Activation of pulmonary mitogen-activated protein kinases during cardiopulmonary bypass.
OBJECTIVE
Cardiopulmonary bypass (CPB) produces an inflammatory response associated with pulmonary dysfunction. Mitogen-activated protein kinases (MAPK) have been shown to mediate pulmonary injury. We hypothesized that MAPK are activated during CPB and potentially contribute to lung injury.


METHODS
Pigs were placed on CPB (n = 6) for 90 min, which included 80 min of cardioplegic arrest, followed by 180 min of post-CPB reperfusion. Control animals (n = 6) underwent sternotomy and heparinization only. Lung samples were collected at baseline, during CPB, and during post-CPB reperfusion. Activated forms of extracellular signal-regulated kinases 1/2 (ERK1/2) and p38 were measured by Western blot. Immunohistochemistry was used for tissue localization of activated MAPK. Pulmonary inflammation was determined by histology. Pulmonary edema was estimated by tissue water percentage.


RESULTS
Activated ERK1/2 and p38 were increased after 90 min of CPB compared with controls (3.94 +/- 0.61- and 2.49 +/- 0.15-fold increase, respectively; both P < 0.01). At 180 min of post-CPB reperfusion, ERK1/2 activity was increased by nearly 5-fold compared with controls (P < 0.01), whereas p38 activity returned to baseline levels. By immunohistochemistry, activated ERK1/2 and p38 in the CPB group were localized to alveolar epithelial cells, vascular endothelial cells, and bronchial smooth muscle. Histologic signs of lung injury included leukocyte infiltration in the CPB group. Tissue water percentage was increased with CPB (89.9 +/- 1.5% versus 82.5 +/- 1.0%, CPB versus control, P < 0.05).


CONCLUSIONS
The results of our study demonstrate that CPB increases pulmonary p38 activity and causes sustained activation of ERK1/2. MAPK activation thus may in part mediate the pulmonary inflammatory response and provide a potential site of intervention to prevent pulmonary dysfunction due to CPB.
Khan
Tanveer A
TA
Division of Cardiothoracic Surgery, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA.
Bianchi
Cesario
C
Araujo
Eugenio G
EG
Ruel
Marc
M
Voisine
Pierre
P
Sellke
Frank W
FW
D000818:Animals; D015153:Blotting, Western; D001834:Body Water; D002315:Cardiopulmonary Bypass; D004730:Endothelium, Vascular / Q000201:enzymology; D004789:Enzyme Activation; D007150:Immunohistochemistry; D007249:Inflammation / Q000201:enzymology / Q000473:pathology; D008168:Lung / Q000098:blood supply / Q000201:enzymology* / Q000473:pathology; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009131:Muscle, Smooth, Vascular / Q000201:enzymology; D011650:Pulmonary Alveoli / Q000201:enzymology; D015424:Reperfusion; D013552:Swine; D048051:p38 Mitogen-Activated Protein Kinases
D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases