SMASE-HPV · Pulmonary hypertension and acute lung injury: Role of sphingomyelinase in the signalling of hypoxia in pulmonary arteries

Pulmonary hypertension and acute lung injury: Role of sphingomyelinase in the signalling of hypoxia in pulmonary arteries

Summary of the project objectives Hypoxic pulmonary vasoconstriction (HPV) is a unique vasoconstrictor response that diverts blood flow away from poorly ventilated lung regions allowing ventilation-perfusion matching. Despite being a highly conserved adaptive physiological mechanism in lung breathing vertebrates that optimises blood oxygen saturation, hypoxia sensing in the lung plays a critical pathophysiological role in a number of pulmonary disorders. Chronic obstructive pulmonary disease (COPD) is associated with chronic hypoxia and can lead in some patients to secondary pulmonary hypertension (PH). Where COPD is confounded with PH, patients have a worse prognosis for survival. In contrast, failure of HPV is often a critical determinant of hypoxemia in sepsis- and trauma-induced lung injury, including the acute respiratory distress syndrome (ARDS). The specific objectives of this project are: 1. to determine the pathophysiological role of neutral sphingomyelinase (nSMase) in the development of PH 2. to identify potential therapeutic targets for the treatment of HPV alterations by excess (PH) 3. to analyse the possible interactions between acid and nSMase signalling in ARDS. These three aims corresponded to five different tasks that had to be accomplished in 36 months. Description of the work performed since the beginning of the project During the 36 months of the project, Dr Laura Moreno has confirmed the role of nSMase and ceramide as modulators of pulmonary vascular tone and their participation in the signalling cascade activated by acute hypoxia in pulmonary arteries from different species (human, rodents and chicken). In addition, we have explored the pathophysiological role of this pathway by analysing the expression levels of nSMase in animal models of pulmonary hypertension and in patients suffering COPD with or without PH as well as the potential therapeutic effects of a chronic treatment with the nSMase inhibitor GW4869 in two models of pulmonary hypertension. The presence of possible polymorphisms in the nSMase2 gene and their contribution to the development of PH has also been analysed in patients with COPD. Finally, we have analysed the role of acid SMase as a candidate to underlie the pulmonary vascular dysfunction (including failure of hypoxic pulmonary voasoconstriction) seen during acute lung injury/ARDS. Description of the achieved results The research activity performed during the first part of this grant has confirmed that both pharmacological modulation and gene silencing of SMase, inhibits all the effects induced by hypoxia in pulmonary arteries: increase in ceramide levels and reactive oxygen species, Kv channel inhibition and vasoconstriction. Furthermore, our findings suggest that this pathway mediates acute oxygen sensing in other vascular tissues, including ductus arteriosus and is conserved between species (chicken, rodents and humans). Further supporting a pathophysiological role of nSMase in the development of pulmonary hypertension, we found a decrease in the messenger ribonucleic acid (mRNA) levels of nSMase in lungs from several animal models of pulmonary hypertension as well as in plasma from patients suffering COPD with pulmonary hypertension. These results were confirmed at the protein level, where a change in the electrophoretic mobility of the nSMase protein was also detected in patients and animals with PH as compared to control subjects. Similarly, we have identified a missense mutation (C617Y) in the SMPD3 gene of 3 of 29 patients with pulmonary hypertension but in none of the subjects without pulmonary hypertension (p=0.16). These data suggest that if this mutation has any role in the development of PH it would affect a very small proportion of these patients. Finally, pilot studies assessing the potential therapeutic benefit of chronic nSMase inhibition (by GW4869) yielded negative results, with no significant improvements on mortality, right ventricular hypertrophy or pulmonary artery pressure. During the last part of this grant, we have assessed the potential role of an acidic form of SMase in mediating HPV failure and pulmonary vascular dysfunction in an endotoxin model of ARDS. Our data confirm that exposure of pulmonary arteries to bacterial SMase induces pulmonary vascular dysfunction, mimicking the effects of lipopolysaccharide (LPS). In addition, inhibition of acid SMase (by D609) prevented LPS induced pulmonary vascular dysfunction. Expected final results and their potential impact HPV is a fundamental physiological process that allows the ventilation-perfusion matching which is still a subject of great interest not only for its physiological and pathophysiological relevance but also because, after more than half a century from its discovery and in spite of the efforts of numerous research groups, its molecular mechanism of action continues being a mystery. The main results derived from this project confirm that activation of nSMase represents a highly conserved mechanism by which specialised vascular tissues sense acute changes in oxygen tension. Furthermore, our findings reveal that disruption of this mechanism has a pathophysiological role in both adult pulmonary hypertension and neonatal pulmonary disorders, including persistent pulmonary hypertension of the newborn. On the other hand, HPV failure is a determinant of the hypoxemia associated to pneumonia, sepsis and/or ARDS. With a high mortality rate, approximately 40 % of all patients and no currently approved pharmacological therapy, ARDS represents a enormous challenge for the medical and scientific community. A large number of treatments have failed to improve survival, including glucocorticosteroids, prostacyclin or nitric oxide. Our preliminary data suggest that therapeutic strategies directed to prevent the actions of acid SMase might improve pulmonary vascular function, preventing hypoxemia and improving the prognosis of these patients. For further information, please visit the project website at: http://www.ucm.es/centros/webs/d524/index.php?tp=Farmacología vascular: factores vasoactivos&a=invest&d=36908.php

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