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Biomarkers of Childhood Asthma / Mechanisms of Action
Asthma is a chronic inflammatory disorder of the airways and is characterized by bronchial hyperresponsiveness. A number of different cell types play a role in the inflammatory response, in particular mast cells, basophils, eosinophils, and T lymphocytes. Investigations of various methods are underway which may more reliably quantify airway inflammation in order to assist with diagnosis and assessment of treatment efficiency.
Role of Eosinophils and Neutrophils (Csoma et al., 2002):
- Increased eosinophils and neutrophils in asthmatic children have been linked to current asthma symptoms and airway hyperresponsiveness
- Acute exacerbations of childhood asthma and the inflammatory response are characterized by infiltration and activation of both eosinophils and neutrophils
- Mast cells and eosinophils generate cysteinyl leukotrienes (cys-LTs: LTC4, LTD4, LTE4), which induce airway smooth muscle contraction, muscous hypersecretion, and alter mucociliar clearance. cys-LTs may also recruit eosinophils into the lung, which leads to the production of additional cyc-LTs and other inflammatory mediators
- Neutrophils release leukotriene B4 (LTB4) in response to activating stimuli, and may be an important neutrophil chemoattractant in asthma as increased levels are found in asthmatic children and adults
Methods for monitoring biomarkers of inflammation:
- Direct methods, such as flexible bronchoscopy and bronchoalveolar lavage, for monitoring airway inflammation are often invasive; blood and urine samples are indirect indices of airway inflammation
- Noninvasive methods, such as induced sputum, exhaled breath condensate, and measures of exhaled nitric oxide are better suited to investigate airway inflammation in childhood asthma.
- As this website is focusing on children, we are highlighting non-invasive methods of monitoring airway inflammation
- If interested in flow cytometry and intracellular cytokine staining methods, see Brown, V., Warke, T.J., Shields, M.D. & Ennis, M. (2003). T cell cytokine profiles in childhood asthma. Thorax, 58: 311-316.
Exhaled Nitric Oxide:
- Exhaled nitric oxide (eNO) is increased in both adults and children with asthma. Inhaled corticosteroids, a common asthma treatment, reduce eNO levels.
- The relation between eNO levels and the percentage of eosinophils in bronchoalveolar lavage fluid (BAL) was recently investigated by Warke and colleagues (2002) in a group of children having elective surgical procedures. eNO levels were measured pre-surgery by restricted breath analysis and the tidal breathing technique; BAL was performed during the surgical procedure
- eNO levels were significantly higher in asthmatic than in non-asthmatic controls as measured by both breathing methods.
- eNO levels, as measured by both breathing methods, correlated with % of eosinophils in BAL fluid in asthmatic children; eNO levels did not correlate with % of mast cells or any other cell type found in BAL fluid
- This study demonstrates that eNO can be used as a non-invasive predictor of airway inflammation, and the two breathing techniques can be useful methods for indirectly assessing eosinophilic airway inflammation in asthmatic children (methods can be successfully performed in children 3-4 years old). These findings have important diagnosis and treatment implications.
Exhaled Breath Condensate:
- Exhaled breath condensate is another non-invasive tool that is being increasingly used. Leukotrienes, prostaglandins, hydrogen peroxide, nitrotyrosine, and 8-isoprostane have all been measured in exhaled breath condensate. It can be successfully performed in children as young as 3-4 years of age.
- Csoma, Kharitonov et al. (2002) investigated whether LTB4 and cys-LTs are detectable in exhaled breath condensates in children with asthma.
- Evidence of the role of cys-LTs in chronic inflammation in asthmatic airways was previously based on indirect evidence from the efficiency of leukotriene receptor antagonists in asthma treatment.
- Results indicated that cys-LTs as well as LTB4 in exhaled breath condensate are significantly increased in children with persistent asthma, even in the steroid-treated children.
- Lung function measurements did not show airway obstruction in the steroid-treated children, however, and eNO levels were comparable to controls. This supports the view that eNO may be a more sensitive marker of asthma control.
- There was no correlation between cys-LT levels and eNO, indicating they may be independent mechanisms of airway inflammation.
- Shahid, Kharitonov et al. (2002) investigated a specific T helper (Th)-2-like mediated immune response (inverse relation between elevated interleukin (IL)-4 and depressed interferon (IFN)-gamma in the airway and blood of children with asthma).
- IFN- gamma and IL-4 were present in the exhaled breath of controls and subjects. Concentrations of IFN- gamma were decreased and IL-4 was elevated in the children with asthma.
- IL-4 concentrations were significantly lower in children on high-dose inhaled corticosteroids compared with those on low doses; overall, the IL-4/IFN- gamma ratio was significantly higher in children with asthma who were not on inhaled steroids compared to those on steroid therapy and controls.
- There was a weak correlation between exhaled IFN- gamma and eNO, but no correlation between IL-4 and eNO, again indicating independent mechanisms
Together, these studies indicate that cytokines present in exhaled breath condensate and exhaled nitric oxide measurements could play a role in the non-invasive monitoring of airway inflammation. Further research is needed to indicate whether they will be of utility in assisting with diagnosis and medication management in children with asthma in future clinical settings.
Possible Molecular and Cellular Mechanisms of Environmental Tobacco Smoke on Respiratory System
- Based on the journal articles reviewed for this website, it appears that exact mechanisms are unknown or unclear
- Not enough is known about molecular and cellular airway and lung function to put together a clear picture
- Not enough is known about health effects of most constituents of ETS, however, some respiratory effects are known
- Acrolein may inhibit neutrophil apoptosis (Finkelstein, 2001)
- Neutrophils involved in inflammation of airways through involvement in the cellular mechanisms involved in airway inflammation
- Antigen (e.g. ETS which contains acrolein) causes B-cell to signal mast cell
- Mast cell signal neutrophils through chemokines which signal neutrophils
- This mechanisim leads to inflammation.
- This inflammation contributes to hyperresponsiveness of airways to allergens
- Reaction to allergens cause an asthma attack
- Acrolein specifically prevented activation of caspase-3 which is a necessary step in neutrophil apoptosis
- The result is exposure to acolein from ETS increase neutrophil recruitment but reduces clearance of these cells