COPD Flashcards
What are the three theories of lung destruction in COPD?
Protease – Antiprotease theory
Apoptosis (cell suicide) & Autophagy (self digestion)
Autoimmune mediated destruction
Describe the features of vascular remodelling and emphysema in COPD
Theory argues that microvascular destruction (capillaries) contributes to emphysema
– Apoptosis
– Loss of VEGF survival factors
– Autoimmunity
Pulmonary vascular tree in emphysematous patients is not as extensive
What is the clinical evidence of the role of oxidative stress in the pathogenesis of COPD?
Only smokers or those exposed to high pollution get COPD
Increased H2O2 in breath
Increased RNS in smokers leading to increased tyrosine nitrosylation
Increased free carbonyls correlate with disease severity
Increased carbonyl modified protein - locally & systemically
Reduced/impaired anti-oxidant protection correlates with disease severity (eg Nrf-2)
Increased MPO activity with disease severity
COPD Alveolar Macs release increased ROS
Reduced dietary anti-oxidant intake = decreased lung function
Disease progression continues after smoking cessation (trigger point is reached)
What is the mechanistic evidence of the role of oxidative stress in the pathogenesis of COPD?
Oxidative stress enhances inflammatory response in vivo & in vitro
Smoke exposed mice/rats get COPD-like pathology
Chronic Ozone exposure in mice = emphysema
SOD mimetic AEOL10150 reduces cigarette smoke induced lung inflammation in mice
Anti-oxidants protect from Cigarette smoke induced emphysema in mice
What is the therapeutic based evidence for the role of oxidative stress in the pathogenesis of COPD?
Therapeutic based evidence Antioxidant NAC 600mg bid oral = reduced exhaled H2O2
Bronchus study 600mg NAC once daily Oral = less exacerbations BUT no change in lung function
- Much higher doses needed to see clinical impact (e.g. 600mg tid – GSH levels raised by 50%)
Erdosteine 300mg bid = less exacerbations & hospitalisation
Diet rich in anti-oxidants (varied evidence) - reduced COPD mortality risk & improved lung function
What is the role of dendritic cells in COPD?
Increased numbers of dendritic cells around the small airways in COPD
Mature DCs migrate to local lymphatics where stimulation of TLRs leads to CD80-CD86 expression and enhanced cytokine release.
Ideal environment for proliferation of Th1 cytotoxic CD8+ T-cells.
DC-derived IL-6 favours production of effector T-cells by overcoming Treg signals.
Effector T-cells express tissue-specific chemokine receptors for lung homing – linked to disease severity.
Absence of tolerance linked to GOLD3/4.
What is the evidence for autoimmunity in COPD?
More B & T cells (2o lymphoid follicles) More Dendritic cells & Macrophages Increased IL-17 and Th17cells Decreased Treg (CD4+/CD25+) cells Increased auto-antibody & ANA Increased Compliment activation
What is the purpose of bronchodilators in the treatment of COPD?
Target airflow limitation, bronchodilating by altering airway smooth muscle tone
Improve emptying of the lung
Reduce hyperinflation at rest and during exercise
Improve exercise performance
What is the aim of treatment in COPD?
Treatment of COPD is now aimed at immediately relieving and reducing the impact of symptoms, as well as reducing the risk of future adverse health events such as exacerbations.
What is the difference between COPD and asthma?
Different causes Different inflammatory cells Different mediators Different inflammatory consequences Different ‘lung’ sites Different response to treatment
