Angiotensin II in apoptotic lung injury: potential role in meconium aspiration syndrome

Uhal, Bruce D.; Abdul-Hafez, Amal

doi:10.1038/jp.2008.149

Cited by 16 publications

(14 citation statements)

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“…A key event involved in the pathogenesis of PF is apoptotic cell death of the lung parenchyma (43). It is believed that an altered RAS is a potent inducer of pulmonary apoptosis (44,45). Recent data suggest that ACE2 inhibits apoptosis of alveolar epithelial cells to exert antifibrotic effects (46).…”

Section: Discussionmentioning

confidence: 99%

Diminazene Attenuates Pulmonary Hypertension and Improves Angiogenic Progenitor Cell Functions in Experimental Models

Shenoy¹,

Gjymishka²,

Jarajapu³

et al. 2013

Am J Respir Crit Care Med

152

184

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Rationale : Studies have demonstrated that angiotensin-converting enzyme 2 (ACE2) plays a protective role against lung diseases, including pulmonary hypertension (PH). Recently, an antitrypanosomal drug, diminazene aceturate (DIZE), was shown to exert an "offtarget" effect of enhancing the enzymatic activity of ACE2 in vitro. Objectives: To evaluate the pharmacological actions of DIZE in experimental models of PH. Methods: PH was induced in male Sprague Dawley rats by monocrotaline, hypoxia, or bleomycin challenge. Subsets of animals were simultaneously treated with DIZE. In a separate set of experiments, DIZE was administered after 3 weeks of PH induction to determine whether the drug could reverse PH. Measurements and Main Results: DIZE treatment significantly prevented the development of PH in all of the animal models studied. The protective effects were associated with an increase in the vasoprotective axis of the lung renin-angiotensin system, decreased inflammatory cytokines, improved pulmonary vasoreactivity, and enhanced cardiac function. These beneficial effects were abolished by C-16, an ACE2 inhibitor. Initiation of DIZE treatment after the induction of PH arrested disease progression. Endothelial dysfunction represents a hallmark of PH pathophysiology, and growing evidence suggests that bone marrow-derived angiogenic progenitor cells contribute to endothelial homeostasis. We observed that angiogenic progenitor cells derived from the bone marrow of monocrotaline-challenged rats were dysfunctional and were repaired by DIZE treatment. Likewise, angiogenic progenitor cells isolated from patients with PH exhibited diminished migratory capacity toward the key chemoattractant stromal-derived factor 1a, which was corrected by in vitro DIZE treatment. Conclusions: Our results identify a therapeutic potential of DIZE in PH therapy.Keywords: pulmonary hypertension; ACE2; angiogenic progenitor cells; diminazene Pulmonary hypertension (PH) is a life-threatening disease characterized by elevated pressure in the pulmonary arteries and What This Study Adds to the FieldWe show that diminazene, an antitrypanosomal drug, attenuates hemodynamic changes, prevents maladaptive right ventricular remodeling, and enhances pulmonary vasorelaxation in experimental models of PH through activation of ACE2. Furthermore, diminazene improves the functions of APCs obtained from experimental animals and patients with PH. This study identifies a new application for an existing drug, which could be successfully developed for PH therapeutics.

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Section: Discussionmentioning

confidence: 99%

Diminazene Attenuates Pulmonary Hypertension and Improves Angiogenic Progenitor Cell Functions in Experimental Models

Shenoy¹,

Gjymishka²,

Jarajapu³

et al. 2013

Am J Respir Crit Care Med

152

184

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“…A protease inhibitor cocktail prevented the cell detachment induced by meconium suggesting that they may be useful in the treatment and/or prophylaxis [61]. Recent data show that some of the cell death induced by meconium occurs by apoptosis, and therefore has the potential for pharmacologic inhibition through the use of apoptosis blockers or other strategies [62]. …”

Section: Management Of Masmentioning

confidence: 99%

Advances in the Management of Meconium Aspiration Syndrome

Swarnam

Soraisham

Sivanandan

2012

International Journal of Pediatrics

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Meconium aspiration syndrome (MAS) is a common cause of severe respiratory distress in term infants, with an associated highly variable morbidity and mortality. MAS results from aspiration of meconium during intrauterine gasping or during the first few breaths. The pathophysiology of MAS is multifactorial and includes acute airway obstruction, surfactant dysfunction or inactivation, chemical pneumonitis with release of vasoconstrictive and inflammatory mediators, and persistent pulmonary hypertension of newborn (PPHN). This disorder can be life threatening, often complicated by respiratory failure, pulmonary air leaks, and PPHN. Approaches to the prevention of MAS have changed over time with collaboration between obstetricians and pediatricians forming the foundations for care. The use of surfactant and inhaled nitric oxide (iNO) has led to the decreased mortality and the need for extracorporeal membrane oxygenation (ECMO) use. In this paper, we review the current understanding of the pathophysiology and management of MAS.

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“…Although the incidence of severe MAS requiring ventilatory care in the developed world is decreasing, the use of advanced respiratory supports has not altered the duration of mechanical ventilation in some severe cases 1. The pathogenesis of MAS has been reported to include local obstruction of the airway with associated impairment of gas exchange, patchy atelectasis, pulmonary vascular hypertension, pulmonary inflammation, chemical pneumonitis, surfactant inactivation, activation of cytokines and the pulmonary renin‐angiotensin system (RAS), and epithelial cell apoptosis,2–7 Nonetheless there are still some open questions related to these mechanisms. Further studies are crucial in order to improve future management of severe MAS.…”

Section: Introductionmentioning

confidence: 99%

Meconium exposure dependent cell death and apoptosis in human alveolar epithelial cells

Jeng

Soong

Lee

et al. 2010

Pediatric Pulmonology

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Alveolar epithelial cells of neonates are directly exposed to aspirated meconium during meconium aspiration syndrome (MAS). This study was designed to investigate the influence of quantity and time of meconium exposure on the cell viability and caspase activity in type II human alveolar epithelial cells. Human alveolar epithelial cells were incubated with human meconium suspension at different concentrations and for different times. Cell viability and DNA fragmentation were investigated together with caspases activity and the amount of Bcl-2 protein present. We found that cell viability was significantly lower in cells exposed to a higher concentration of meconium. This was also true for cells exposed to meconium for longer. Significantly higher DNA fragmentation, an approximately two- to fivefold increase, was observed in cells that had been exposed to higher (5% and 10%) concentration of meconium compared to those treated with lower (0.1% and 1%) concentrations (P < 0.05). The activity of most apoptotic initiators (caspase 2, 8, 9, 10) and effectors (caspase 3, 6) were found to be significantly higher in cells subject to greater meconium exposure compared to cells with no or minor meconium exposure. The level of Bcl-2 was also found to be significantly decreased in meconium-exposed cells (P < 0.05). In conclusion, human meconium would seem to induce direct cell death as well as caspase-dependent apoptosis in alveolar epithelial cells; the amount and period of exposure to meconium are crucial factors in this process. Thus, removing aspirated meconium should alleviate lung cell damage in neonates and improve the outcome with MAS.

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Angiotensin II in apoptotic lung injury: potential role in meconium aspiration syndrome

Cited by 16 publications

References 66 publications

Diminazene Attenuates Pulmonary Hypertension and Improves Angiogenic Progenitor Cell Functions in Experimental Models

Diminazene Attenuates Pulmonary Hypertension and Improves Angiogenic Progenitor Cell Functions in Experimental Models

Advances in the Management of Meconium Aspiration Syndrome

Meconium exposure dependent cell death and apoptosis in human alveolar epithelial cells

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