Heart, Lung and Circulation
Original Article| Volume 32, ISSUE 3, P424-433, March 2023

Download started.


Myeloid Progenitor Inhibitory Factor-1 (CCL23) Inhibits Lung Leukocyte Recruitment in a Primate Cardiopulmonary Bypass-Induced Pulmonary Ischaemia Model

Published:January 09, 2023DOI:


      Bone marrow (BM)-derived polymorphonuclear leukocytes (PMNs) and monocytes (MO) induced by cardiopulmonary bypass (CPB) are highly proteolytic and cause postoperative lung injury. Although CCL23/Myeloid progenitor inhibitory factor-1 is a human CC chemokine with potent suppressor effects on myeloid progenitor cells, in vivo inhibitory effects on BM-derived leukocyte kinetics associated with CPB are unknown.


      Two-hour CPB was surgically performed in cynomolgus monkeys and BM-derived leukocytes kinetics were monitored postoperatively by flow cytometry with 5’-bromo-2’-deoxyuridine (BrdU) and cytokine ELISA. Monkeys were given CCL23 (n=5) or saline (control, n=5) intravenously daily for 3 days before BrdU labelling and peripheral blood/bronchoalveolar lavage fluid (BALF) timepoint sampling to reveal BrdU-labelled cells. Levels of cytokines, CD11b, and L-selectin were considered leukocytic activation markers.


      The CCL23 treatment significantly prolonged BM transit of leukocytes (PMNs, 118.4±11.7–95.5±4.1 hours [control]; MO, 91.6±5.0–62.0±3.0 hours [control]) and reduced their alveolar appearance. The BM pool size of MO was decreased by CCL23 but PMNs were unaffected. CD11b, L-selectin expression of PMNs and MO during CPB, and post-surgical increases of interleukin (IL)-6, IL-8, TNF-α, MCP-1, and PMN elastase in the BALF were not suppressed.


      CCL23 treatment slows turnover of PMN and MO progenitors in BM and suppresses their circulatory release and lung recruitment. CCL23 has inhibitory effects specifically on the CPB-induced BM response and could hold value for preventing CPB-induced lung injury.


      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to Heart, Lung and Circulation
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Goto Y.
        • Hiramatsu Y.
        • Ageyama N.
        • Sato S.
        • Kanemoto S.
        • Sato Y.
        • et al.
        Cardiopulmonary bypass induces recruitment of bone marrow-derived leukocytes to the lungs in monkeys.
        Ann Thorac Surg. 2014; 97: 617-622
        • van Eeden S.F.
        • Kitagawa Y.
        • Sato Y.
        • Hogg J.C.
        Polymorphonuclear leukocytes released from the bone marrow and acute lung injury.
        Chest. 1999; 116: 43S-46S
        • Johnson D.
        • Thomson D.
        • Hurst T.
        • Prasad K.
        • Wilson T.
        • Murphy F.
        • et al.
        Neutrophil-mediated acute lung injury after extracorporeal perfusion.
        J Thorac Cardiovasc Surg. 1994; 107: 1193-1202
        • Weiss S.J.
        Tissue destruction by neutrophils.
        N Engl J Med. 1989; 320: 365-376
        • Edmunds Jr., L.H.
        Inflammatory response to cardiopulmonary bypass.
        Ann Thorac Surg. 1998; 66 (S12–6; discussion S25–8)
        • Tang Z.H.
        • Hu J.T.
        • Lu Z.C.
        • Ji X.F.
        • Chen X.F.
        • Jiang L.Y.
        • et al.
        Effect of mild hypothermia on the expression of toll-like receptor 2 in lung tissues with experimental acute lung injury.
        Heart Lung Circ. 2014; 23: 1202-1207
        • Goto Y.
        • Hiramatsu Y.
        • Ageyama N.
        • Sato S.
        • Mathis B.J.
        • Kitazawa S.
        • et al.
        Rolipram plus Sivelestat inhibits bone marrow-derived leukocytic lung recruitment after cardiopulmonary bypass in a primate model.
        J Artif Organs. 2019; 22: 44-52
        • de Amorim C.G.
        • Malbouisson L.M.
        • da Silva Jr., F.C.
        • Fiorelli A.I.
        • Murakami C.K.
        • Carmona M.J.
        Leukocyte depletion during CPB: effects on inflammation and lung function.
        Inflammation. 2014; 37: 196-204
        • Arruda-Silva F.
        • Bianchetto-Aguilera F.
        • Gasperini S.
        • Polletti S.
        • Cosentino E.
        • Tamassia N.
        • et al.
        Human neutrophils produce CCL23 in response to various TLR-agonists and TNFalpha.
        Front Cell Infect Microbiol. 2017; 7: 176
        • Nardelli B.
        • Morahan D.K.
        • Bong G.W.
        • Semenuk M.A.
        • Kreider B.L.
        • Garotta G.
        Dendritic cells and MPIF-1: chemotactic activity and inhibition of endogenous chemokine production by IFN-gamma and CD40 ligation.
        J Leukoc Biol. 1999; 65: 822-828
        • Patel V.P.
        • Kreider B.L.
        • Li Y.
        • Li H.
        • Leung K.
        • Salcedo T.
        • et al.
        Molecular and functional characterization of two novel human C-C chemokines as inhibitors of two distinct classes of myeloid progenitors.
        J Exp Med. 1997; 185: 1163-1172
        • Hwang J.
        • Son K.N.
        • Kim C.W.
        • Ko J.
        • Na D.S.
        • Kwon B.S.
        • et al.
        Human CC chemokine CCL23, a ligand for CCR1, induces endothelial cell migration and promotes angiogenesis.
        Cytokine. 2005; 30: 254-263
        • Kim C.S.
        • Kang J.H.
        • Cho H.R.
        • Blankenship T.N.
        • Erickson K.L.
        • Kawada T.
        • et al.
        Potential involvement of CCL23 in atherosclerotic lesion formation/progression by the enhancement of chemotaxis, adhesion molecule expression, and MMP-2 release from monocytes.
        Inflamm Res. 2011; 60: 889-895
        • de Wynter E.A.
        • Heyworth C.M.
        • Mukaida N.
        • Jaworska E.
        • Weffort-Santos A.
        • Matushima K.
        • et al.
        CCR1 chemokine receptor expression isolates erythroid from granulocyte-macrophage progenitors.
        J Leukoc Biol. 2001; 70: 455-460
        • Shih C.H.
        • van Eeden S.F.
        • Goto Y.
        • Hogg J.C.
        CCL23/myeloid progenitor inhibitory factor-1 inhibits production and release of polymorphonuclear leukocytes and monocytes from the bone marrow.
        Exp Hematol. 2005; 33: 1101-1108
        • Honjo S.
        The Japanese Tsukuba Primate Center for Medical Science (TPC): an outline.
        J Med Primatol. 1985; 14: 75-89
        • Japan PSo
        Guiding principles for animal experiments using nonhuman primates.
        Primate Res. 1986; 2: 111-113
        • Goto Y.
        • Hogg J.C.
        • Suwa T.
        • Quinlan K.B.
        • van Eeden S.F.
        A novel method to quantify the turnover and release of monocytes from the bone marrow using the thymidine analog 5'-bromo-2'-deoxyuridine.
        Am J Physiol Cell Physiol. 2003; 285: C253-C259
        • Shih C.H.
        • Whalen B.A.
        • Goto Y.
        • Hogg J.C.
        • van Eeden S.F.
        Flow cytometric method for enumeration and characterization of newly released polymorphonuclear leukocytes from the bone marrow using 5'-bromo-2'-deoxyuridine.
        Am J Physiol Cell Physiol. 2005; 289: C757-C765
        • Bicknell S.
        • van Eeden S.
        • Hayashi S.
        • Hards J.
        • English D.
        • Hogg J.C.
        A non-radioisotopic method for tracing neutrophils in vivo using 5'-bromo-2'-deoxyuridine.
        Am J Respir Cell Mol Biol. 1994; 10: 16-23
        • Finch C.A.
        • Harker L.A.
        • Cook J.D.
        Kinetics of the formed elements of human blood.
        Blood. 1977; 50: 699-707
        • Apostolakis E.
        • Filos K.S.
        • Koletsis E.
        • Dougenis D.
        Lung dysfunction following cardiopulmonary bypass.
        J Card Surg. 2010; 25: 47-55
        • Asimakopoulos G.
        • Smith P.L.
        • Ratnatunga C.P.
        • Taylor K.M.
        Lung injury and acute respiratory distress syndrome after cardiopulmonary bypass.
        Ann Thorac Surg. 1999; 68: 1107-1115
        • van Eeden S.F.
        • Kitagawa Y.
        • Klut M.E.
        • Lawrence E.
        • Hogg J.C.
        Polymorphonuclear leukocytes released from the bone marrow preferentially sequester in lung microvessels.
        Microcirculation. 1997; 4: 369-380
        • Finn A.
        • Naik S.
        • Klein N.
        • Levinsky R.J.
        • Strobel S.
        • Elliott M.
        Interleukin-8 release and neutrophil degranulation after pediatric cardiopulmonary bypass.
        J Thorac Cardiovasc Surg. 1993; 105: 234-241
        • Suwa T.
        • Hogg J.C.
        • English D.
        • Van Eeden S.F.
        Interleukin-6 induces demargination of intravascular neutrophils and shortens their transit in marrow.
        Am J Physiol Heart Circ Physiol. 2000; 279: H2954-H2960
        • Finn A.
        • Morgan B.P.
        • Rebuck N.
        • Klein N.
        • Rogers C.A.
        • Hibbs M.
        • et al.
        Effects of inhibition of complement activation using recombinant soluble complement receptor 1 on neutrophil CD11b/CD18 and L-selectin expression and release of interleukin-8 and elastase in simulated cardiopulmonary bypass.
        J Thorac Cardiovasc Surg. 1996; 111: 451-459
        • Nakagawa M.
        • Bondy G.P.
        • Waisman D.
        • Minshall D.
        • Hogg J.C.
        • van Eeden S.F.
        The effect of glucocorticoids on the expression of L-selectin on polymorphonuclear leukocyte.
        Blood. 1999; 93: 2730-2737
        • Sato Y.
        • Hiramatsu Y.
        • Homma S.
        • Sato S.
        • Onizuka M.
        • Sakakibara Y.
        Phosphodiesterase type 4 inhibition of activated polymorphonuclear leukocytes in a simulated extracorporeal circulation model.
        J Thorac Cardiovasc Surg. 2003; 125: 172-177