ROLE of LONG – ACTING ß-AGONISTS IN COPD

ROLE of LONG – ACTING ß-AGONISTS IN COPD

Dr. Abdel Hakeim Mohamed

Professor of Chest Cairo University

Chronic obstructive pulmonary disease is defined as chronic airflow obstruction which is due to a mixture of emphysema and peripheral airway obstruction from chronic bronchitis (bronchiolitis)

Airflow limitation in COPD is not fully reversible and is both progressive and associated with an abnormal inflammatory response of the lungs to noxious particles or gases.

Extensive pulmonary damage occurs before the patient is aware of symptoms, such as exertional dyspnea, owing to the slowly progressive nature of the airflow obstruction.

COPD is a serious public health problem. More than half of patients with COPD die within 10 years of diagnosis.

COPD is a progressive disease and mortality rates are related to level of airway obstruction

CAUSATIVE FACTORS

- Cigarette smoking

- Air pollution

- Occupational exposure

- Infection (viral)

- Nutrition

. Low dietary intake of antioxidant vitamins (A,C and E)

. High dietary intake of salt.

. Low intake of unsaturated fatty acids.

- Atopy ?

- Genetic factors

- Low birth weight

The fact that only 10 – 20% of heavy smokers develop COPD may be largely determined by as yet unidentified genetic factors.

UNLIKE ASTHMA : in the early stages of COPD, there may be no sudden episodes of acute chest tightness, dyspnea, or wheeze that might catch the patient's attention.

At first, all that may be noticed is increasing breathlessness during activities

Most patients with COPD have a reversible component to their airway obstruction, as evidenced by an increase in FEV1 following use of an inhaled bronchodilator.

COPD is characterized by a progressive with an FEV1 decline averaging 70 ml / yr. In bronchial asthma, the rate of decrement is only 5 ml / yr.

Long acting ß-agonists (LAßAs) are commonly used as bronchodilators to treat patients with COPD (to treat any airflow obstruction that is reversible)

Prolonged bronchodilation is due to activation of adenylate cyclase in airway smooth muscle, which in turn increases concentration of intracellular cyclic adenosine monophosphate (CAMP)

In addition to prolonged bronchodilation, LAßAs exert other effects that are of clinical relevance in COPD management.

LAßAs can inhibit human airway smooth muscle cell proliferation by inhibiting DNA synthesis in airway smooth muscle cells.

The antiproliferative activity of LAßAs has the capacity to limit the degree of airway remodeling and resulting airflow obstruction.

A recent study has shown that LAßAs reduce the degree of ongoing angiogenesis, a recognized component of airflow obstruction, a property not shared by corticosteroids.

LAßAs affect the force of muscular contraction of the diaphragm and intercostal muscles.

This result in an improvement of respiratory muscle function and increased ventilation. Airway inflammation in COPD is characterized by an increased numbers of neutrophils and Lymphocytes, particularly CD8 + cells.

BAL and induced sputum from patients with COPD contain increased numbers of neutrophils and concentration of the neutrophils chemoattractant, interleukin- 8 (IL-8).

(IL-8 ) is important in COPD pathophysiology because it is produced and released by several types of airway cells including:

- Epithelial cells

- Smooth muscle cells

- Macrophages

- Neutrophils

It is chemoattractant and an activator for neutrophils, and results in a persistent inflammatory cycle. ß-adrenergic receptors are present on neutrophils.

Therefore LAßAs exert effects on these cells leading to reduction in neutrophil number and function. It leads also to reduction of markers of neutrophil activation, myleoproxidase and elastase in BAL and sputum of COPD patients. Neutrophil-endothelial cell adhesion is attenuated by agents as LAßAs that elevate CAMP through inhibition of neutrophils Mac-1 cell surface expression.

In addition to their effects on adhesion, LAßAs inhibit neutrophil accumulation by producing significant reductions in serum E- selection, an adhesion molecule involved in neutrophil recruitment.

LAßAs induce neutrophil apoptosis or programmed cell death through activation of ß-adrenergic receptors and elevation of intracellular cAMP. The action 1f LAßAs contrasts with glucocorticoids, which block apoptosis.

Altogether, these data indicate that LAßAs increase cAMP in neutrophils and therefore inhibit :

- Adhesion

- Accumulation

- Activation

- Induce apoptosis

The end result is a reduction in the number and activation status of neutrophils in airway lumen. Neutrophilic inflammation plays a major role in COPD pathogenesis

Although evidence suggest that, unlike asthma, the epithelium is largely intact in COPD epithelial dysfunction still contributes to the disease.

The epithelium:

. Provides an efficient physical barrier to the airway.

. Provides a first - line defense against irritants and pathogens.

. Preserves the integrity of the airway by facilitating mucociliary clearance with associated coordinated ciliary beating.

. Releases a range of cytokines chemokines that can drive the inflammatory response.

Bacterial infection: Can damage the respiratory epithelium and inactivate cilia directly and indirectly by release of:

. Toxins

. Proteases

. Oxidants

. Defensins

. Other mediators

Bacteria can lead to recruitment of inflammatory cells through release of chemotactic mediators. Inflammatory cells, in turn, can release oxidants, proteases, and toxic peptides.

Acute viral infection can also cause damage of the epithelium, and initiate an inflammatory response. Epithelium, damaged by bacteria or by inflammation, is more easily colonized. Patients with stable COPD are frequently colonized by bacteria such as :

. Unencapsulated H. influenzae

. Streptococcus pneumoniae.

. Moraxella catarrhalis.

LAßAs protect the respiratory epithelium against the effects of microorganisms probably by maintaining intracellular cAMP concentrations, which is known to fall under these conditions.

Reduction in epithelial damage was marked by:

1- Decrease in tight junction separation and resultant exposure of collagen fibers and the basement membrane

2- Preservation of the number of both ciliated and unciliated cells

Reduction in epithelial damage was associated with a reduction in the total number of bacteria adherent to the respiratory mucosa, consistent with the observation that P. aeruginosa and H. influenzae preferentially adhere to damaged epithelial cell surfaces.

If LAßAs decrease bacterial colonization, they may render patients less prone to acute bacterial exacerbations.

A meta - analysis revealed that incidence of respiratory infections in a 16 – week study in COPD patients was 15 % with placebo compared with 8% with LAßAs.

Thus, it appears that LAßAs offer some protection against respiratory infections, perhaps by altering the airway epithelium, and preventing, its ultra structural damage.

Effective mucociliary transport depends on coordinated ciliary beating so that particles (including bacteria) and debris are carried out of the airways.

Maintenance of ciliary beating can attenuate bacterial-induced damage by preventing bacterial adherence .

There by protecting against the development or persistence of infection . Stimulation of epithelial ß-adrenergic receptors by LAßAs can increase ciliary beat frequency (CBF) and mucociliary transport. This effect was sustained for 15 to 20 h.

During exacerbations of COPD the airways are obstructed by mucus as a result of altered production as well as by defective mucociliary clearance.

. Bronchial mucous glands are enlarged.

. Gland ducts are dilated.

. Goblets cells are more numerous.

Membranous bronchioles, < 2 mm in diameter, are important sites of airflow obstruction and show varying degrees of plugging with mucus. In addition, alternations in mucus rheology renders the mucus difficult to transport.

The combination of increased mucus production and altered rheology causes mucus plugging, reduction in airway cross - sectional area and impairment of mucociliary clearance.

LAßAs increased mucociliary transport, and significantly increased mucociliary clearance by 46% compared with placebo in COPD patients after 6 days of treatment

Alteration in the amount and composition of surfactant in COPD may be one of the mechanisms leading to decreased airflow . In addition to its surface activity, airway surfactant:

. Improves bronchial clearance.

. Regulates airway liquid balance.

. Immunomodulatory activities which include suppression of cytokine secretion and lymphocyte proliferation.

Cigarette smoke, an important risk factor for COPD, is known to adversely affect surfactant. In 1992, Lusuardi and colleagues showed that there was a marked decrease ( 6 – 7 fold ) in the total phospholipid content of surfactant in BAL of smokers with COPD compared with healthy subjects.

ß-adrenergic agents enhance secretion of surfactant (phospholipid component phosphatidyl choline) by type ⅠⅠ epithelial cells. LAßAs stimulated phosphatidyl choline (PC), secretion and caused a 50% increase in PC with a duration of action > 6 h. More investigations evaluating the potential benefits of modulating surfactant secretion are needed.

The efficacy of LAßAs in COPD can be explained by more than bronchodilatore effects additional effects on:

. Neutrophils

. Epithelium

. Airway smooth muscle

. Respiratory muscle

Improvement in quality of life