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Nitrit und die Lunge: Mechanismen und Bedeutung der Reduktion von Nitrit zu Stickstoffmonoxid unter physiologischen und pathophysiologischen Bedingungen in vivo

Antragsteller Dr. Philipp Pickerodt
Fachliche Zuordnung Anästhesiologie
Förderung Förderung von 2011 bis 2018
Projektkennung Deutsche Forschungsgemeinschaft (DFG) - Projektnummer 196780285
 
Erstellungsjahr 2019

Zusammenfassung der Projektergebnisse

The overarching hypothesis of this project was that carbonic anhydrase (CA) is a nitrite (NO2-) reductase in vivo (Hypothesis I) and that strategies applying CA inhibitors and nitrite-based therapies (alone or in conjunction) lead to enhanced pulmonary artery pressure reduction and mitigation of lung injuries via nitric oxide (NO) dependent mechanisms (Hypothesis II). We worked in two animal models (rodents, pigs) to test our hypothesis in lung health and disease. We found that CA is not a nitrite anhydrase in the anesthetized pig and that nitric oxide and pulmonary artery pressure reduction production is not enhanced with combined CA inhibition and sodium nitrite inhalation. These findings make it highly unlikely that the effects of acetazolamide or any other CA inhibitor on pulmonary artery pressure during alveolar hypoxia are to be explained by increased physiological bioavailability of NO. In addition, our findings contradict ex vivo data by others (Aamand et al. 2009) that CA is a nitrite anhydrase with increased nitrite to nitric oxide reduction in vivo. if the pulmonary vasodilatory properties of ACZ – if not mediated by nitrite to NO reduction or CA inhibition – are dependent on lung (alveolar) or blood (pulmonary circulation) hypoxia, we established a model of veno-venous extracorporeal membrane oxygenation (vvECMO). During these experiments, we found that measurements of cardiac output (CO) by thermodilution based techniques are largely influenced by blood recirculating though the extracorporeal circuit. The magnitude of the difference between “true” cardiac out (as measured directly at the aortic root by a ultrasonic flow probe) and cardiac output as measured by the pulmonary artery catheter or trans-pulmonary thermodilution was ~ 2.4- L/min. These data show that measurements of CO during vvECMO may largely falsified by recirculating blood and thus the invasiveness of pulmonary artery catheterization or transpulmonary measurement may by no means justified by relevant information gain during severe acute respiratory distress syndrome (ARDS) treated with vvECMO. In addition to measuring CO at the aortic root and measuring it by classic thermodilution-based methods, we also calculated cardiac output during vvECMO therapy using a novel formula and tested the validity of our calculations. We found that calculation of CO using blood gas analysis and ECMO blood flow overestimated CO as compared to flow measurements at the aortic root, but the mean difference was ~1.5 l/min and thus i) lower and ii) less deviant from the blood flow measured at the aortic root. To test if these findings are relevant in human ARDS, me measured the blood recirculation volume in n= 18 patients treated with vvECMO at our ICU in Berlin. The “Measurement of blood recirculation an adjustment of vvECMO blood flow” (BRAvvE)-study was a single center prospective observational cohort study. We found that in 11 of 18 patients recirculation volume was > 10% of total ECMO blood flow, but that the magnitude of recirculation volume was not directly correlated to absolute ECMO blood flow. In those patients, in wich our pre-defined safety criteria allowed reduction of ECMO blood flow to test the importance of recirculation volume on blood oxygenation and systemic oxygen delivery, decreasing ECMO blood flow to minimize recirculation volume did not cause clinical relevant decreases in SpO2. Interestingly, in none of these patient’s blood flow needed to be increased during the next 3 days. In parallel to these experiments, we followed up on our original hypothesis - based on findings from the first granting period of this project - that NaNO2-- and CA inhibitorbased therapeutic strategies limit lung injury and reduce pulmonary artery pressure in VILI and other acute lung injuries. Thus, we tested if i) inhaled or ii) intravenous application of sodium nitrite reduces acute lung injury (ALI) in the surfactant washout model (pigs). We found no inter-group differences with regards to blood oxygenation, shunt formation or mean pulmonary artery pressure and pulmonary vascular resistance after lung injury Yet, MPAP and PVR were lower as compared to ALI baseline in NaNO2- (high dose i.v.) treated animals. Neither lung edema formation, exhaled nitric oxide nor systemic arterial pressure or resistance and standard respiratory parameters were different between groups. Of relevance, we found that although exhaled nitric oxide was increased after inhalation of NaNO2-, it did not decrease shunt formation nor reduce pulmonary artery pressure in severe lavage-induced lung injury in pigs. Interestingly, exhaled NO in pigs was only about 1/3 higher as compared to gaseous nitric oxide in vitro, indicative of relatively large contribution of non-enzymatic, pH dependent disproportionation of NO2- to NO. Thus, although we found clear evidence for lung protective properties of sodium nitrite in anesthetized rodents, these effects were lost in translation to a large animal model with more relevance to the clinical environment and treatment of human lung injuries. Loss of effect may also be important to our additional findings in the anesthetized rat, testing the effects of carbonic anhydrase inhibition on development of ventilator induced lung injury. We found that rats had higher arterial partial pressures of oxygen, higher arterial blood pressure and less lung edema formation when intravenously treated with the CA inhibitor acetazolamide prior to lung injury.

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