The Adenosinergic A2A Receptor Prevents Exacerbation of Systemic Inflammation and Lung Inflammation Secondary to Polymicrobial Sepsis
BG Belikoff, S Hatfield, F Cracium, JA Buras, M Sitkovsky, DG Remick. Boston University School of Medicine, Boston, MA; Northeastern University, Boston, MA
Background: Endogenous tissue protection mechanisms protect normal tissues from immune cell mediated damage during inflammation. One pathway responsible for the inhibition of activated immune cells is the hypoxia-driven adenosine A2A receptor (R) mediated pathway. A2AR activation in direct inhalation models of acute lung injury prevents immune cell mediated destruction of normal tissues. However, it is unclear whether A2AR's protect pulmonary tissue during systemic inflammation.
Design: Male C57BL/6 mice and A2AR knock out (KO) mice were subjected to cecal ligation and puncture (CLP)-induce sepsis and assessed for systemic inflammation 6 hours post-CLP and lung injury at 24 hours.
Results: Systemic inflammation is exacerbated in A2AR KO mice compared to wt mice. A2AR KO mice had significantly increased serum IL-6 levels vs. wt mice (Table; P<0.001). To determine the effect of A2AR signaling on lung inflammation secondary to systemic infection, bronchoalveolar lavage fluid (BALF) was analyzed for total protein content and total cell count following CLP. Both cell number and total protein were increased in BALF of A2AR KO CLP mice compared to wt CLP mice (Table; P=0.026, P=0.0098, respectively).
A2AR KO Mice Have Increased Inflammation During Sepsis.All groups are expressed as mean +/- SE; n=6-14. *Statistical significance is defined as P<0.05.
|CLP group||*IL-6 (pg/ml)||*BALF total cell count||*BALF protein (ug/ml)|
|Wild type||8,371 1,646||36,710 5,944||108.2 11.45|
|A2AR KO||18,110 2,041||63,750 7,603||157.2 9.708|
Conclusions: Increased systemic inflammation with increased secondary lung inflammation was found in the absence of A2AR signaling during sepsis. These findings suggest that adenosinergic A2AR's function to inhibit exacerbation of pulmonary inflammation during sepsis.
Tuesday, March 10, 2009 1:00 PM
Poster Session IV # 220, Tuesday Afternoon