CC BY-NC-ND 4.0 · Journal of Child Science 2017; 07(01): e110-e119
DOI: 10.1055/s-0037-1605579
Original Article
Georg Thieme Verlag KG Stuttgart · New York

Early Macrophage Activation in Preterm Newborns and Respiratory Disease

Anna Milan
1   Department of Women's and Children's Health, Neonatal Intensive Care Unit, Padova University Hospital, Padova, Italy
Elena Priante
1   Department of Women's and Children's Health, Neonatal Intensive Care Unit, Padova University Hospital, Padova, Italy
Daniel Nardo
1   Department of Women's and Children's Health, Neonatal Intensive Care Unit, Padova University Hospital, Padova, Italy
Francesca Tosato
2   Department of Laboratory Medicine, Padova University Hospital, Padova, Italy
Giorgia Pantano
2   Department of Laboratory Medicine, Padova University Hospital, Padova, Italy
Eugenio Baraldi
1   Department of Women's and Children's Health, Neonatal Intensive Care Unit, Padova University Hospital, Padova, Italy
Patrizia Zaramella
1   Department of Women's and Children's Health, Neonatal Intensive Care Unit, Padova University Hospital, Padova, Italy
› Author Affiliations
Further Information

Publication History

09 May 2017

10 July 2017

Publication Date:
08 August 2017 (online)


Monocyte-macrophages have a role in host defense and tissue remodeling. Classically activated (M1) and alternatively activated (M2) macrophages from preterm newborns are analyzed, and the role in acute respiratory distress syndrome (RDS) and bronchopulmonary dysplasia (BPD) is evaluated. Observational study was conducted on the blood samples (BSs) and tracheal aspirates (TAs) collected at 48 to 72 hours of life in preterm newborns. Flow-cytometry was performed to identify monocytes and M1 or M2. Prenatal factors, gestational age, birth weight, acute RDS and BPD were assessed and related to the M1 and M2 levels and M2/M1. One hundred nine subjects were included, and 100 were followed up. M1 and M2 increase and decrease, respectively, according to the gestational age and birth weight. Higher M2 and lower M1 levels in TAs were found after maternal chorioamnionitis. BPD patients have low M1 with high M2 in blood samples (BSs), as well as in tracheal aspirates (TAs). No relation was found between activation pattern and prenatal variables or the RDS grade. The correlation between gestational age or birth weight and M1 could reflect a more mature macrophage system, capable to push undifferentiated macrophages toward the classical pathway. We speculate that adequate early classical macrophage activation could be crucial to protect lungs from post-natal injuries, preventing the development of BPD.


The study is a clinical research, conducted with financial and ethic supports of the University Padova Hospital (AOP 2724P/Nov 2012).

  • References

  • 1 Stoll BJ, Hansen NI, Bell EF. , et al; Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network. Neonatal outcomes of extremely preterm infants from the NICHD Neonatal Research Network. Pediatrics 2010; 126 (03) 443-456
  • 2 Balasubramaniam V, Ryan SL, Seedorf GJ. , et al. Bone marrow-derived angiogenic cells restore lung alveolar and vascular structure after neonatal hyperoxia in infant mice. Am J Physiol Lung Cell Mol Physiol 2010; 298 (03) L315-L323
  • 3 Geissmann F, Jung S, Littman DR. Blood monocytes consist of two principal subsets with distinct migratory properties. Immunity 2003; 19 (01) 71-82
  • 4 Gordon S, Taylor PR. Monocyte and macrophage heterogeneity. Nat Rev Immunol 2005; 5 (12) 953-964
  • 5 Dale DC, Boxer L, Liles WC. The phagocytes: neutrophils and monocytes. Blood 2008; 112 (04) 935-945
  • 6 Chambers SE, O'Neill CL, O'Doherty TM, Medina RJ, Stitt AW. The role of immune-related myeloid cells in angiogenesis. Immunobiology 2013; 218 (11) 1370-1375
  • 7 Varin A, Gordon S. Alternative activation of macrophages: immune function and cellular biology. Immunobiology 2009; 214 (07) 630-641
  • 8 Novak ML, Koh TJ. Macrophage phenotypes during tissue repair. J Leukoc Biol 2013; 93 (06) 875-881
  • 9 Troiani S, Cardona A, Milioni M. , et al. Evidence of impaired microvascular dilatation in preterms with acute respiratory distress syndrome. Int J Cardiol 2017; 241: 83-86
  • 10 Redline RW, Faye-Petersen O, Heller D, Qureshi F, Savell V, Vogler C. ; Society for Pediatric Pathology, Perinatal Section, Amniotic Fluid Infection Nosology Committee. Amniotic infection syndrome: nosology and reproducibility of placental reaction patterns. Pediatr Dev Pathol 2003; 6 (05) 435-448
  • 11 Agrawal V, David RJ, Harris VJ. Classification of acute respiratory disorders of all newborns in a tertiary care center. J Natl Med Assoc 2003; 95 (07) 585-595
  • 12 Ehrenkranz RA, Walsh MC, Vohr BR. , et al; National Institutes of Child Health and Human Development Neonatal Research Network. Validation of the National Institutes of Health consensus definition of bronchopulmonary dysplasia. Pediatrics 2005; 116 (06) 1353-1360
  • 13 Prince LR, Maxwell NC, Gill SK. , et al. Macrophage phenotype is associated with disease severity in preterm infants with chronic lung disease. PLoS One 2014; 9 (08) e103059
  • 14 Gratama JW, Kraan J, Keeney M, Granger V, Barnett D. Reduction of variation in T-cell subset enumeration among 55 laboratories using single-platform, three or four-color flow cytometry based on CD45 and SSC-based gating of lymphocytes. Cytometry 2002; 50 (02) 92-101
  • 15 Novak ML, Weinheimer-Haus EM, Koh TJ. Macrophage activation and skeletal muscle healing following traumatic injury. J Pathol 2014; 232 (03) 344-355
  • 16 Iliodromiti Z, Anastasiadis A, Varras M. , et al. Monocyte function in the fetus and the preterm neonate: immaturity combined with functional impairment. Mediators Inflamm 2013; 2013: 753752
  • 17 Fleer A, Krediet TG. Innate immunity: toll-like receptors and some more. A brief history, basic organization and relevance for the human newborn. Neonatology 2007; 92 (03) 145-157
  • 18 Maródi L. Innate cellular immune responses in newborns. Clin Immunol 2006; 118 (2-3): 137-144
  • 19 Currie AJ, Curtis S, Strunk T. , et al. Preterm infants have deficient monocyte and lymphocyte cytokine responses to group B streptococcus. Infect Immun 2011; 79 (04) 1588-1596
  • 20 Yachie A, Takano N, Ohta K. , et al. Defective production of interleukin-6 in very small premature infants in response to bacterial pathogens. Infect Immun 1992; 60 (03) 749-753
  • 21 Short EJ, Kirchner HL, Asaad GR. , et al. Developmental sequelae in preterm infants having a diagnosis of bronchopulmonary dysplasia: analysis using a severity-based classification system. Arch Pediatr Adolesc Med 2007; 161 (11) 1082-1087
  • 22 Strunk T, Temming P, Gembruch U, Reiss I, Bucsky P, Schultz C. Differential maturation of the innate immune response in human fetuses. Pediatr Res 2004; 56 (02) 219-226
  • 23 Tang MX, Hu XH, Liu ZZ, Kwak-Kim J, Liao AH. What are the roles of macrophages and monocytes in human pregnancy?. J Reprod Immunol 2015; 112: 73-80
  • 24 Brown MB, von Chamier M, Allam AB, Reyes L. M1/M2 macrophage polarity in normal and complicated pregnancy. Front Immunol 2014; 5: 606
  • 25 Cappelletti M, Della Bella S, Ferrazzi E, Mavilio D, Divanovic S. Inflammation and preterm birth. J Leukoc Biol 2016; 99 (01) 67-78
  • 26 Gomez-Lopez N, Romero R, Arenas-Hernandez M. , et al. In vivo T-cell activation by a monoclonal αCD3ε antibody induces preterm labor and birth. Am J Reprod Immunol 2016; 76 (05) 386-390
  • 27 Baraldi E, Filippone M. Chronic lung disease after premature birth. N Engl J Med 2007; 357 (19) 1946-1955
  • 28 Coalson JJ. Pathology of bronchopulmonary dysplasia. Semin Perinatol 2006; 30 (04) 179-184
  • 29 Porzionato A, Zaramella P, Macchi V. , et al. Fluoxetine may worsen hyperoxia-induced lung damage in neonatal rats. Histol Histopathol 2012; 27 (12) 1599-1610
  • 30 Singla DK, Wang J, Singla R. Primary human monocytes differentiate into M2 macrophages and involve Notch-1 pathway. Can J Physiol Pharmacol 2017; 95 (03) 288-294
  • 31 Thébaud B, Abman SH. Bronchopulmonary dysplasia: where have all the vessels gone? Roles of angiogenic growth factors in chronic lung disease. Am J Respir Crit Care Med 2007; 175 (10) 978-985
  • 32 Zhang YH, He M, Wang Y, Liao AH. Modulators of the balance between M1 and M2 Macrophages during Pregnancy. Front Immunol 2017; 8: 120
  • 33 Ménégaut L, Thomas C, Lagrost L, Masson D. Fatty acid metabolism in macrophages: a target in cardio-metabolic diseases. Curr Opin Lipidol 2017; 28 (01) 19-26
  • 34 Marchant EA, Kan B, Sharma AA. , et al. Attenuated innate immune defenses in very premature neonates during the neonatal period. Pediatr Res 2015; 78 (05) 492-497