Neutrophil adhesion blockade with NPC 15669 decreases pulmonary injury after total cardiopulmonary bypass.
BACKGROUND
Total cardiopulmonary bypass, in an ovine model, is associated with increased pulmonary thromboxane A2 production, cellular sequestration of white cells and platelets, transient pulmonary hypertention, and increased lung lymph flow and lymph protein clearance when compared with respective findings with partial cardiopulmonary bypass. This study evaluates the effect of neutrophil adhesion blockade on lung injury after cardiopulmonary bypass.


METHODS
Two groups of anesthetized sheep were placed on total cardiopulmonary bypass without assisted ventilation. One group of seven sheep was treated before and during total cardiopulmonary bypass with the neutrophil adhesion blocker NPC 15669. A second group of seven sheep did not receive NPC 15669 treatment before total cardiopulmonary bypass. A third group of seven sheep was treated with NPC 15669 before initiation of partial cardiopulmonary bypass with continued assisted ventilation. Aortic occlusion and hypothermia were not used. After 90 minutes all sheep were separated from cardiopulmonary bypass, with resumption of assisted ventilation and pulmonary arterial flow. After 30 minutes the left atrial pressure was elevated mechanically. Hemodynamics, thromboxane A2 levels, platelet levels, and white blood cell and plasma protein concentrations were measured before cardiopulmonary bypass and afterwards at four 15-minute intervals. Samples were taken from the right and left atria simultaneously. Lung lymph protein levels and flow were measured before and after cardiopulmonary bypass at two 30-minute intervals.


RESULTS
In the total cardiopulmonary bypass group not treated with NPC 15669 signs of lung injury developed after cardiopulmonary bypass. Animals treated with NPC 15669 did not manifest a similar degree of lung injury after either partial or total cardiopulmonary bypass. Increased pulmonary vascular resistance did not develop in treated sheep nor did sequestration of platelets or white blood cells occur. Despite the drug, increased pulmonary capillary permeability after total cardiopulmonary bypass persisted, but was reduced.


CONCLUSIONS
Compared with unmodified total cardiopulmonary bypass, blockade of neutrophil adhesion with NPC 15669 reduces, but does not entirely eliminate, lung derangement after total cardiopulmonary bypass.
Friedman
M
M
Department of Surgery, Beth Israel Hospital, Boston, Mass 02215, USA.
Wang
S Y
SY
Sellke
F W
FW
Cohn
W E
WE
Weintraub
R M
RM
Johnson
R G
RG
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology* / Q000627:therapeutic use; D002315:Cardiopulmonary Bypass / Q000009:adverse effects*; D002448:Cell Adhesion / Q000187:drug effects; D007930:Leucine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D008168:Lung / Q000187:drug effects / Q000503:physiopathology; D008171:Lung Diseases / Q000209:etiology* / Q000517:prevention & control; D009504:Neutrophils / Q000187:drug effects* / Q000502:physiology*; D015427:Reperfusion Injury / Q000209:etiology* / Q000517:prevention & control; D012756:Sheep; D013929:Thromboxane B2 / Q000097:blood; D014655:Vascular Resistance
D000894:Anti-Inflammatory Agents, Non-Steroidal; C071244:N-(9H-(2,7-dimethylfluoren-9-ylmethoxy)carbonyl)leucine; D013929:Thromboxane B2; D007930:Leucine