This study shows that SP-D and CC16 are sensitive markers of lung injury and that they can be useful in the setting of cardiac surgery. After CABG, with or without CPB, higher SP-D and CC16 plasma concentrations were associated with more lung injury as assessed by the PaO2/FiO2 ratio and the Aa-O2 gradient early on the ICU. Secondly, higher SP-D and CC16 plasma concentrations after CABG with CPB as compared to OPCAB were found.
The use of lung epithelium specific proteins for describing lung injury is attractive because there are hardly any direct lung injury markers available. To our knowledge only the group of Boven et al
. has utilised this before by measuring CC16 and KL-6 (Krebs von den Lungen-6) for comparing standard CPB with a mini extracorporeal circuit
]. They found that CC16 is a potential biomarker for damage to the alveolar capillary membrane during coronary artery bypass surgery.
There are several hypotheses for explaining the increase of lung epithelium specific proteins, 1) increased permeability of the alveolar capillary membrane, 2) increased production or secretion of these proteins, or 3) decreased renal clearance
The increase in elastase plasma concentration, and its association with ΔSP-D, supports the notion of increased permeability of the alveolar capillary membrane after CPB, a well-described phenomenon caused by an inflammation reaction induced by CPB. This reaction includes activation of the coagulation cascade, the complement system and release of cytokines and adhesion receptors which results in neutrophil-endothelial cell interactions that liberate lung macrophage proteases and neutrophilic enzymes, such as elastase, and produce diffuse tissue injury and increased pulmonary vascular permeability
]. It is well known that elastase has multiple effects on the respiratory epithelium; one of them is the reduction in integrity of the epithelium by cleaving E-cadherin
]. Furthermore, the increase in elastase represents leukocyte activation, which also results in generation and release of reactive oxygen species
]. Reactive oxygen species contribute to a decrease in pulmonary endothelial barrier function by disrupting intercellular tight junctions and redistribution of focal adhesions
Another explanation for higher lung epithelium specific proteins levels might be an increased production or secretion of these proteins in the bronchioli and alveoli after CPB, suggesting a protective function of these lung proteins. This is supported by a three-fold increase of SP-B and SP-C in tracheal aspirates after surgery with CPB in children
]. Literature does not provide reference values for CC16 in bronchoalveolar lavage fluid (BALF) after cardiac surgery. However, Determan et al
. analysed CC16 plasma and BALF concentrations following various surgical procedures to compare the influence of two mechanical ventilation strategies. The authors compared CC16 concentrations directly after intubation and after 5
h of surgery and they found an increase in plasma concentrations but not in BALF concentrations
]. This supports the explanation of increased permeability rather than increased production or secretion.
Whether higher concentrations of lung epithelium specific proteins in the epithelium lining fluid lead to higher plasma concentrations without an increased permeability is not clear. Perhaps only a larger concentration gradient between alveoli and circulation is sufficient for increasing plasma concentrations. Our finding that plasma concentrations of lung epithelium specific proteins returned to baseline 24
h after surgery (paralleled by elastase plasma concentrations) suggests a temporary increase in permeability of the alveolar capillary membrane.
The third possible explanation for increased plasma concentration of lung epithelium specific proteins is decreased renal function. Although there is always some degree of decreased renal function following CABG, about 7% decrease in creatinine clearance in a recent study
], this small decrease is not likely responsible for the increase in SP-D and CC16. Moreover, we found no difference in creatinine clearance between groups, but we did find higher concentrations of lung epithelium specific proteins in the CABG group.
Our second finding was the reduction of lung epithelium specific proteins in the OPCAB group. OPCAB is known to reduce the inflammatory reaction as compared to CABG with CPB
]. Therefore, it may be expected that OPCAB can reduce the occurrence of diffuse tissue injury and a reduced leakage of lung epithelium specific proteins.
The benefits of preventing clinical lung injury and/or dysfunction by OPCAB are still debated; there are studies that report better gas exchange after OPCAB
] and others that do not
]. These results are based on clinical parameters such as the gradient between inspired oxygen concentration and arterial blood oxygen tension. Possibly these parameters are not sensitive enough to detect injury to the alveolar capillary membrane in low risk patients with relatively short operation times. The use of lung epithelium specific biomarkers can be of use, as we were able to show an increase in SP-D and CC16 plasma concentrations in the CABG group. This may explain the finding that OPCAB significantly reduced pulmonary complications such as ventilation time and pneumonia and also a shorter ICU stay and 30
day mortality in a recent study by others
Myeloperoxidase, which is considered as a measure for the activation of neutrophils, increased right after the administration of heparin. This profile of MPO during CPB surgery has been reported before
], and it can be explained by heparin-induced liberation of endothelial bound MPO
]. Moreover, the liberation of MPO seems to be dose dependent as the CABG group reveived three times more heparin than the OPCAB group. Altogether, these observations suggest that MPO might not be a good biomarker for activation of neutrophils in the setting of CPB.