Abstract:
:Hemolysis-associated pulmonary hypertension (HA-PH) is a serious clinical complication of various hemolytic disorders, and pulmonary hypertension (PH) is considered the greatest risk factor for death in patients with a hemolytic disorder. It is now well established that hemolysis causes the release of soluble hemoglobin and arginase from injured erythrocytes into plasma. This leads to nitric oxide (NO) deficiency, oxidative stress and a state of endothelial dysfunction that is associated with clinical development of PH. We challenge this concept and propose that in addition to the NO-arginase pathway, the adenosine deaminase-adenosine pathway plays a significant role in HA-PH and that modulation of this pathway may offer protective/therapeutic effects in HA-PH. Our preliminary data suggest that in HA-PH adenosine deaminase (ADA) is released from injured erythrocytes into plasma and that metabolic conversion of adenosine (ADO) to inosine by ADA reduces extracellular ADO levels. Adenosine, mainly via activation of adenosine A(2A) receptors, mediates a number of biological responses that may reduce hemolysis-induced vasculopathy and the risk of PH. Hypoxia is the strongest stimulus for ADO synthesis, and this increased ADO production counteracts some of the tissue/vascular injury caused by hypoxia itself. Unfortunately, under hypoxic conditions (anemia, vasoconstriction, and vaso-occlusion) in HA-PH, this "ADO negative-feed back" is abolished and the vascular protective effects of ADO are severely diminished by ADA released from injured erythrocytes. We hypothesize that in hemolytic anemia the repetitive release of ADA increases the risk for vaso-occlusive events and PH. We also propose that increase in extracellular ADO levels or activation of adenosine A(2A) receptors attenuates HA-PH, and we suggest further preclinical and clinical investigation of ADA inhibitors and ADO agonists in HA-PH.
journal_name
Med Hypothesesjournal_title
Medical hypothesesauthors
Tofovic SP,Jackson EK,Rafikova Odoi
10.1016/j.mehy.2008.12.043subject
Has Abstractpub_date
2009-06-01 00:00:00pages
713-9issue
6eissn
0306-9877issn
1532-2777pii
S0306-9877(09)00054-1journal_volume
72pub_type
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