Systemic oxidative stress associated with lung resection during single lung ventilation

We read with interest the recent report from Misthos et al. [1] describing the relationship between oxidative stress and cardiopulmonary complications following lung resection. These investigators [2] as well as others [3] have previously linked the intentional collapse and subsequent re-expansion of the operative lung with increased plasma and urinary levels of malondialdehyde (MDA), a stable non-specific marker of lipid peroxidation by free radicals. Of particular note in the recent report was the increased incidence of pulmonary hypertension in patients that had undergone intentional lung collapse for ≥120 min. Although the methods for quantification of changes in pulmonary arterial pressure in this clinical population are not described, the data appear qualitatively consistent with observations we have made during an ongoing study in swine focusing upon specific, physiologically active byproducts of perioperative oxidative/nitrosative stress. One of the prominent regulators of pulmonary vasomotor tone is nitric oxide (NO) released from endothelial NO synthase (eNOS) following conversion of l-arginine to l-citrulline + NO in the presence of the essential cofactor tetrahydrobiopterin (BH4) [4]. In the setting of both chronic and acute oxidative stress, BH4 bioavailability is diminished largely as a consequence of oxidization to dihydrobiopterin (BH2) [4]. Although both pterin moieties bind to eNOS with similar affinities, BH2-bound eNOS produces superoxide instead of NO. Accordingly, events that elicit pterin oxidation facilitate the formation of subpopulations of NO-producing and superoxide-producing eNOS, ultimately promoting formation of peroxynitrite (ONOO−). More reactive than either parent radical, ONOO− can illicit further pterin oxidation, amplifying local oxidative stress in a ‘feed forward’ process. Within the circulation, increased BH2 is associated with endothelial dysfunction and has been implicated in the pathogenesis of numerous conditions, including pulmonary hypertension [5]. In an IACUC-approved preliminary study of swine that had undergone left upper lobectomy during single lung ventilation 3 days prior to tissue harvest, we measured BH2 and BH4 levels in both the remaining left lower lobe and non-operated right lung. When compared to the lung of control animals (BH2 = 22 ± 12% of total pterin), lobectomy animals exhibited a rise in BH2 not only in the operative lung (61 ± 8% of total pterin), but also in the non-operative side (51 ± 2%), indicating the stimulus involves more than a local inflammatory response to surgical trauma. Our preliminary observations appear consistent with those of Misthos et al. in that they indicate a systemic oxidative stress response to lung resection that facilitates generation of a byproduct that may modulate pulmonary vasomotor tone. However, in contrast to the findings of Misthos et al. that plasma MDA levels essentially normalize over the first 12 h postoperatively, our data suggest ongoing oxidative stress in the lung parenchyma of both the operative and non-operative hemithorax 3 days postoperatively, possibly due to the fact that BH2 binding to eNOS produces a feed forward perpetuation of superoxide/peroxynitrite production. We look forward to further studies regarding how the oxidative stress response to lung collapse, resection, and re-expansion influence both local and remote aspects of cardiovascular function.