Inhaled nitric oxide combined with prostacyclin and adrenomedullin in acute respiratory failure with pulmonary hypertension in piglets

Abstract

Our aim was to evaluate if the combined inhalation of both nitric oxide (iNO) and aerosolized prostacyclin or iNO and adrenomedullin (ADM) is more effective in lowering pulmonary arterial pressure (PAP) and improving oxygenation than nitric oxide alone in an animal model with pulmonary hypertension (PH). Moreover, we studied the effect on pulmonary mechanics, surfactant activity, and pulmonary oxidative stress of the different treatments. Twenty-eight piglets with acute lung injury induced by lung lavages with saline were randomized to receive nitric oxide, nitric oxide plus prostacyclin, nitric oxide plus ADM or saline, after. Dynamic compliance, tidal volume, and airway resistance were measured. Lung tissue oxidation was evaluated by measuring total hydroperoxide and advanced oxidation protein products in bronchial aspirate samples. Surface surfactant activity was studied using Capillary Surfactometer. Inhaled nitric oxide combined with prostacyclin or ADM was more effective than nitric oxide alone in lowering PAP and improving oxygenation. Nitric oxide alone or combined increased lung compliance and tidal volume, and decreased airway resistance. No effects on surfactant surface activity and lung tissue oxidation were observed. The treatment with nitric oxide alone or combined with prostacyclin or ADM were effective in decreasing mean PAP and improving oxygenation in a piglet model of PH. However, nitric oxide plus prostacyclin and nitric oxide plus ADM were more effective than nitric oxide alone. The combination of aerosolized prostacyclin and ADM with nitric oxide might have a role in the treatment of infants with PH refractory to nitric oxide alone.

Orotracheal treprostinil administration attenuates bleomycin‐induced lung injury, vascular remodeling, and fibrosis in mice

“…Lung function was preserved at most time points, with lung mechanics of the prostacyclin analogue‐treated group in early inflammatory phase (days 7, 14) approaching control values. Our results are supported by previous findings reporting the effects of inhaled PGI 2 on lowering airway resistance and improving lung compliance in a PH model 27 . Additionally, another PGI 2 analogue was recently shown to maintain lung function in BLM‐challenged mice 28 and COX 2 ‐derived prostacyclin managed to prevent BLM‐induced pulmonary fibrosis using genetically modified mice 10 .…”

“…Our results are supported by previous findings reporting the effects of inhaled PGI 2 on lowering airway resistance and improving lung compliance in a PH model. 27 Additionally, another PGI 2 analogue was recently shown to maintain lung function in BLM-challenged mice 28 and COX 2 -derived prostacyclin managed to prevent BLM-induced pulmonary fibrosis using genetically modified mice. 10 Overall, accumulative data support that administration of prostanoids can be beneficial to lung function, a phenomenon also supported by our findings.…”

Inhaled Nitric Oxide for the Treatment of Preterm Infants with Respiratory Distress Syndrome

“…It is likely, therefore, that the beneficial effects of iNO on pulmonary function in this model of chronic lung disease reflect primarily nonsurfactant actions, such as anti-inflammatory [27][28][29][30][31] and antioxidant actions [32][33][34][35] . These results are in agreement with the observation that iNO increases lung compliance and tidal volume, and decreases airway resistance, without affecting surfactant surface activity in an animal model of acute lung injury [56] .…”

Sustained Activation of CLR/RAMP Receptors by Gel-Forming Agonists

“…ADM and ADM2 have organ-protective effects in animals with heart failure, myocardial infarction, stroke, resistant hypertension, pulmonary arterial hypertension, preeclampsia, secondary lymphedema, or diabetic ulcer [ 19 , 72 , 73 , 74 , 75 , 76 , 77 , 78 , 79 , 80 , 81 , 82 , 83 , 84 , 85 , 86 , 87 , 88 , 89 , 90 , 91 , 92 , 93 , 94 , 95 ]. These peptides may prevent organ injuries by improving endothelial cell functions and vascular barrier integrity and reducing oxidative stress as well as by improving cardiac output and renal glomerular filtration [ 6 , 72 , 73 , 74 , 83 , 96 , 97 , 98 , 99 , 100 , 101 ].…”

“…In clinical studies, ADM was shown to improve hemodynamics and renal functions in patients with heart failure or pulmonary hypertension [ 72 , 76 , 85 , 86 , 87 , 101 ] and decrease pulmonary vascular resistance and arterial pressure in patients with pulmonary hypertension [ 83 , 87 , 120 ]. However, the development of therapeutic ADM peptides was largely bogged down in the last decade because these peptides have short half-lives (i.e., ~20 min) and may induce compensated tachycardia at pharmacological doses [ 72 , 73 , 74 , 75 , 76 , 83 , 101 ].…”