Format

Send to

Choose Destination
J Artif Organs. 2019 Mar;22(1):44-52. doi: 10.1007/s10047-018-1071-0. Epub 2018 Oct 3.

Rolipram plus Sivelestat inhibits bone marrow-derived leukocytic lung recruitment after cardiopulmonary bypass in a primate model.

Author information

1
Department of Thoracic Surgery, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki, 305-8575, Japan. ygoto@md.tsukuba.ac.jp.
2
Department of Cardiovascular Surgery, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki, 305-8575, Japan. yuji3@md.tsukuba.ac.jp.
3
Tsukuba Primate Research Center, National Institute of Biomedical Innovation, Health and Nutrition, Tsukuba, Japan.
4
Department of Thoracic Surgery, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki, 305-8575, Japan.
5
Department of Cardiovascular Surgery, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki, 305-8575, Japan.
6
Medical English Communications Center, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.

Abstract

Cardiopulmonary bypass (CPB) recovery is complicated by lung inflammation from bone marrow (BM)-derived polymorphonuclear leukocytes (PMNs) and monocytes (MO). Although Sivelestat reduces inflammatory mediators and Rolipram inhibits PMN and MO activation, any kinetic effects to improve CPB recovery in vivo are unknown. We hypothesized that intraoperative co-administration of these compounds would reduce CPB-induced lung inflammation through downregulation of PMN and MO recruitment. A 2-h CPB was surgically established in cynomolgus monkeys (n = 13), and BM leukocyte release and lung recruitment were monitored postoperatively by flow cytometry with 5'-bromo-2'-deoxyuridine (BrdU) and cytokine ELISA. Either Sivelestat, Sivelestat plus Rolipram, or saline (control) was administered intraoperatively and both peripheral and perfusion sampling courses revealed BrdU-labeled cells representative of activated leukocyte infiltration. Levels of cytokines CD11b and CD18 were leukocytic activation markers. Sivelestat plus Rolipram attenuated increases in CPB-associated circulating band cells, prolonged BM-transit time (PMN: 121.0 ± 3.7 to 96.2 ± 4.3 h [control], p = 0.012; MO: 84.4 ± 4.1 to 61.4 ± 3.0 h [control], p = 0.003), and reduced their alveolar appearance. CD11b-mediated PMN and MO changes during CPB and the post-surgical increases of Interleukin (IL)-6 and IL-8 in the bronchoalveolar lavage fluid were suppressed. Sivelestat alone increased PMN transit time to 115.8 ± 6.6 h, but monocytes were unaffected. Therefore, Rolipram has additive inhibitory effects with Sivelestat on the CPB-induced activation and release of BM-derived PMNs and MO and their recruitment to the lungs. Co-administration of these compounds could, therefore, hold value for preventing CPB-induced lung injury.

KEYWORDS:

Acute respiratory distress syndrome; Animal model; Cardiopulmonary bypass, CPB; Lung; Stem cells

PMID:
30284168
DOI:
10.1007/s10047-018-1071-0
[Indexed for MEDLINE]

Supplemental Content

Full text links

Icon for Springer
Loading ...
Support Center