Cardiosphere-derived cells in the primary prevention of sepsis-induced acute lung injury in pigs

TL;DR

This study shows that cardiosphere-derived cells can prevent sepsis-induced lung injury in pigs, suggesting potential for human clinical trials.

Contribution

Demonstrates the preventive efficacy of CDCs in a large animal model of sepsis-induced acute lung injury.

Findings

CDCs improved gas exchange and chest mechanics in septic pigs.

CDCs reduced pulmonary artery pressures and systemic inflammation markers.

Histopathological improvements were observed in lungs treated with CDCs.

Abstract

Acute respiratory distress syndrome (ARDS) prevention in patients coincide with significant risk factors, including severe sepsis. Cardiosphere-derived cells (CDCs) are cardiac stromal/progenitor cells with anti-inflammatory and immunomodulatory effects, which may impact favorably on sepsis-induced acute lung injury (ALI). We used a pig model of sepsis (lipopolysaccharide, LPS) to test whether CDCs, given IV in a preventive paradigm, can ameliorate ALI, relative to placebo. Yorkshire/Landrace hybrid domestic pigs (n = 34) were divided into 3 groups: 1) healthy controls; 2) LPS (60ug/kg) + saline (placebo) group; and 3) LPS + CDC group, with CDCs given in 3 different doses (25, 50 and 100 million cells) after LPS. All pigs were briefly intubated on mechanical ventilation on room air to obtain baseline and 1-hour data and again at the final endpoint of 48hours. Chest mechanics, gas exchange, hemodynamics, blood, bronchoalveolar lavage assays and lung histology were assessed. LPS + CDCs compared with LPS + saline improved: gas exchange (increased hypoxemia ratio [p = 0.03],chest mechanics (respiratory compliance [p = 0.002]; peak and plateau pressures [p = 0.01/0.049]), pulmonary hemodynamics (decreased pulmonary artery pressures [p = .0008]), reduced BAL neutrophils [p = 0.04]), and systemic cytokines, e.g., IL-1, IL-6, IL-18 and IFNγ [p < 0.05]) and serum creatinine (p = 0.02), while alveolar lavage cytokines, e.g., IL-1, IL-6,IL-8,and IL-18 were changed. Histopathology was improved (decreased atelectasis, hemorrhage and arteriolar thickness). In summary, CDCs given in a preventive fashion, attenuated manifestations of LPS-induced ALI. As CDCs have an extensive safety record in hundreds of patients, our findings motivate clinical testing of CDCs for the primary prevention of sepsis-induced ARDS.

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