration increased lung lucency decreased vessel size Flattening of the Diaphragm Increased Lung Height Decreased Peripheral Vascular Markings

Chest X-Ray Changes in Emphysema: The two primary findings are: Increased Lung Volumes, i.e., hyperaeration or overinflation. Lung Destruction (bullae or decreased vascularity which gives increased lung lucency and decreased vessel size ). In end-stage disease, emphysema and chronic obstructive pulmonary disease can result in pulmonary arterial hypertension and eventually cor pulmonale (cp) - which causes an increase in the pulmonary arterial size, as well as right ventricular enlargement and cardiomegaly.

Normal acinus

Morphology Centrilobular Emphysema Panlobular Emphysema

Peripheral alveolar damage Paraseptal Peripheral alveolar damage

Other types of Emphysema 1 Bullous Emphysema (also known as Bullous Lung Disease): Bullous emphysema is so named when there are multiple large bullae associated with a compromise in pulmonary function. It is usually associated with concomitant emphysema, although occasionally, it can be familial

Bullous Emphysema   Subpleural Type: These subpleural bullae contain only gas with no alveolar remnants or blood vessels. They are often located in the apex of the upper lung zone, and along the costophrenic rim of the middle lobe and lingua, but may be seen in the vicinity of parenchymal scars. Superficial Type: These bullae are found along the anterior edge of the upper and/or middle lung zones, or lingula, and over the diaphragms. They contains blood vessels and strands of partially-destroyed lung. Deep Type: These bullae are found within the lung substance and contain strands of partially-destroyed lung tissue and blood vessels.

2.Giant Bullous Emphysema: ("Vanishing Lung Syndrome" or "Primary Bullous Disease of the Lungs") It is usually associated with young males who show large progressive upper lung zone bullae that are often asymmetric. The giant bullous lesions occupy greater than or equal to one-third of the hemithorax.

Cont. 3.Focal Dust Emphysema ( This is focal emphysema surrounding silicotic nodules. 4.Congenital Lobar Emphysema (CLE) 5.Interstitial Emphysema

Bronchiectasis Bronchiectasis is a chronic lung disease that is characterized by permanent dilatation of the bronchi and fibrosis of the lung. It is defined as the pathological, irreversible dilation of bronchi , due to destruction of the bronchilal walls and their supporting tissues It is highly associated with chronic bacterial infection Often looked at, as the final common pathway of many injurious processes

Cont. Bronchiectasis , although uncommon,bears the potential to cause severe illness , including repeated respiratory infections , disabling cough, purulent sputum, shortness of breath, chest pain and occasionally hemoptysis, with significant impact on the health and the quality of life of the affected person

Types of Bronchiectasis Bronchiectasis means irreversible dilation and distortion of the bronchi and bronchioles. Pathologically, bronchiectasis can be divided into four types

Cylindrical Bronchiectasis The first type, cylindrical bronchiectasis, is characterized by uniform dilatation of bronchi, that extends into the lung periphery, without tapering. Tubular bronchiectasis is simply the absence of normal bronchial tapering and is usually a manifestation of severe chronic bronchitis rather than of true bronchial wall destruction

Bronciectasis Cylindrical Forma

Varicose Bronchiectasis The second type is called varicose bronchiectasis and is characterized by irregular and beaded outline of bronchi, with alternating areas of constriction and dilatation.

Saccular Bronchiectasis. The third type is called cystic or saccular bronchiectasis and is the most severe form of the disease. The bronchi dilate, forming large cysts, which are usually filled with air and fluid. Saccular bronchiectasis is the classic advanced form characterized by irregular dilatations and narrowing. The term cystic is used when the dilatations are especially large and numerous

Bronchiectasis Saccular Form

Follicular Bronchiectasis The fourth type of bronchiectasis is called follicular and is characterized by extensive lymphoid nodules within the bronchial walls. It usually occurs following childhood infections

Cont. Repeated or prolonged episodes of pneumonitis, Inhaled foreign objects or Neoplasms have been known to cause bronchiectasis. When the bronchiectatic process involves most or all of the bronchial tree, whether in one or both lungs, it is believed to be genetic or developmental in origin

ASTHMA Definition Asthma is a chronic inflammatory disorder of airways. Many cells and mediators are involved in this process – eosinophils, mast cells and T-lymphocytes.

Asthma Reversible inflammation & obstruction Intermittent attacks Sudden onset Varies from person to person Severity can vary from shortness of breath to death

Bronchial Hypersensitivity Chronic inflammation is connected with bronchial hyperreactivity and leads to episodes of wheezing, coughing, tightness in the chest, breathlessness, shortage of breath specially at night and in the morning. This episodes are usually connected with variable obstruction which is reversible spontaneously or by treatment.

Types A) Allergic asthma B) Non-allergic asthma asthma induced by immunological mechanisms. IgE induced asthma IgE antibodies triggers early and late-phase of response, T- lymphocytes late and opožděné responses. B) Non-allergic asthma asthma induced by non-immunological triggers Intermittent and persistent

Response of Inflammation Inflammation causes obstruction of airways by: Acute bronchoconstriction Swelling of bronchial wall Chronic production of mucous Remodeling of airways walls

Risk factors: Individual predisposition Environment genetic variability – 5. a 11. chromosome atopy, bronchial hyperreactivity, male or female, nation Environment exposition to allergens professional chemicals which lead to sensitivity, viral and bacterial infection, food, smoking, social and economic society, number of family members, psychosomatic influence

Asthma: Pathophysiology Swelling of mucus membranes (edema) Spasm of smooth muscle in bronchioles Increased airway resistance Increased mucus gland secretion

Asthma: Pathophysiology Early phase response: 30 – 60 minutes Allergen or irritant activates mast cells Inflammatory mediators are released histamine, bradykinin, leukotrienes, prostaglandins, platelet-activating- factor, chemotactic factors, cytokines Intense inflammation occurs Bronchial smooth muscle constricts Increased vasodilation and permeability Epithelial damage Bronchospasm Increased mucus secretion Edema

Late phase response: 5 – 6 hours Characterized by inflammation Eosinophils and neutrophils infiltrate Mediators are released mast cells release histamine and additional mediators Self-perpetuating cycle Lymphocytes and monocytes invade as well Future attacks may be worse because of increased airway reactivity that results from late phase response Individual becomes hyperresponsive to specific allergens and non-specific irritants such as cold air and dust Specific triggers can be difficult to identify and less stimulation is required to produce a reaction

Cells involved in chronic allergic inflammation 1. Eosinophils 2. Mast cells 3. T-lymphocytes 4. Neutrophils 5. Basophils

T-lymphocytes Eosinophils Basophils Macrophage NEUTROPHIL Mast cell

Pathogenesis Acute inflammation Remodeling of airways Chronic inflammation Symptoms of bronchoconstriction Exacerbation nonspecific hyperreactivity Ongoing obstruction of airway

Remodeling destruction of brush epithelium in airways swelling of the bronchial wall stimulation of proliferation of fibroblasts deposition of collagen in lamina reticularis of basal membrane hypertrophy of smooth muscles hyperplasia of goblet cells

The process of remodeling is involved by: Th2 lymphocytes (CD25+, production of IL-4,13,5,6,10) antigen presenting cells mast cells (tryptase-converting angiotensin I to angiotensin II, hypertrophy of smooth muscles, histamin – fibrogenetic effect) eosinophils (long-living in epithelium and submucoses, create lipids –PAF, LTC4,LTD4, LTB4, peptides, cytokines, TGF-α, TGF-β, IL-1,3, GM-CSF, ECP) alveolar macrophages (production of TNF-α, IL-6) epithelial cells (desquamation of epithelium, lost of integrity, TGF-β, IGF-1, KGF- β, alteration of differentiation and proliferation of epithelial cells, apoptosis) endothelial cells

Cont. myocytes (proliferation of myocytes - after stimulation with IL- 11, which is produced by mezenchymal cells after stimulation with allergen, PGDF, EGF, the effect of gelatinase A (MMP-2) and B (MMP-9), production of IL-6,8, eotaxin, PGE2, RANTES, MCP-1,2,3, expression of ICAM-1, VCAM-1, production of NO, GM-CSF, IL-5) fibroblasts (activation of fibroblasts, creation of myofibroblasts, release of GM-CSF and TGF-β, increasing proinflammatory activity of eosinophils)

Subepithelial structures: thickness of basal membrane increasing deposition of extracellular matrix under epithelium deposition of collagen I., III., IV., V. and VII. in reticular membrane increasing deposition of proteoglycans (lumican, biblycan, decorin, fibromodulin, hyaluron, versica) tenascin (corresponds with activity of chronic inflammation) fibronectin

Decrease of elasticity of the wall Inflammation Increasing number of mucous glands Increasing number of smooth muscles fibres Sever bronchospasms during exacerbation Increase of mucous secretion during Release of fibrogenetic factors Ongoing of inflammatory cells Elastolysis Deposition of collagen in basal and Epithelial membranes Decrease of elasticity of the wall Inflammation

Cytokines involved in pathogenesis of asthma IL-4 - cross-linking of immunoglobulines in B lymphocytes – production of IgE and IgG4 - increases of expression of VCAM-1 and mucous secretion - inhibits of activation of Th1 and production of IFNγ IL-13 - induces production of IgE a IgG4 - activates mast cells - increases bronchial hyperreactivity and contractility of smooth muscles, affects the differentiation of cilia - induces the production of eotaxin, VCAM-1 - suppress production of pro-inflammatory cytokines

Cont. IL-5 - produced by mast cells and Th2 lymphocytes, epithelial cells and eosinophils - affects the proliferation and the differentiation of B lymphocytes - induces expression of IL-2R - proliferating and differentiating factor for eosinophils IL-12 - produced by macrophages, dendritic cells and monocytes - decreases production of Th2 cytokines and then production of IgE and IgG1 - decreases number of eosinophils in peripheral blood and in sputum

Cont. IL-10 - large immunosupressive and anti-inflammatory effect - decreases expression of iNOS, COX2 decreases release of IL-2, expression of MHC class II., CD80, CD86 and CD32 on the surface of APC and then presentation of allergen, RANTES, IL-5 - correlation with asthma severity

Cont. - IFNγ - low levels in atopic people - stimulatory effects on Th1 cells, inhibitory effects on Th2 cells - the nebulissation of IFNγ decreases the number of eosinophils in BAL but this effect is not significant TGF-β - remodeling - induction of expression of Fas receptor on the surface of epithelial cells, activation of apoptosis, phagocytosis by macrophages, exudation of plasma,fibrosis

Etiological Classification of asthma: A. Atopic (allergic) asthma - in combination with allergic rhinitis, atopic dermatitis, genetic predisposition - confirmation of spec. IgE antibodies, prick tests, inhalation challenge B. Endogenous asthma - without specific known influence, obviously in women after exposition to cold weather, refract to the standard therapy C. Exercise induced asthma - physical exercising, provocation by inhalation of chemicals, cold or hot weather

Cont. D. Aspirin induced asthma - typical triads-nasal polyps, urticaria and asthma induced by application of aspirin - other drugs E. Allergic bronchopulmonary aspergillosis - aspergillus acts as an allergen challenge in atopic people and induces aspergillus asthma or alergic bronchopulmonary aspergillosis - in the chest radiography are intermitent infiltrates in lungs, the viscosity of mucous is increased and mucous plugs, bronchiectasia

Cont. F. Gastroesophageal reflux - bronchospasm induced by reflex G. Sinobronchial syndrome - combination of sinusitis with nasal polyps and with asthma H. Professional asthma - induced by inhalation and exposition to industry chemicals CH. Asthmatic equivalent - dry cough, irritating, without breathlessness

Classification of grading of asthma Grade 1. Intermitent asthma - rare symptoms < than 1x per week, short episodes of worsening - night symptoms 2x monthly - no symptoms between attacks - PEF or FEV1 > 80%, variability < 20% Grade 2. Mild persistent asthma - symptoms <1x per day >1x per week - night symptoms > 2x per month - exacerbation can affect daily activity or sleeping - PEF or FEV1 > 80%, variability 20-30%

Cont. Grade 3. Moderate persistent asthma - Everyday symptoms - Exacerbation affects daily activity and sleeping - Night symptoms > 1x per week - Everyday use of releasing drugs - PEF or FEV1 between 60- 80%, variability > 30% Grade 4. Severe persistent asthma - Continuous symptoms - Frequent exacerbation - Physical activity is decreased - Frequent night symptoms - PEF or FEV1 < 60%, variability > 30%

Asthma: Early Clinical Manifestations Expiratory & inspiratory wheezing Dry or moist non-productive cough Chest tightness Dyspnea Anxious &Agitated Prolonged expiratory phase Increased respiratory & heart rate Decreased PEFR

Asthma: Early Clinical Manifestations Wheezing Chest tightness Dyspnea Cough Prolonged expiratory phase [1:3 or 1:4]

Asthma: Severe Clinical Manifestations Hypoxia Confusion Increased heart rate & blood pressure Respiratory rate up to 40/minute & pursed lip breathing Use of accessory muscles Diaphoresis & pallor Cyanotic nail beds Flaring nostrils