Adenosine Signaling in Asthma

zkt

Member
Current Opinion in Pulmonary Medicine
Adenosine Signaling in Asthma and Chronic Obstructive Pulmonary Disease
Amir Mohsenin, Michael R. Blackburn
Disclosures
Curr Opin Pulm Med. 2006;12(1):54-59.


Adenosine Receptor Agonists and Antagonists in the Treatment of Asthma and Chronic Obstructive Pulmonary Disease
While adenosine-induced mast cell degranulation and bronchoconstriction is an important component of adenosine's role in asthma, it is likely not the complete story. As mentioned earlier, adenosine formation is seen at sites of cellular stress and damage when hypoxia and inflammation are prominent.[36] It is not surprising, therefore, that patients with asthma have been shown to have increased lung adenosine levels.[36,37] There is also evidence that adenosine not only plays a role in allergic asthma, but also in exercise-induced asthma. A recent study from Vizi et al.[38] demonstrated that plasma adenosine levels increase during exercise to a greater degree in asthma patients than in controls, and that this increase in adenosine is related to decreases in forced expiratory volume in 1 s (FEV1). Studies from the same group have recently demonstrated a significant increase in adenosine in exhaled breath condensates (EBCs) of asthma patients during exercise-induced bronchoconstriction with no change being observed in controls.[39] Importantly, this observed increase in EBC adenosine was not a result of the bronchoconstriction itself, as methacholine challenge did not change EBC adenosine values.

Mucus overproduction and secretion are important clinical features of asthma. The etiology of mucus overproduction and secretion is not well understood, and represents an area in which adenosine signaling may also have an impact. Elevations in lung adenosine levels are associated with mucus overproduction in mouse models of chronic lung disease,[40,41] and a recent study suggests that adenosine can upregulate mucin gene expression in human airway epithelial cells.[42**] In this study, McNamara and colleagues demonstrated that adenosine within tracheal aspirates from asthma patients can stimulate the transcription of the mucin genes MUC5AC and MUC2 in a receptor-dependent manner. These findings have important implications for the ability of endogenously generated adenosine to impact mucus production in the airways of asthma patients.

Airway remodeling is an important feature of asthma. Alterations in airway structure such as basement membrane thickening and airway fibrosis can contribute to the chronic alteration of the airways.[2] The mechanisms that regulate such chronic features of asthma are not fully understood. There is increasing evidence suggesting that adenosine signaling can activate features of chronic lung disease[43] and perhaps serve as the regulatory link between cell damage and exacerbation of tissue injury. Adenosine can access signaling pathways that can potentially impact the genesis of chronic inflammation. Ryzhov et al.[44**] have shown that stimulation of the adenosine receptors on human mast cells results in T-helper type 2 (Th2) cytokine expression, namely interleukin (IL)-4 and IL-13, which can promote immunoglobulin (Ig)E synthesis in B lymphocytes. Additionally, engagement of A2BAR on human mast cells is involved in the production and secretion of IL-8[45,46] - an important chemokine which is elevated in the bronchial alveolar lavage fluid and sputum of patients with asthma and COPD.[47-49] Studies using human lung fibroblasts demonstrate that adenosine, via A2BAR, can induce release of IL-6 which, in turn, causes differentiation of the cells into myofibroblasts.[50**] Interestingly, exposure of these fibroblast cells to hypoxia increased A2BAR levels and potentiated the adenosine-induced release of IL-6. Taken together, these findings are significant because they demonstrate that not only can adenosine induce the release of cytokines and chemokines that impact aspects of chronic lung disease, but it is also a participant in the airway remodeling seen in diseased individuals.
 

zkt

Member
[ame=http://en.wikipedia.org/wiki/Adenosine]Adenosine - Wikipedia, the free encyclopedia[/ame]
[ame=http://en.wikipedia.org/wiki/Dipyridamole]Dipyridamole - Wikipedia, the free encyclopedia[/ame]
Aggrenox (Aspirin, Extended-Release Dipyridamole Capsules) Drug Information: Description, User Reviews, Drug Side Effects, Interactions - Prescribing Information at RxList
[ame=http://en.wikipedia.org/wiki/theophylline]Theophylline - Wikipedia, the free encyclopedia[/ame]

I got a clue to all this during a pharmacological cardiac stress test past Tuesday.
The injection of Lexiscan produced bronchial constriction of the nth degree, exactly like what I have been experiencing the past few years but more severe.
So I started looking for adenosine receptor antagonists and found Theophylline, which I knew was sometimes beneficial in COPD and asthma, but didn't know the details and dipyridamole, a component of Aggrenox, an ainticoaggulant, which I have taken befor and switched to Plavix many years ago.
There are clinical trials using adenosine receptor antagonists currently underway. But until that is all sorted out the Rx is persantine, maybe asprin, theophylline, and Nibivolol to control tachycardia. This will necessitate charging the HT meds, of course.
This is pretty much the end of the line as I am able to understand the problem as the echo cardiogram and cardiac stress test came back normal.
I cant get a consult with my primary care nor with cardiology nor pulmonary for 2 months. Havent ruled out pulmonary HT yet but the Sx don't fit. The cardiology consult is to confirm. Primary care Dr. doesn't have a clue. Was afraid to RX PDE5I until this is all sorted out. Doubt seriously that he is up to speed on cAMP effect on bronchial muscle.
Hope this is helpful to someone other than me.
If not it is good place to keep track of my thoughts.
 

Michael Scally MD

Doctor of Medicine
Pulmonary HTN is an uncommon problem. Further, even walking is difficult. This is one of those disorders that use the 6MWT (6 Minute Walk test) for treatment success. Are you having a hard time walking?

You started off the thread with overall info. But, your latest post paints a whole different scenario. A negative echo and stress test. This sounds serious.
 

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