COPD Flashcards
Normal lung ageing - ECM
With age senile emphysema occurs: alteration in the collagen network leads to alveolar duct dilation
- Lung become more rigid and loose elasticity due to changes in ECM proteins:
• Elastin is degraded
• Fibronectin is enhanced
• Collagen is enhanced
These changes lead to thicker and more brittle alveolar septa –> less oxygen respiration and more easily break causing decreased alveolar surface area due to dilated alveoli (and their ducts)
Normal lung ageing - cells
bronchial epithelium:
- fewer cells
- less mucous
- less cilliary function
alveolar epithelium:
- changes in surfactant
- higher ROS
- less stem cells (type 2)
- more senescence
- more apoptosis
fibroblasts:
- increased senescence
- less eslastin and lamin
- more collagen and fibronectin
leukocytes:
- less phagocytosis (for the phagocytes)
- altered cytokine production
- more ROS
- decreased function for all types (innate and adaptive)
extrapulmonary changes (healthy angeing)
Decreased chest wal compliance
- weaker and smaller muscles
- osteoporosis to spine –> kyphosis
- stiffening of ribcage
Decreased curvature of diaphragm
Decreased effectiveness of cough reflex
COPD - definition
“COPD a common preventable and treatable (not curable) disease is characterized by airflow limitations that is usually progressive and associated with an abnormal inflammatory response of the airways and lungs to noxious particles or gases. Exacerbations and comorbidities contribute to the overall severity in individual patients”.
COPD - associated phenotypes
The two most common conditions of COPD are emphysema and chronic bronchitis, and they have been the two classic COPD phenotypes.
- Emphysema is defined as enlarged airspaces (alveoli) whose walls break down resulting in permanent damage to the lung tissue.
- Chronic bronchitis is defined as a productive cough that is present for at least three months each year for two years.
- -> the hyperproduction of mucus and closure of airways due to inflammation
COPD and inflammation
Chronic obstructive pulmonary disease (COPD) is characterized by lung inflammation that persists after smoking cessation.
• This inflammation is heterogeneous but the key inflammatory cell types involved are macrophages, neutrophils and T cells and epithelial cells (!)
• Most prominent in the walls of the bronchioles
• ROS production is higher in COPD lungs due to persistent bacterial infections and higher instability of Nrf2 (less AOX)
- COPD is also associated with systemic inflammation: linked to cardiovascular disease and othr co-morbidities
inflammatory pathway
- Inhaled irritants activate epithelial cells and macrophages (PRRs)
- They release chemokines (after NFkB and inflammasome activation) to attract neutrophils (and other lymphocytes)
- The attracted lymphocytes, resident macrophages and epithelial cells release proteases (normally very specific but in large amounts will cause emphysema)
• These include neutrophil elastase and matrix metalloproteinases (MMP) 9 and 12 and lead to elastin degradation, emphysema, mucus hypersecretion and fibrosis in the small airways - Epithelial cells release TGF-beta and FGF (after PRR binding to irritant) to stimulate fibroblasts to release connective tissue growth factor –> fibrosis of small airways
- Later adaptive immune cells like Tc, Th1 and Th17 will be present in the lung
• Tc release perforin like NK cells which contributes to alveolar wall destruction emphysema
risk factors
- genes
- infections
- socio-economic status
- aging
- smoke (maternal, secondhand)
- air polution (inside outside)
genetics and COPD
Not all smoker get COPD and not everyone that has COPD smokes/smoked this difference in sensitivity suggests involvement of genetics
SERPINA1 gene codes for alpha-1-antitripsin
• AAT is an acute phase protein so produced mainly in the liver
• Also produced by macrophages, neutrophils, monocytes and epithelial cells (in lungs)
AAT neutralises serine proteases: • Mainly elastase • To smaller extend cathepsin G • Trypsin • Proteinase
The SERPINA1 gene has 3 common alleles: • M = normal • S = mild reduction in AAT serum levels • Z = severe reduction • Null alleles also occur = no protein
When the Z allele is present many of the produced AAT is polymerised prevents it from neutralising the serine proteases –> they start to damage lung tissue
• The polymers also have chemotactic function: increased neutrophils attraction and increased inflammation (and thus lung damage)
telomere attrition and COPD
Telomere attrition has been linked to ROS production, and thus COPD might be correlated to telomere attrition due to the chronic inflammation and ROS production in patients
• When ROS causes damage to the telomere overhang the BER pathway does not have a template to use to fix the damage –> telomeres accumulate damage and shorten over time in an accelerated fashion in COPD patients (due to larger ROS production in lungs)
senescence and COPD
Senescence may be triggered by both cell-intrinsic factors (e.g., telomere shortening) and extrinsic stressors (e.g., oxidative damage) that may lead to accelerated or premature senescence in the lung –> especially type 2 cells
• Cellular markers of senescence, including p16 expression, have been shown in both the airway epithelium and endothelium of subjects with COPD
• Cellular senescence in lung fibroblasts also contributes to the accelerated ageing by dysregulating lung extracellular matrix
epigentic modifications and COPD
Epigenetic modification may affect the expression of multiple inflammatory genes in lungs of patients with COPD due to smoke induced activation of enzymes that regulate epigenetic modifactions:
• Hypermethylation of the SERPINA1 gene causes a lack of AAT and might cause COPD
• Hypomethylation of genes involved in lung remodelling and immune system
Loss of proteostasis
Defective UPS and chaperones due to DNA damage (ROS) causes build up of toxic protein aggregates in lung epithelium in COPD (causes inflammation and apoptosis)
• Cigarette smoke also causes ER stress and worse folded proteins
treatments
- Bronchodilators: this type of medication relaxes the muscles around the airways, which helps to keep them open and makes breathing easier.
• Beta-agonists –> relax the muscles that surround the airways
• Anticholinergics –> block AcH that normally causes the airways to contract - Corticosteroids (Steroids): these drugs help reduce swelling and mucus production in the airways, making it easier to breathe.
- Antibiotics: bacterial infections can lead to exacerbations, like intensified coughing, mucus production, and shortness of breath.
- Supplemental oxygen: if you have severe COPD and low levels of oxygen in your blood, you may require extra oxygen.
- The treatment that you get depends on severity:
• Low severity: advice to stop smoking (life style changes)
• Medium: bronchodilators and/or steroids
• Severe: oxygen therapy
