The Possible Role of Hematopoietic Cell Kinase in the Pathophysiology of COPD Abstract

Background:
Hematopoietic cell kinase (Hck) is a myeloid cell-specific tyrosine kinase, which is known to induce neutrophil infiltration to the lungs. Although the overexpression of Hck causes emphysema-like histologic changes in mice, its expression and activity in patients with COPD are unclear.

Method:
The aim of this study was to clarify the expression and activity of Hck in neutrophils from COPD patients, and to investigate the association between the degree of Hck expression and the lung function parameters in COPD patients. Peripheral blood neutrophils were isolated from 22 patients with COPD and 9 healthy subjects (HSs). The protein levels of Hck and phosphorylated Hck were assessed, and the correlation with various background characteristics was evaluated.

Results:
The Hck protein level was significantly higher in

neutrophils from COPD patients compared with HSs (COPD patients, 1.094; HSs, 0.801; p < 0.05). A significant positive correlation was observed between the protein level of Hck and the surface expression of the integrin molecule CD-11b (r = 0.540; p < 0.01) or CXC chemokine receptor-1 (r = 0.432; p < 0.05). In contrast, there was no difference in the phosphorylation of the Hck protein between COPD patients and HSs.

Conclusion:
The Hck protein level in peripheral blood neutrophils was increased in COPD patients, suggesting that Hck might have an important role in the neutrophil function and play a key role in the pathophysiology of COPD. The possible role of hematopoietic cell kinase in the pathophysiology of COPD. Chest 2009;135(1):94-101. BACKGROUND: Hematopoietic cell kinase (Hck) is a myeloid cell-specific tyrosine kinase, which is known to induce neutrophil infiltration to the lungs. Although the overexpression of Hck causes emphysema-like histologic changes in mice, its expression and activity in patients with COPD are unclear.

METHOD: The aim of this study was to clarify the expression and activity of Hck in neutrophils from COPD patients, and to investigate the association between the degree of Hck expression and the lung function parameters in COPD patients. Peripheral blood neutrophils were isolated from 22 patients with COPD and 9 healthy subjects (HSs). The protein levels of Hck and phosphorylated Hck were assessed, and the correlation with various background characteristics was evaluated. RESULTS: The Hck protein level was significantly higher in neutrophils from COPD patients compared with HSs (COPD patients, 1.094; HSs, 0.801; p < 0.05). A significant positive correlation was observed between the protein level of Hck and the surface expression of the integrin molecule CD-11b (r = 0.540; p < 0.01) or CXC chemokine receptor-1 (r = 0.432; p < 0.05). In contrast, there was no difference in the phosphorylation of the Hck protein between COPD patients and HSs. CONCLUSION: The Hck protein level in peripheral blood neutrophils was increased in COPD patients, suggesting that Hck might have an important role in the neutrophil function and play a key role in the pathophysiology of COPD. THE POSSIBLE ROLE OF HEMATOPOIETIC CELL KINASE IN THE PATHOPHYSIOLOGY OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE

Abstract Background Hematopoietic-cell-kinase (Hck) is a myeloid cell specific tyrosine kinase, known to induce neutrophil infiltration to the lungs. Although the over-expression of Hck causes emphysema-like histological changes in mouse, its expression and activity in patients with chronic obstructive pulmonary disease (COPD) are unclear. Method The aim of this study is to clarify the expression and activity of Hck in neutrophils from COPD patients, and to investigate the association between the degree of Hck expression and the lung function parameters in COPD. Peripheral blood neutrophils were isolated from 22 patients with COPD and 9 healthy subjects (HS). The protein level of Hck and phosphorylated-Hck (p-Hck) were assessed, and the correlation with various background characteristics was evaluated. Results The Hck protein level was significantly higher in the neutrophils from COPD patients compared with HS (COPD = 1.094, HS = 0.801, p < 0.05). A significant positive correlation was observed between the protein level of Hck and the surface expression of integrin molecule, CD-11b (r = 0.540; p < 0.01), or CXC chemokine receptor-1 (r = 0.432; p < 0.05). In contrast, there was no difference in the phosphorylation of Hck protein between COPD patients and HS. Conclusion The Hck protein level in peripheral blood neutrophils was increased in COPD patients, suggesting that Hck might have an important role in the neutrophil function and play a key role in COPD pathophysiology. Comments on this publication Pulmonary Pathology COPD 2.ppt - Presentation Transcript 1. Two major lung diseases 1. Obstructive airway disease a) limitations of airflow i) partial or complete obstruction at any level major causes a) asthma obstructive b) emphysema loss of elastic recoil c) chronic bronchitis d) Bronchiectasis e) cystic fibrosis f) bronchiolitis 2. o 1. Obstructive (cont) o In these diseases:

o o o

TLC and FVC are normal or slightly increased Marked by decreased expiratory flow (FEV 1 ) Ratio of FEV 1 to FVC is decreased Obstructive Lung Disease

3.
o

The factors involved in the pathogenesis of Cor Pulmonale in Chronic Obstructive Pulmonary Disease (COPD) can be seen in the following

diagram.

As seen in the pathogenesis of Cor Pulmonale diagram above, hypoxemia exerts an effect on the pulmonary vasculature separate from alveolar hypoxia, as does acidosis. The increased pulmonary vascular resistance is contibuted by the reduction in pulmonary capillary surface area caused by emphysema. Further more, an erythrocytosis may augment the pulmonary hypertension.

What is bronchiectasis? Bronchiectasis is another abnormality that can be found in patients with COPD. In bronchiectasis, serious and repeated infections of the lung as well as abnormal development of the lung results in permanent damage to the airways. The damaged airways become enlarged tubes or, in more severe cases, large sacs. These segments of lung can impair clearance of secretions. The damaged, mucus-filled airways often become infected, resulting in further inflammation and damage to the airways. Patients with bronchiectasis often have a vigorous cough producing large amounts of infected mucus. [edit] Differences between COPD and asthma Although COPD and asthma are both respiratory diseases characterised by underlying inflammation, the nature of the inflammation is quite different in each case. In COPD inflammation is characterised by inflammatory cells such as neutrophils, CD8+ T-lymphocytes and macrophages and the disease is associated with airflow limitation that is not fully reversible.1,2 In asthma, airflow limitation is often fully reversible, either spontaneously or with treatment and is characterised by a different profile of inflammatory cells, namely eosinophils and CD4+ T-lymphocytes. In COPD, both the airways and lung parenchyma are affected by the disease and airflow limitation is progressive, however in asthma only the airways are affected. Asthma is usually present from childhood whereas COPD is predominantly diagnosed in patients > 40.2

Table 1: Summary of differences between COPD and Asthma.2

COPD Predominant Neutrophils cells in airways Other cells present

Asthma Eosinophils

Macrophages CD4+lymphocytes CD8+lymphocytes Mast cells Childhood onwards Reversible spontaneously or with treatment

Age of onset >40 Nature of airway limitation [edit] Not fully reversible

1. 1. Asthma o Characterized by episodic, reversible bronchospasm resulting from broncho constriction in response to various stimuli o a) basis of hyperactivity of bronchi is unclear o i) thought to be from persistent/chronic bronchial inflammation of the airways o - eosinophils o - mast cells, epithelial cells o - macrophages o - neutrophils, T-lymphocytes 2. b) clinically i ) dyspnea ii) cough iii) wheezing (expiratory) triggered via bronchospasm iv) 5% adults and 10%children v)
o

status asthmaticus fatal outcome vi) between attacks asymptomatic 3. Classification a) extrinsic asthma initiated by type I hypersensitivity reaction induced by exposure to extrinsic antigen b) 3 types of extrinsic asthma i) atopic (most common); 1st 2 decades; increased IgE; CD4 and T cells - type I hypersensitivity ii) occupational (many forms) iii) allergic bronchopulmonary aspergilluss (bacterial colonization followed by IgE antibodies) 4. o Major etiologic factors of asthma o a) genetic predisposition to type I hypersensitivity (atopy) o i) precise cellular response is unknown o b) type 2 helper T (T H 2) cells are important components of bronchial inflammation o i) release cytokines (IL) o - promote inflammatory response o - stimulate B-cells to IgE and other antibodies o c) (T H 1) IFN-1 and IL-2 o i) kill viruses, etc by activating macrophages and cytotoxic T cells 5. o Both these two T cell types regulate one o another o a) imbalance between these may be the key to asthma o b) when IFN-1 is altered and fails to check T H 2 airway inflammation o i) patients with allergic asthma have increased T H 2 o - etiology is unclear o ii) transcription factor T-bet is required for T H 1 cell differentiation o - asthmatics are deficient in this transcription factor 6. 7. o Airway remodeling o a) seen several years prior to onset of symptoms o i) ADAM-33 gene linkage to asthma

- found in bronchial SM o - found in lung fibrobalsts o ii) ADAM-33 polymorphism causes o - proliferation of bronchial SM cells and fibrobalst, thereby contributing to: o bronchial hyperactivity o subepithelial fibrosis o iii) Mast cells 8. iv) thickening of basement membrane v) edema vi) size of submucosal glands vii) muscular hypertrophy viii) inflammatory infiltrate in bronchial walls (eosinophils and Mast cells) 9. o Atopic asthma o a) most common type of asthma o i) childhood o ii) triggered by environmental antigen o (dust, pollen, food, etc) o iii) positive family history is common o iv) attacks usually preceded by allergic rhinitis, utricaria or eczema 10. o Proposed progression o a) sensitization to allergen in lung results in o b) T H 2 synthesis/activation o c) release of cytokines (IL-4, IL-5) o d) promote IgE by B-cells, growth of Mast cells (IL-4), and eosinophils (IL-5) o e) acute phase response (4-8 hrs) o f) initial Mast cell reactions occur on mucosal surface releasing mediators o i) opens mucosal tight junctions o - promotes antigen movement to mucosal Mast cells o ii) stimulation of parasympathetics o - bronchoconstriction 11. g) acute phase begins within minutes of exposure i) edema ii) mucus secretion iii) hypotension (rare occurrence) h) Mast cells release other mediators i) other leukocytes o

neutrophils - lymphocytes - monocytes - basophils - eosinophils (mainly IL-5) i) these inflammatory cells set stage for late phase reaction (12-24 hrs) 12. o Late phase reaction o a) induced by leukocyte chemotaxis induced by Mast cells o b) other cells can also produce mediators o i) vascular endothelial cells o ii) airway epithelial cells o - produce cytokines in response to infections, drugs, gases. o - eotaxin chemoattractant and activator of eosinophils o - basic protein of eosinophils causes epithelial damage bronchoconstriction 13. 14. o Mediators o a) leukotrienes C 4 D 4 E 4 bronchoconstriction, vascular permeability, mucus secretion o b) Ach SM constriction (via muscarinic) o c) histamine PGD 2 PAF (serotonin) bronchoconstriction o d) IL-1, TNF, IL-6, eotaxin, NO, endothelin o Nonatopic (i.e., intrinsic) asthma o a) usually triggered by respiratory viral infection (rhino-, parainfluenza) o b) family history uncommon 15. o c) serum IgE are normal o d) no associated allergies o e) exercise o f) cold o Theory hyperirritability of airways o a) virus lowers threshold of vagal receptors to irritants bronchoconstriction o Occupational induced asthma o a) fumes (epoxy resins, plastic) o b) gases (toluene)

c) dust (wool, wood, platinum) o d) penicillin products o e) formaldehyde 16. o Drug induced asthma o a) aspirin o Since so many patients have overlapping o characteristics and IgE, this classification is o no longer clinically applicable. o Asthma developing early in life has strong o allergic (i.e., extrinsic) component, whereas o developing late in life more often intrinsic (i.e., o nonatopic) 17. o Clinical Course o a) labors to get air in and cant exhale well o b) Bronchodilators and corticosteroids o Status asthmaticus last days to weeks and o does not respond to therapy o a) hypercapnia o i) acidosis may be fatal 18. 19. o COPD o Affects more than 10% of US adult o population and is 4th leading cause of o death in US o Irreversible airflow obstruction of COPD o distinguishes it from asthma (largely o reversible) o Refer to emphysema and chronic o bronchitis (smoking common to both) 20. 21. o 2. Emphysema o Permanent enlargement of airspaces o distal to terminal bronchioles and is
o

accompanied by destruction of their o walls o Overinflation enlargement of airspaces o w/no destruction o a) compensated overinflation due to contralateral pneumonectomy o Morphological definition (based on area o w/in lobule) 22. Types of emphysema a) Panacinar (panlobular) emphysema i) uniformly enlarged acini ii) lower lung zones iii) 1-antitrypsin definciency b) Centrilacinar emphysema i) dilation upstream with normal distal portions ii) more common than panacinar (~ 95% of cases) iii) more common/severe in upper lobes - contain black pigment 23. Centriacinar (cont) iv) in severe disease distal acini may be involved differentialte from panacinar difficult v) seen in heavy smokers, often in association with chronic bronchitis c) Distal Acinar (paraseptal) emphysema i) proximal acini normal and distal part most involved ii) upper half of lungs/near pleura iii) associated with spontaneous pneumothorax in the young 24. o d) irregular o i) acini irregularly involved o ii) airspace enlargement with fibrosis o iii) may be the most common o - most autopsies show some scarring from healed inflammation o iv) most are asymptomatic and not clinically significant o Centriacinar and panacinar are the ones o that cause clinical airflow obstruction 25. 26. o Incidence o Common disease (~50% of patients on o autopsy) asymptomatic o Centrilobular most common and severe in o men
o

Clear association with cigarette smoking o 5th and 8th decade becomes disabling o Chronic mild inflammation of lung architecture o a) mediators o Centriacinar and panacinar o a) genesis not completely understood o b) 2 Theories o i) protease-antiprotease imbalance o ii) oxidant-antioxidant imbalance 27. o Protease-antiprotease Hypothesis o a) patients with deficiency of antiprotease, 1-antitrypsin (AAT) have increased tendency to develop emphysema o b) about 1% of all patients have this defect o c) 1-antitrypsin major inhibitor of proteases, particularly elastase d) homozygous patients w/genetic AAT deficiency develop emphysema o e) PiMM normal phenotype for 1- antitrypsin o f) PiZZ common phenotype for AAT deficiency 28. o Sequence: o a) neutrophils (primary source of proteases) sequestered in pulmonary capillaries (lower zones primarily) o i) smoking neutrophils & macrophages o ii) CD8+ T cells cause direct damage and/or recruit macrophages o b) few gain access to alveolar space o c) release of proteolytic enzymes + ROS o d) low levels of 1-antitrypsin damage to elastin (via elastase) o e) emphysema ensues 29. o Oxidant-antioxidant hypothesis o Lung has antioxidants o a) superoxide dismutase o b) glutathione o Smoke has many oxidant species which
o

deplete these normal scavengers o a) activated neutrophils also has ROS o Oxidative injury depletes or destroys o native antiproteases o a) Functional 1- antitrypsin definciency even though blood enzyme is not deficient 30. o Smoking (ROS) and 1 - antitrypsin deficiency SEVERE DAMAGE!!! o Signs: o a) Barrel chested and dyspneic o b) Hyperventilation o c) Normal blood gases (- pink puffers) o Some patients have other pulmonary disease o a) do not hyperventilate and become cyanotic o i) blue-bloaters (chronic bronchitis) o b) death from Right CHF, coma, acidosis, pulmonary fatigue 31. o Other o a) Obstructive overinflation o i) ball valve affect o ii) sub total obstruction by tumor, etc o iii) classic example: o - congenital lobar overinflation o - - hypoplasia? o b) Bullous o i) large subpleural blebs (> 1-2 cm dia) o ii) apical regions o iii) may cause pneumothorax o c) interstitial o i) air o - alveolar tears, etc. 32. 33. o Chronic Bronchitis o Common in smokers (> 90%), passive o inhalation of smoke and smog-ridden cities
o

Definition: Based on clinical grounds. o persistent productive cough for at least 3 o consecutive months and at least 2 consecutive o years o Occurrence: (Increased mucus production) o a) simple chronic bronchitis o i) raises mucoid sputum o ii) airflow not obstructed o b) chronic mucopurulent bronchitis o i) mucus and pus o ii) from secondary infection 34. o c) chronic asthmatic bronchitis o i) bronchitis with intermittent hypersensitivity and asthmatic constriction (difficult to diagnose from atopic asthma) o d) chronic obstructive bronchitis o i) difficult outflow as measured by pulmonary function test o Involves large bronchioles o Small airway disease (bronchiolitis) o resulting from fibroses and inflammation o may lead to (chronic bronchitis) a) increase goblet cells in small bronchi and bronchioles (i.e., bronchiolitis obliterans) 35. o Pathogenesis o Hypersecretion of mucus o a) beginning in large airways o b) smoking single most important causative factor o Eosinophils are lacking o Increased transcription of mucin gene o (MUC5AC) by cigarette smoke o a) enlargement of mucus secreting glands (major consequence) o b) hyperplasia and hypertrophy of mucus secreting cells and increase proportion of mucus to serous secretions. o i) Reid index size of mucus glands 36.
o

o o o o o o o o o o o o o

Cough with sputum may last indefinitely without respiratory obstruction usually accompanies emphysema Some patients develop COPD with outflow obstruction a) hypercapnia b) hypoxemia c) exertional dyspnea d) cyanosis blue-bloaters Progression of disease a) pulmonary hypertension (Cor Pulmonale) b) cardiac failure Metaplasia of bronchial epithelium

37. 38. o Bronchiectasis o Permanent dilation of bronchi and o bronchioles caused by destruction of the o muscle and elastic supporting tissue o resulting or associated with o chronic necrotizing infection. o Is not primary disease but secondary to o persisting infection or obstruction caused o by variety of conditions. o Cough and purulent sputum o Irreversible Bronchial dilation 39. o Most often caused by: o a) bronchial obstruction o i) tumors o ii) foreign bodies o iii) localized to obstructed lung segment o b) congenital or hereditary condition o i) cystic fibrosis o ii) immunodeficiency states (IgE deficiency) repeated infections

iii) Kartagener syndrome (Structural abnormalities of cilia (decreased mucocilliary clearance) o - Sterility in males/females 40. c) necrotizing pneumonia (S. aureus, K. pneumoniae) i) post tubercular bronchiectasis significant cause of morbidity 41. Inflammation and Airway Restriction 42. The major cause of COPD in the United States is cigarette smoking, although it has also been linked to other factors, such as hyperresponsive airways, respiratory infections, and exposure to dust and environmental pollutants. The longer and more heavily people smoke, the more likely they are to develop COPD. 43. COPD is usually a progressive disease that develops slowly, often over the course of decades. In a typical case, a cigarette smoker would experience declining lung function for many years before being diagnosed with COPD and receiving therapy. During those years, while the disease is developing, the lungs are undergoing several changes characteristic of the disease. 44. The bulk of lung tissue is composed of alveoli, or tiny sacs, where the exchange of oxygen and carbon dioxide takes place. One of the primary factors in COPD is emphysema, which occurs when alveoli enlarge and cluster. This process destroys the very sensitive areas where gases are exchanged across thin walls. Emphysema occurs in stages. First, chronic exposure to an irritant, such as cigarette smoke, causes inflammatory cells (such as macrophages and neutrophils) to gather in the airspaces of the lung. These inflammatory cells release chemicals that damage the extracellular matrix of the lung, that is, the proteins that are responsible for providing structure to the lungs. Finally, the ability of the lung to repair the extracellular matrix is compromised, resulting in the coalescence of alveoli into larger, less efficient air chambers. 45. People with emphysema also suffer from airway obstruction, especially in airways less than 2 mm in
o

diameter. A number of changes occur in these airways that aggravate the disease, including hypertrophy of smooth muscle cells, the formation of scar tissue in the airway walls (fibrosis), and the infiltration of inflammatory cells. 46. Underlying all this damage is an inflammatory response mounted by the immune system. In a typical case, cigarette smoke in the lungs would come into contact with macrophages (immune system cells) that normally patrol the airspace. In response to the toxins in the smoke, the macrophages release inflammatory chemicals and begin to recruit more immune-system cells, which in turn release more inflammatory chemicals, as well as enzymes that degrade the extracellular matrix. 47. These changes in the lung are detectable but incremental. Symptoms appear gradually and may actually have been present for many years before a patient seeks medical treatment. Coughing, sputum production, and breathlessness are the characteristic symptoms associated with COPD. Early in the disease, the patients physical examination may even be normal. Later in the disease, however, patients sometimes develop the classic barrel chest associated with COPD. It occurs because residual air is trapped in the lungs, leading to their hyperinflation. In addition, the increased effort required to exhale can produce wheezing, while pursed lips or grunting respirations may signal the patients efforts to keep the airways open by increasing pressure at the beginning of expiration (Lim TK 1996). 48. COPD is a variable condition, with some patients having more symptoms of emphysema, such as breathlessness and air hunger, while others manifest more symptoms of chronic bronchitis or asthma, such as wheezing and air trapping (Kasper DL et al 2005). The manifestations of COPD are not limited to the lungs. COPD also puts patients at increased risk of atherosclerosis and osteoporosis. Poor lung function and

poor nutrition may cause muscle weakness, abnormalities in fluid and electrolyte balance, and depression 49. Pathogenesis and Pathophysiology 50. Although cigarette smoking is the most important cause of COPD, only 10-15% of long term smokers develop clinically significant COPD, and approximately half will never develop any symptomatic physiological deficit.28 Why the normal, protective inflammatory response becomes an exaggerated, harmful one in only some smokers is poorly understood, and the precise mechanisms underlying the development of this disorder remain largely unknown. Presumably the inflammation caused by cigarette smoking interacts with other host or environmental factors to produce excess decline in lung function that results in COPD. 51. It is believed that inhaled noxious particles and gases result in lung inflammation, induce tissue destruction, and impair defense mechanisms that serve to limit or repair this damage. This damage leads to the mucous hypersecretion, airway narrowing and fibrosis, destruction of lung parenchyma and vascular changes. In turn, these pathological changes lead to airflow limitation and other physiological abnormalities characteristic of COPD. It is characterized by an increase in neutrophils, macrophages and T-lymphocytes in various parts of the lung. These activated inflammatory cells release a variety of chemical mediators, many of which (e.g. leukotreine B4, interleukin8, and tumour necrosis factor) are capable of damaging lung structures and/or sustaining neutrophilic inflammation. In addition to inflammation, two other processes thought to be important in the pathogenesis of COPD are an imbalance of proteinases and antiproteinases in the lung, and oxidative stress.29-31 Although both these processes may themselves result from ongoing inflammation, they can also arise from genetic (e.g. alpha-1 antitrypsin deficiency) or

environmental (e.g. oxidant compounds in cigarette smoke) factors. 52. The peripheral airways are the major site of airways obstruction in patients of COPD. The structural changes in the airway wall, as well as airway edema and mucus hypersecretion contribute to airway narrowing. The irreversible component of airflow limitation is primarily due to remodelling of the smaller airways; lung parenchymal destruction may also play a role. In advanced COPD, peripheral airways obstruction, parenchymal destruction, and pulmonary vascular abnormalities reduce the lungs capacity for gas exchange, producing hypoxemia and, later on, hypercapnia. Ventilation-perfusion mismatch is the dominant mechanism of hypoxemia in COPD.

Pathophysiology of COPD COPD is a complex syndrome comprised of airway inflammation, mucociliary dysfunction and consequent airway structural changes. 1 Airway inflammation COPD is characterised by chronic inflammation of the airways, lung tissue and pulmonary blood vessels as a result of exposure to inhaled irritants such as tobacco smoke. The inhaled irritants cause inflammatory cells such as neutrophils, CD8+ T-lymphocytes, B-Cells, macrophages and dendritic cells to accumulate.2 When activated, these cells initiate an inflammatory cascade triggering the release of inflammatory mediators such as tumour necrosis factor (TNF), interferon (IFN), matrix-metalloproteinases (MMP-6, MMP9), C-reactive protein (CRP), Interleukins (IL-1, IL-6, IL-8) and fibrinogen. The inflammatory markers sustain the inflammatory process and lead to tissue damage as well as a range of systemic effects. The chronic inflammation is present from the

outset of the disease and leads to various structural changes in the lung which further perpetuate airflow limitation. The chronic inflammatory cascade for COPD is illustrated in Figure 1.

Figure 1: The chronic inflammatory cascade for COPD.2 Adapted from Barnes et al. Lancet, 2004;9438(364):985-996.

Available at http://www.sciencedirect.com/science/journal/01406736.

Structural changes Airway remodelling in COPD is a direct result of the inflammatory response associated with COPD and leads to narrowing of the airways. Three main factors contribute to this: peribronchial fibrosis, build up of scar tissue from damage to the airways and over-multiplication of the epithelial cells lining the airways.3,4 Emphysema is also associated with loss of lung tissue elasticity, which occurs as a result of destruction of the structures supporting and feeding the alveoli. This means that the small airways collapse during exhalation, impeding airflow, trapping air in the lungs and reducing lung capacity (Figure 2).

Figure 2: Airflow limitation in COPD.

Mucociliary dysfunction Smoking and inflammation enlarge the mucous glands that line airway walls in the lungs, causing goblet cell metaplasia and leading to healthy cells being replaced by more mucussecreting cells.5 Additionally, inflammation associated with COPD causes damage to the mucociliary transport which is responsible for clearing mucus from the airways. Both these factors contribute to excess mucus in the airways which eventually accumulates, blocking them and worsening airflow (Figure 3).

Figure 3: Mucociliary effects in the COPD airway.

References 1. Agusti. A. COPD, a multicomponent disease: implications for management. Respir Med 2005;99:670-682. 2. Barnes PJ, Hansel TT. Prospect for new drugs for COPD. Lancet, 2004;364:985-996. 3. Chung KF. The role of airway smooth muscle in the pathogenesis of airway remodelling in COPD. Proc Am Thorac Soc 2005;2:347-354.

4. Laperre TS, Sont JK, van Schadewijk A, et al. Smoking cessation and bronchial epithelial remodelling in COPD: a crosssectional study. Respir Res 2007;8:85-93. 5. Danahay H, Jackson AD. Epithelial mucus-hypersecretion and respiratory disease. Curr Drug Targets Inflamm Allergy 2005;4:651-664.
Chronic obstructive pulmonary disease (COPD) is a pathology characterized in terms of pathophysiology, by chronic airflow obstruction, which is caused by the association between chronic obstructive bronchitis and emphysema, with the predominance of one or another. Airway obstruction has the following characters:

It is chronic, meaning that the respiratory flow variations are not important during a period of several months; Is irreversible or partially reversible under the action of bronchodilator medication; It is progressive, with a slow natural evolution to aggravation.

COPD is the fourth leading cause of mortality worldwide, its prevalence is in constant growth. COPD is more common in men than in women, which is explained by the greater number of men who smoke.

Damage to the endothelium impairs the mucociliary response that clears bacteria and mucus. Inflammation and secretions provide the obstructive component of chronic bronchitis. In contrast to emphysema, chronic bronchitis is associated with a relatively undamaged pulmonary capillary bed. Emphysema is present to a variable degree but usually is centrilobular rather than panlobular. The body responds by decreasing ventilation and increasing cardiac output. This V/Q mismatch results in rapid circulation in a poorly ventilated lung, leading to hypoxemia and polycythemia. Eventually, hypercapnia and respiratory acidosis develop, leading to pulmonary artery vasoconstriction and cor pulmonale. With the ensuing hypoxemia, polycythemia, and increased CO2 retention, these patients have signs of right heart failure and are known as "blue bloaters." Pathophysiology of COPD COPD is a chronic lung disease caused due to the narrowing and/or blockage of the airways or alveoli. The pathophysiology of COPD reveal the structural changes of the airways, dysfunction of cilia and inflammatory responses.

Chronic obstructive pulmonary disease (COPD) encompasses a group of lung conditions that cause narrowing of the airways, leading to the shortness of breath and difficulty in breathing. It is a progressive disease in which symptoms worsen with time. Chronic bronchitis and emphysema are the most common forms of COPD. In chronic bronchitis, the lining of the airways is thickened as a result of constant irritation, which leads to an excess secretion of mucous. In case of emphysema, the elasticity of mucous lining is reduced, resulting in the obstruction of airflow. Majority of the cases of chronic obstructive pulmonary disease are caused due to long-term smoking. Inhalation of lung irritants such as pollens, air pollutants, dust, smoke and other chemicals may also contribute to developing COPD. The early signs of COPD are chronic cough and coughing up mucous secretions. Other symptoms of COPD may include

breathing difficulty, chest tightness or discomfort, wheezing and other respiratory symptoms. A patient with COPD is more susceptible to constant chest infections than a healthy person. COPD is one of the leading causes of illness and death in many countries. Pathophysiology of COPD The pathophysiology of COPD is very complex and is not clearly identified as yet. A resistance to the airflow can be attributed to many factors such as mucociliary disorders, inflammatory responses and structural changes. In short, the blockage and/or narrowing of the airways may be caused due to loss of elasticity of the airways, damage or inflammation in the walls of the airways, secretion of excess mucous in the airways and decrease in the surface area for the exchange of air. According to medical studies, it is revealed that chronic inflammatory responses of the airways is the major contributing factor to the development of COPD. It is stated that inflammatory responses resulted from COPD and those from asthma are different. COPD associated inflammation induces the production of neutrophils, macrophages and lymphocytes. These cells along with reactive oxygen and proteases enzymes are responsible for causing damage to the airways (alveoli). When smoking, the number of neutrophils is increased than the normal level. Gradually, the airways are thickened, excess smooth muscles and connective tissues are produced by the

body, leading to fibrosis in the airways. All these inflammatory responses are caused due to prolonged cigarette smoking and at times, frequent exposure to lung irritants. The pathophysiology of COPD thus includes the narrowing of the airways, damage to the lungs and other supportive tissues, hyperactivity of the lungs, dysfunction of the cilia in the airways and constant damage of the alveolar walls. As the COPD condition progresses, patients of COPD manifest wheezing, productive cough, difficulty in clearing alveoli and shortness of breath (dyspnea). As the pressure in the chest increases, the patient faces more difficulty during exhaling air, rather than inhalation. There is no cure for COPD, as damage in the airways cannot be reversed back. However, there are certain treatment options in order to manage the breathlessness symptoms. The effective treatment of COPD is to quit smoking; one can opt for nicotine replacement therapy to cope up the withdrawal symptoms. Other treatment options of COPD include oxygen therapy (if necessary) and medications such as corticosteroids and antibiotics (for chest infection). Pathophysiology of COPD By Elizabeth Morgan Ads by Google

Siemens answers: Early detection & prevention: Molecular Medicine. www.siemens.com/answers Buy Oxygen Concentrator Rs 27000 Only Offer valid till 7th september www.indiamart.com/taurus-healthcare Best Asthma Treatment Effective Homeopathic treatment for asthma at Dr. Batra's www.drBatras.com/Asthma+attack COPD, or chronic obstructive pulmonary disease, is a progressive inflammatory disease connecting the airways, lung parenchyma, and vasculature. It causes the damage and remodeling of the airways and lung tissue. Proper functioning of lungs is rejected continuously by COPD. Over a period of time, these changes result in more severe conditions such as pulmonary hypertension and right heart failure. The precise pathophysiology of COPD is unidentified. The inflammatory process is a driving aspect in the pathophysiology of COPD. Recent verification suggests that the inflammatory response results in a number of effects, including an arrival of inflammatory cells such as macrophages, neutrophils and lymphocytes. Thickened airways and structural changes such as increased smooth muscle and fibrosis may also be manifested. Cigarette smoking causes an inflammatory response in the lungs. This response does not cease with the removal of the stimulus, but progresses for an unlimited period of time. COPD is a subset of obstructive lung diseases that includes cystic fibrosis, bronchiectasis and asthma. Degeneration and destruction of the lung and supporting tissue are characteristic of COPD. These processes result in emphysema, chronic bronchitis, or both. Emphysema begins with a small airway disease and progresses to alveolar destruction, with a predominance of small airway narrowing and mucous gland hyperplasia.

The pathophysiology of COPD is not entirely understood. Chronic inflammation of the cells lining the bronchial tree plays a major role. Smoking and, seldom, other inhaled irritants, perpetuates an ongoing inflammatory response that results in airway narrowing and hyperactivity. Airways become edematous, excessive mucus production occurs and cilia function weakly. Patients face increasing difficulty clearing secretions with disease progression. Accordingly, they develop a chronic productive cough, wheezing and dyspnea. How Our Lungs Work The chest cavity contains two lungs - one on the right side and one on the left side of the chest. Each lung is composed of sections, called lobes. The right lung has three lobes and the left, only two. Each lobe is further divided into segments and lobules. The space between the lungs that contains the heart, great vessels and esophagus is called the mediastinum. A set of tubes, or airways, delivers oxygen to each section of the lung. As we breathe air in through our nares, the oxygen passes through the nasopharynx (area of throat behind nose) and the oropharynx (area of throat behind mouth). These structures make up the upper airways and are lined with ciliated mucosa, a protective, moist tissue layer containing tiny hair-like projections which help warm and humidify inhaled oxygen and remove foreign particles from it. Cilia also help rid the airways of excess mucus. Oxygen then passes through the larynx (voice-box), a structure that connects the upper and lower airways, down through the trachea (windpipe), which connects the larynx to the bronchi.

The bronchi are larger airways of the lungs which subsequently terminate into smaller airways called bronchioles. Together, the bronchi and bronchioles make up the bronchial tree. The bronchioles end in alveolar ducts which lead to alveolar sacs made up of millions of alveoli. The alveoli are the primary, gasexchanging structures in the lungs where oxygen enters the blood and carbon dioxide is removed. To learn more about how your lungs function, take a tour of the respiratory system. The Purpose of the Lungs The lungs are made up of spongy, elastic fibers which allow them to stretch and constrict when we breathe in and out, respectively. The purpose of the lungs is twofold: To deliver oxygen (O2) to the cells of the body, while removing carbon dioxide (CO2). Oxygen, the body's most important nutrient, helps our bodies turn the food that we eat into energy and, similar to the exhaust on our cars, CO2, the waste product of respiration, is removed from our bodies every time we exhale. Some COPD Tidbits COPD is an umbrella term for a broad classification of disorders, including emphysema, chronic bronchitis, and bronchiectasis. COPD is an irreversible lung disease associated with dyspnea upon exertion and a reduction of airflow both into, and out, of the lungs. Cigarette smoking is the number one cause of COPD,

but secondhand smoke, air pollution and occupational exposure (to coal, cotton, grain) are also important risk factors that contribute to its development. COPD Pathophysiology Not Completely Understood According to the American Academy of Family Physicians, COPD pathophysiology is not completely understood. Playing a major role is that of chronic inflammation of the cells which line the bronchial tree. Smoking, and other airway irritants, perpetuates an ongoing inflammatory response which leads to hyperactivity of the airways, whereby the smooth muscle of the airways constrict and narrow excessively. This causes the airways to become swollen, excess mucus to be produced and the cilia to function poorly. As the disease progresses, COPD patients find it increasing difficulty to clear their secretions, developing a chronic, productive cough, wheezing and dyspnea, the hallmark symptoms of COPD. To further complicate matters, as excess mucus is produced, it begins to pool in the airways, providing a perfect breeding ground for bacteria to multiply. This leads to further inflammation, the formation of diverticula (pouch-like sacs) in the bronchial tree and bacterial infections which occur frequently in COPD patients. What About Airway Obstruction? The airway obstruction that causes a reduction in airflow in COPD patients varies according to the

disease. For example, in chronic bronchitis and bronchiectasis, blockage of the airways is a direct result of excess mucus and secretions. In emphysema, the obstruction to oxygen and carbon dioxide exchange results from the enlargement and destruction of the alveoli. A Word About COPD Treatment The main goal of COPD treatment, no matter which type of COPD, is to improve quality of life, slow the progression of the disease, control COPD symptoms and prevent COPD exacerbation. No other factor carries more weight in slowing the progression of COPD than smoking cessation. Other treatment options include antibiotics (for those with evidence of bacterial infection), inhaled bronchodilators, corticosteroids, aerosol therapy, pulmonary rehabilitation, oxygen therapy (for patients who are hypoxic), flu shots, and, in those suffering from end-stage COPD who meet specific criteria, surgical intervention.

Pathophysiology Chronic obstructive pulmonary disease (COPD) is a mixture of 3 separate disease processes that together form the complete clinical and pathophysiological picture. These processes are chronic bronchitis, emphysema and, to a lesser extent, asthma.

Progression of COPD is characterized by the accumulation of inflammatory mucous exudates in the lumens of small airways and the thickening of their walls. These walls become infiltrated by adaptive and innate inflammatory immune cells. Infiltration of the airways with substances such as polynuclear and mononuclear phagocytes and CD4 T cells increases with each stage of disease progression. This is also true for B cells and CD8 T cells, which organize into lymphoid follicles. This chronic inflammatory process is associated with tissue repair and remodeling that ultimately determines the pathologic type of COPD. It appears that smoking may overcome the body's natural mechanisms for limiting this immune response. This process can continue in susceptible individuals even after smoking cessation. Even if the original noxious insults are removed, COPD is still characterized by progressive accumulation of cells of the immune system, fibrosis, and mucus hypersecretion. The molecular basis for the lung inflammation seen in COPD is still an area of great research and debate, with the potential roles of cytokines, complex autoimmune processes, and immune modulation from chronic infection all under investigation. . The basic pathophysiologic process in COPD consists of increased resistance to airflow, loss of elastic recoil and decreased expiratory flow rate. The alveolar walls frequently break because of the increased resistance of air flows. The hyper inflated lungs flatten the curvature of the diaphragm and enlarge the rib cage. The altered configuration of the chest cavity places the respiratory muscles, including the diaphragm, at a mechanical disadvantage and impairs their force-generating capacity. Consequently, the metabolic work of breathing increases, and the sensation of dyspnea heightens Pathology:

In terms of pathology, COPD is a combination of various degrees of chronic bronchitis with emphysema.

Morphological changes characteristic for COPD occur in the central airways in the peripheral airways, lung parenchyma and vessels in the lungs.

In central airways (trachea and bronchi with diameter greater than 2 mm), inflammatory cells infiltrate the covering epithelium and hypertrophy of mucus-secreting glands and increased number of goblet cells are associated with hypersecretion of mucus.

In peripheral airway (small bronchi and bronchi with diameter less than 2 mm), chronic inflammation cause repeated cycles of aggression and bronchial wall repair. Repair process result is the airway wall remodeling, with increased content of collagen and formation of ciactriceal tissue, leading to lumen narrowing and the occurrence of irreversible airway obstruction.

So, in COPD, airflow obstruction is the result of narrowing of the airways, especially those with diameter less than 2 mm. To these chronic inflammatory narrowing are added viscous mucus hypersecretion, mucosal and submucosal edema and hypertrophy and spasm of bronchial smooth muscles. Pathogenesis:

COPD is characterized by chronic inflammation of the airways, lung parenchyma and pulmonary vessels, caused by exposure to cigarette smoke and other harmful particles. In this process, in different areas of the lung, number and activity of macrophages, T lymphocytes and neutrophils are increased. Activated inflammatory cells release inflammatory mediators like leukotriene B4, interleukin 8 and tumor necrosis factor alpha, able to destroy the lung structures and maintaining the inflammation.

Destruction of lung parenchyma is the major change of COPD, created by an imbalance between proteinases and anti-proteinases in the lung (imbalance between elastase hypersecretion an alpha 1 antitrypsin deficit) in favor of proteinase, and oxidative stress as a consequence of inflammation. Sources of oxidizing agents are phagocytes and the products of combustion of tobacco. Their action is complex: accentuate the enzymatic proteolysis, degrades cellular matrix components, inactivate the anti-proteases system and injures the cells that synthesize the matrix cell.

The defining feature of COPD is irreversible airflow limitation during forced expiration. This may be a result of a loss of elastic recoil due to lung tissue destruction or an increase in the resistance of the conducting airways. The standard measure of COPD is the measure of forced expiratory volume in 1 second (FEV1) and its ratio to forced vital capacity (FVC), FEV1/FVC. Overview To understand COPD, it helps to understand how the lungs work. The air that you breathe goes down your windpipe into tubes in your lungs called bronchial tubes or airways.

Within the lungs, your bronchial tubes branch into thousands of smaller, thinner tubes called bronchioles. These tubes end in bunches of tiny round air sacs called alveoli (al-VEE-uhl-eye). Small blood vessels called capillaries run through the walls of the air sacs. When air reaches the air sacs, the oxygen in the air passes through the air sac walls into the blood in the capillaries. At the same time, carbon dioxide (a waste gas) moves from the capillaries into the air sacs. This process is called gas exchange. The airways and air sacs are elastic (stretchy). When you breathe in, each air sac fills up with air like a small balloon. When you breathe out, the air sacs deflate and the air goes out. In COPD, less air flows in and out of the airways because of one or more of the following:

The airways and air sacs lose their elastic quality. The walls between many of the air sacs are destroyed. The walls of the airways become thick and inflamed. The airways make more mucus than usual, which tends to clog them.

Pathophysiology

Enlarged view of lung tissue showing the difference between healthy lung and COPD It is not fully understood how tobacco smoke and other inhaled particles damage the lungs to cause COPD. The most important processes causing lung damage are:

Oxidative stress produced by the high concentrations of free radicals in tobacco smoke Cytokine release due to inflammation as the body responds to irritant particles such as tobacco smoke in the airway Tobacco smoke and free radicals impair the activity of antiprotease enzymes such as alpha 1-antitrypsin, allowing protease enzymes to damage the lung

Potential role of coagulation and the complement system in COPD; a complex cascade of blood plasma proteins and platelet activation as molecular perturbations associated with patients suffering from COPD Narrowing of the airways reduces the rate at which air can flow to and from the air sacs (alveoli) and limits the effectiveness of the lungs. In COPD, the greatest reduction in air flow occurs when breathing out (during expiration) because the pressure in the chest tends to compress rather than expand the airways. In theory, air flow could be increased by breathing more forcefully,

increasing the pressure in the chest during expiration. In COPD, there is often a limit to how much this can actually increase air flow, a situation known as expiratory flow limitation.[35] If the rate of airflow is too low, a person with COPD may not be able to completely finish breathing out (expiration) before he or she needs to take another breath. This is particularly common during exercise, when breathing has to be faster. A little of the air of the previous breath remains within the lungs when the next breath is started, resulting in an increase in the volume of air in the lungs, a process called dynamic hyperinflation. Dynamic hyperinflation is closely linked to dyspnea in COPD.It is less comfortable to breathe with hyperinflation because it takes more effort to move the lungs and chest wall when they are already stretched by hyperinflation. Another factor contributing to shortness of breath in COPD is the loss of the surface area available for the exchange of oxygen and carbon dioxide with emphysema. This reduces the rate of transfer of these gases between the body and the atmosphere and can lead to low oxygen and high carbon dioxide levels in the body. A person with emphysema may have to breathe faster or more deeply to compensate, which can be difficult to do if there is also flow limitation or hyperinflation. Some people with advanced COPD do manage to breathe fast to compensate, but usually have dyspnea as a result. Others, who may be less short of breath, tolerate low oxygen and high carbon dioxide levels in their bodies, but this can eventually lead to headaches, drowsiness and heart failure. Advanced COPD can lead to complications beyond the lungs, such as weight loss (cachexia), pulmonary hypertension and right-sided heart failure (cor pulmonale). Osteoporosis, heart disease, muscle wasting and depression are all more common in people with COPD.[4]

Several molecular signatures associated to lung function decline and corollaries of disease severity have been proposed, a majority of which are characterized in easily accessible surrogate tissue, including blood derivatives such as serum and plasma. A recent 2010 clinical study proposes alpha 1Bglycoprotein precursor/A1BG, alpha 2-antiplasmin, apolipoprotein A-IV precursor/APOA4, and complement component 3 precursor, among other coagulation and complement system proteins as corrollaries of lung function decline, although ambiguity between cause and effect is unresolved.[37] Chronic bronchitis Main article: chronic bronchitis Lung damage and inflammation in the large airways results in chronic bronchitis. Chronic bronchitis is defined in clinical terms as a cough with sputum production on most days for 3 months of a year, for 2 consecutive years.[13] In the airways of the lung, the hallmark of chronic bronchitis is an increased number (hyperplasia) and increased size (hypertrophy) of the goblet cells and mucous glands of the airway. As a result, there is more mucus than usual in the airways, contributing to narrowing of the airways and causing a cough with sputum. Microscopically there is infiltration of the airway walls with inflammatory cells. Inflammation is followed by scarring and remodeling that thickens the walls and also results in narrowing of the airways. As chronic bronchitis progresses, there is squamous metaplasia (an abnormal change in the tissue lining the inside of the airway) and fibrosis (further thickening and scarring of the airway wall). The consequence of these changes is a limitation of airflow.[14] Patients with advanced COPD that have primarily chronic bronchitis rather than emphysema were commonly referred to as "Blue Bloaters" because of the bluish color of the skin and lips (cyanosis) seen in them.[15] The hypoxia and fluid retention leads to them being called "Blue Bloaters".

In chronic bronchitis, the mucous glands in the lungs become larger. The airways become inflamed, and the bronchial walls thicken. These changes and the loss of supporting alveolar (air space) attachments limit airflow by allowing the airway walls to deform and narrow the airway lumen (the inside of the airway tube). Each case of COPD is unique in the blend of processes; however, 2 main types of the disease are recognized. Chronic bronchitis In this type, chronic bronchitis plays the major role. Chronic bronchitis is defined by excessive mucus production with airway obstruction and notable hyperplasia of mucus-producing glands, as depicted in the images below.

Chronic obstructive pulmonary disease (COPD). Histopathology of chronic bronchitis showing hyperplasia of mucous glands and infiltration of the airway wall with inflammatory

cells. Chronic obstructive pulmonary disease (COPD). Histopathology of chronic bronchitis showing hyperplasia of mucous glands and infiltration of the airway wall with inflammatory cells (high-powered view).

Emphysema Main article: emphysema Lung damage and inflammation of the air sacs (alveoli) results in emphysema. Emphysema is defined as enlargement of the air spaces distal to the terminal bronchioles, with destruction of their walls.[13] The destruction of air space walls reduces the surface area available for the exchange of oxygen and carbon dioxide during breathing. It also reduces the elasticity of the lung itself, which results in a loss of support for the airways that are embedded in the lung. These airways are more likely to collapse causing further limitation to airflow. The effort made by patients suffering from emphysema during exhalation, causes a pink color in their faces, hence the term commonly used to refer to them, "Pink Puffers".There are two types of emphysema: 1- Centrilobular: focal enlargement of air spaces around the bronchioles 2- Panlobular: enlargement of all air spaces (around bronchioles and in the periphery)

Emphysema The second major type is that in which emphysema is the primary underlying process. Emphysema is defined by destruction of airways distal to the terminal bronchiole. Physiology of emphysema involves gradual destruction of alveolar septae and of the pulmonary capillary bed, leading to decreased ability to oxygenate blood. The body compensates with lowered cardiac output and hyperventilation. This V/Q mismatch results in relatively limited blood flow through a fairly well oxygenated lung with normal blood gases and pressures in the lung, in contrast to the situation in blue bloaters. Because of low cardiac output, however, the rest of the body suffers from tissue hypoxia and pulmonary cachexia. Eventually, these patients develop muscle wasting and weight loss and are identified as "pink puffers."