Inflammation Research

, Volume 59, Issue 10, pp 889–895 | Cite as

Circulating CD34+ cells are elevated in neonates with respiratory distress syndrome

  • Yuanyuan Qi
  • Liling Qian
  • Bo Sun
  • Chao Chen
  • Yun Cao
Original Research Paper

Abstract

Objectives

The objective of the paper was to determine whether circulating stem-progenitor cells were elevated along with its mobilizing cytokines in neonatal respiratory distress syndrome (RDS).

Subjects and methods

Circulating CD34+ cells were identified by flow cytometry in 41 RDS in comparison with 20 preterm and 14 term controls without diffuse lung diseases. Plasma concentrations of vascular endothelial growth factor, stromal cell-derived factor-1 (SDF-1) and granulocyte–macrophage colony-stimulating factor were determined by immunochemical assays.

Results

The number of CD34+ cells was significantly higher in RDS [25(6–174) cells/μl] than in the preterm controls [15(1–100) cells/μl, P < 0.05]. RDS survivors had higher level of CD34+ cells than non-survivors (P < 0.05), and low CD34+ cell level in RDS was correlated with prolonged duration of ventilation (r = −0.396, P < 0.05). Likewise, the CD34+ cell level was inversely associated with Score for Neonatal Acute Physiology Perinatal Extension II (r = −0.473, P < 0.01) in RDS. Plasma SDF-1 concentration was significantly higher in RDS than in the preterm controls (P < 0.01), and was correlated with the level of CD34+ cells (r = 0.305, P < 0.01).

Conclusions

The level of circulating CD34+ cells was elevated in RDS along with an increase of plasma SDF-1, suggesting CD34+ cells might be involved in reparation of neonatal lung injury.

Keywords

Respiratory distress syndrome CD34+ cells Neonate 

Introduction

Respiratory distress syndrome (RDS) remains an important cause of mortality and morbidity in preterm infants despite widely used exogenous surfactant and lung protective ventilation strategies[1]. Both mechanical ventilation and hyperoxia may contribute to acute and chronic lung injury at alveolar and vascular compartments [2], leading to development of bronchopulmonary dysplasia (BPD). The strategy of prevention or early treatment of BPD is dependent on lung reparation mechanisms for growth and development.

A small number of CD34+ cells normally circulates in peripheral blood, they indirectly reflect hematopoiesis, but are also believed to be involved in tissue repair. In recent years, great attention has been paid to bone marrow-derived cells in the repair of injured lungs of adult animals [3, 4, 5, 6, 7]. More studies revealed that depletion of circulating CD34+ cells should be involved in the pathophysiology of chronic obstructive pulmonary disease [8, 9]. Further studies indicated that the level of circulating endothelial progenitor cells (EPC), which is a subpopulation of CD34+ cells [10], was increased in adult patients with pneumonia [11] and strongly correlated with improved survival from acute lung injury (ALI) [12]. Very recent study showed that extremely preterm neonates with RDS had high levels of CD34+ cells [13], and a decrease in circulating EPC might participate in the development of BPD in neonatal mice [14]. However, it is unclear whether circulating CD34+ stem and progenitor cells contribute to the repair of lung injury and consequently improve the outcome of RDS infants.

Vascular endothelial growth factor (VEGF), stromal cell-derived factor-1 (SDF-1) and granulocyte–macrophage colony-stimulating factor (GM-CSF) play key roles in mobilization of stem and progenitor cells [15, 16, 17]. However, our knowledge of these mobilizing cytokines in the pathological condition during lung injury and reparation in RDS is very limited. The objective of the present study was to determine the level of circulating CD34+ cells along with the plasma concentrations of VEGF, GM-CSF and SDF-1 in RDS during early postnatal life, and to determine whether they are associated with the disease severity and outcome.

Subjects and methods

Patients

Forty-one RDS infants admitted to the neonatal intensive care units (NICU) were enrolled in the study from February 2007 to May 2008. Preterm (n = 20) and term infants (n = 14) without diffuse lung diseases admitted to the neonatal ward during the same period served as controls. RDS was defined as the presence of respiratory distress with increasing need for oxygen during the first 6 h of life, accompanied by a characteristic chest radiograph (such as a reticulogranular pattern, decreased lung volume and air bronchogram), and no signs of sepsis. All the RDS infants received mechanical ventilation or nasal continuous positive airway pressure (nCPAP). Infants were excluded from the study if they had major congenital anomalies, hemolytic jaundice, or blood transfusion which might influence the number of CD34+ cells. The study was approved by the Ethics Committee of Children’s Hospital of Fudan University.

Data collection

Patient information was collected, including demographic characteristics, pregnant history of mother, Score for Neonatal Acute Physiology Perinatal Extension II (SNAPPE-II), duration of assisted ventilation and oxygen support, and length of hospital stay. Death and the presence of common neonatal morbidities, including patent ductus arteriosus (PDA), air leak and BPD, were also documented. The presence of PDA was diagnosed via echocardiogram. BPD was defined as a requirement of supplement oxygen to maintain adequate oxygenation after 28 days of life for an infant of ≥32 weeks’ gestational age (GA), or 36 weeks’ corrected GA for an infant who was born at <32 weeks’ GA [18].

Flow cytometry

Peripheral blood (1 ml) was collected in a tube containing heparin within 72 h after birth. About 0.1 ml blood was used for cytometric analysis. The expression of cell surface antigen CD34 was analyzed by the gating strategy of a modified ISHAGE protocol (Fig. 1) [19]. Briefly, 50 μl of peripheral blood was incubated with 10 μl of PE-conjugated anti-human CD34 and 10 μl of FITC-conjugated anti-human CD45 MAb (BD Biosciences, San Jose, CA, USA) at room temperature for 20 min. Anti-isotype antibody served as a control. Subsequently, red cells were lysed, the remainders were washed and finally resuspended in 400 μl phosphate-buffered saline. Flow cytometry was performed using a FACSCalibur flow cytometer (BD Biosciences, Mountain View, CA, USA). In total, 70,000 events were acquired. The same trained operator, who was blind to clinical status of the patients, performed all the tests throughout the study. Circulating CD34+ cells were expressed as absolute number and the percentage of total nucleated cells in peripheral blood.
Fig. 1

FACS analysis for circulating CD34+ cells using ISHAGE gating strategy (see Ref [19]). An initial gate (R1) is set on CD45 versus SSC to include CD45+ events (a), then, a second gate (R2) is set on CD34 versus SSC to include CD34+ events (b), R1 and R2 is displayed on and produced R3 to include SSClowCD45low to med cells (c), the “lymph-blast” region (R4) is set to include events no smaller than lymphocytes (d), calculate the events fulfilling the R1, R2 and R3 gate displayed on R4 (e)

Enzyme-linked immunosorbent assay

The plasma levels of VEGF, GM-CSF (Jingmei Biotech, Shenzhen, China) and SDF-1 (R&D Systems, Minneapolis, MN, USA) were assessed using enzyme-linked immunosorbent assay kits. The procedures were performed according to the manufacturer’s instructions.

Statistical analysis

Statistical analysis was performed using SPSS 12.0 for Windows (SPSS, Inc., Chicago, IL, USA). Data were expressed as means and SD or medians and range for continuous variables, or as number and percentage for categorical variables. Comparisons between continuous variables were made using Mann–Whitney U test. Comparisons between categorical data were performed by a two-tailed Pearson Chi square and Fisher’s exact test wherever appropriate. Spearman’s rank correlation test was used for correlation between two parameters. All tests were two-tailed and P values <0.05 were considered statistically significant.

Results

Characteristics of patients

There were no significant differences in GA, birth weight (BW) and white blood cell (WBC) counts between RDS and preterm control groups. The RDS infants had lower 5-min Apgar scores and higher SNAPPE-II (P < 0.01). In addition, the age at sampling was earlier in the preterm control [median (range): 5.5 h (2–48 h)] than in RDS [median (range): 20 h (1–72 h)]. Other perinatal data were similar between groups (Table 1). The CRP values were <8 mg/l in all enrolled infants.
Table 1

Characteristics of RDS and preterm control infants enrolled in the study

Variables

RDS

(n = 41)

Preterm controls

(n = 20)

Term controls

(n = 14)

P value*

Sex, M/F

29/12

13/7

8/6

0.770

GA, mean ± SD (weeks)

32.0 ± 3.0

32.5 ± 2.0

39.6 ± 1.8

0.381

BW, mean ± SD (g)

1752 ± 554

1866 ± 546

3169 ± 602

0.402

Fetal distress, n (%)

7 (17.1)

3 (15.0)

2 (14.3)

1.000

Multiple births, n (%)

5 (12.2)

3 (15.0)

1 (7.1)

1.000

Cesarean section, n (%)

10 (24.4)

5 (25.0)

2 (14.3)

1.000

Premature rupture of placenta > 24 h, n (%)

5 (12.2)

2 (10.0)

1 (7.1)

1.000

Gestational diabetes

2 (4.9)

1 (2.4)

0

1.000

White blood cells, mean ± SD, ×109/l

20.0 ± 9.2

17.3 ± 9.2

21.6 ± 4.2

0.160

 Neutrophils, mean ± SD (%)

54.6 ± 20.3

55.1 ± 12.5

67.2 ± 8.4

0.749

 Lymphocyte, mean ± SD (%)

33.4 ± 17.8

32.9 ± 10.1

22.3 ± 6.0

0.794

Age at sampling, median (range) (h)

20 (1–72)

5.5 (2–48)

21 (2–72)

0.001

Apgar score at 5 min, median (range)

8 (2–10)

9.5 (5–10)

8.9 (7–10)

0.004

SNAPPE-II, median (range)

14 (5–47)

5 (0–18)

0 (0–8)

0.000

GA gestational age, BW birth weight, SNAPPE-II Score for Neonatal Acute Physiology Perinatal Extension II

*P value for RDS versus preterm control

In RDS, 23 received mechanical ventilation and 18 nCPAP. Initial PaO2/FiO2 was 174.4 ± 58.8 mmHg. Twenty-three infants received at least one dose of surfactant. Median duration of assistant ventilation and oxygen supplement in RDS was 79 (range 23–857) and 139 (range 23–1,115) h, respectively. Complications in RDS include PDA (n = 9, 22.0%), air leak (n = 2, 4.9%) and BPD (n = 3, 7.3%). Three infants died prior to discharge. One infant died of pulmonary hemorrhage and circulatory failure at 6 days postnatal. The other two infants died of progressive and intractable respiratory failure with survival time of 3 and 6 days, respectively.

Of 20 preterm control infants, 11 were admitted to the neonatal ward for prematurity only. In addition, four had apnea of prematurity, two neonatal asphyxia, one cleft palate, one was hypoglycemic, and one had neonatal polycythemia. The term control infants included four pneumothorax, two neonatal asphyxia, two cleft palate, one transient tachypnea, one swallowing syndrome, one fetal distress, one small for GA, one face presentation and one ventricular septal defect.

Circulating CD34+ cells

The numbers of CD34+ cells in RDS, preterm and term control infants are illustrated in Fig. 2. The RDS infants had a significantly higher number of CD34+ cells [median (range): 25 (6–174) vs. 15 (1–100) cells/μl; P < 0.05] than preterm controls. Median (range) numbers of CD34+ cells in the term control were 9 (2–22) cells/μl. Similarly, there was also difference in the percentage of CD34+ cells between RDS and the preterm controls [median (range): 0.14% (0.04–0.50%) vs. 0.08% (0.01–0.27%); P < 0.05]. The number of CD34+ cells was 53 (6–174) and 26 (7–85) cells/μl in infants receiving nCPAP and mechanical ventilation, respectively.
Fig. 2

Numbers of CD34+ cells from term control, preterm control and RDS infants. Values in boxplot are expressed as median, 25th, and 75th percentiles. P < 0.05, RDS versus preterm controls

Relationship of CD34+ cells to demographic factors and outcome in RDS infants

An inverse correlation was observed between CD34+ cell level and SNAPPE-II on admission in RDS (r = −0.473, P < 0.01), but not in the controls. The median number of CD34+ cells was higher in RDS survivors than in the non-survivors [26 (6–174) vs. 4 (8–11) cells/μl; P < 0.05), as was reflected by a trend of low level of CD34+ cells with prolonged duration of ventilation (r = −0.396, P < 0.05).

The number of CD34+ cells was inversely related to the age at sampling. No relationship was found between the number of CD34+ cells and other demographic factors (Table 2). No correlation was noted between the percentage of CD34+ cells and the WBC counts (r = 0.017, P = 0.917). There was no significant difference in the level of CD34+ cells between infants with and without BPD.
Table 2

Relationships of CD34+ cell number to demographic and outcome data

Variables

r value

P value

GA

−0.056

0.727

Age at sampling

−0.434

0.006

SNAPPE-II

−0.473

0.002

Length of ventilation

−0.396

0.011

Oxygenation index

−0.100

0.658

FiO2

−0.217

0.211

Duration of oxygen therapy

−0.259

0.116

PaO2/FiO2

0.314

0.059

Length of stay in hospital

0.127

0.459

GA gestational age, SNAPPE-II Score for Neonatal Acute Physiology Perinatal Extension II

Plasma cytokine levels

Plasma concentration of SDF-1 was significantly higher in RDS than in the preterm controls (mean ± SD: 12.6 ± 1.8 vs. 9.6 ± 1.8 ng/ml, P < 0.01). Moreover, there was a correlation between the level of CD34+ cells and the plasma SDF-1 concentration (r = 0.305, P < 0.01). However, no significant differences were noted in the concentrations of VEGF and GM-CSF between RDS and the control infants (Table 3).
Table 3

Cytokines in peripheral blood (mean ± SD)

 

RDS

Preterm controls

Term controls

P value*

SDF-1 (ng/ml)

12.6 ± 1.8

9.6 ± 1.8

8.9 ± 2.3

0.000

VEGF (pg/ml)

139.0 ± 31.7

140.0 ± 52.2

132.2 ± 37.1

0.739

GM-CSF (pg/ml)

21.0 ± 4.0

23.4 ± 10.8

26.4 ± 14.5

0.980

SDF-1 stromal cell-derived factor-1, VEGF vascular endothelial growth factor, GM-CSF granulocyte–macrophage colony-stimulating factor

*P value for RDS versus preterm controls

Correlation between GA and CD34+ cells

Correlation analysis was performed in all 34 control infants (including 20 preterm and 14 term controls). There was an inverse correlation between the number of CD34+ cells and GA (r = −0.373, P < 0.05) (Fig. 3a). In addition, the percentage of CD34+ cells was significantly higher in control infants with GA <32 weeks than those ≥32 weeks (P < 0.01) (Fig. 3b).
Fig. 3

CD34+ cells by GA in preterm and term controls. a The number of CD34+ cells by GA, r = −0.373, P < 0.05 (spearman’s rank correlation). b The percentage of circulating CD34+ cells in different GA subgroups. *P < 0.01, versus <32 weeks; **P < 0.001, versus <32 weeks

Discussion

Recent studies have suggested that stem and progenitor cells may be a prime candidate for the reparation process of respiratory diseases [20, 21]. Yamada et al. [11] showed that circulating progenitor cells were increased in patients with bacterial pneumonia. Later on, in a study of ALI in adult patients, the EPC colony numbers were found to be twofold higher in ALI than in healthy controls [12]. Nevertheless, little has been reported regarding the reparation mechanism of human neonatal lung injury [14].

The present study demonstrated that compared with preterm control infants, RDS infants had an increased level of circulating stem and progenitor cells in the early postnatal life although delayed sampling time. The result suggested that stem and progenitor cells are mobilized into peripheral circulation, which was consistent with previous reports on adult lung diseases. Bizzarro et al. [13] reported circulating CD34+ cell levels in extremely preterm infants with RDS (99 cells/μl) at <48 h of life, which was higher than that observed in our study. This discrepancy of CD34+ cell levels in the early postnatal life is likely due to different GAs in the study.

Previous studies demonstrated that circulating EPC might serve as a prognostic biomarker and are related to survival and disease severity [8, 9, 12, 22]. Our data showed that a low level of circulating CD34+ cells in the early postnatal life was associated with death and prolonged duration of ventilation in RDS infants. We also found that the lower CD34+ cell amounts were associated with higher SNAPPE-II on admission. This may not generalized as a reliable marker for predicting the clinical outcome unless a systematic assessment of disease severity versus standardized care in NICU is implemented in the protocol. However, the results implied that mobilization of stem and progenitor cells might contribute to the repair of neonatal lung injury.

Recently, Borghesi et al. [23] demonstrated that extremely preterm infants who displayed lower numbers of EPC had an increased risk of developing BPD. And Baker et al. [24] found that the growth of preterm EPC was impaired after hyperoxia exposure in vitro, which might contribute to the development of BPD in preterm newborns. We didn’t find the relation between the number of CD34+ cells and the presence of BPD, possibly due to small BPD population.

Abe et al. [25] demonstrated that stem and progenitor cells in the blood can generate alveolar epithelial cells and lung fibroblasts in the presence of ALI. Intravenously injected EPC could incorporate into the injured lung vascular bed [26]. However, the mechanism of improvement in outcome may not be limited to the homing and integration of stem and progenitor cells into lung issue. A recent study raises the possibility that bone-marrow derived cells decrease the endotoxin-induced ALI partly through the release of anti-inflammation cytokines [4]. The exact mechanism of the protective effect of stem and progenitor cells against lung injury remains unclear.

Mobilization of stem and progenitor cells from bone marrow is mediated by a variety of cytokines [17, 27, 28]. Rafat et al. [22] reported increased serum levels of VEGF and GM-CSF, and a positive correlation between serum VEGF levels and circulating EPC numbers. Moreover, several studies have shown that the SDF-1 level in serum and the damaged tissue was elevated in parallel with increasing numbers of stem and progenitor cells in ischemic disease [29, 30]. In the present study, we found that SDF-1 concentration in plasma was elevated in RDS infants, and the SDF-1 level was related to the number of circulating CD34+ cells, suggesting that SDF-1 participate in the mobilization and homing of CD34+ cells in RDS. Although the concentrations of VEGF and GM-CSF were significantly higher than those in studies of adults, we didn’t find any relationship between circulating CD34+ cells and plasma level of VEGF or GM-CSF, which may implicate different pathobiology between adult and neonatal lungs.

Our study had its potential limitations. First, we concentrated on only the initial level of circulating CD34+ cells and did not measure the circulating CD34+ cells in different time points during the course of RDS. Secondly, the present study analyzed only correlation of outcome with the CD34+ cell levels in the early postnatal life. Thirdly, because of ethical reasons, a real control group was not possible. These limitations should be amended by cohort studies to investigate the dynamic change of CD34+ cell level and the possible mechanism of outcome improvement in relation with circulating stem-progenitor cell function.

In conclusion, circulating CD34+ cells were elevated in RDS infants along with the plasma SDF-1 concentration, and were associated with improved outcome. Despite its preliminary character, circulating stem and progenitor cells might contribute to lung reparation of RDS infants. Further work with a large sample and systematic assessment of disease severity should be implemented to evaluate and predict the role of circulating stem and progenitor cells in neonatal lung injury reparation.

Notes

Acknowledgments

We thank Mrs. Qian Zhang and Ying Wang for the flow cytometry analysis, and assistance by staff from the Department of Neonatology is highly appreciated. This study was supported by the National Natural Science Foundation (No. 30600687) of China.

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Copyright information

© Springer Basel AG 2010

Authors and Affiliations

  • Yuanyuan Qi
    • 1
  • Liling Qian
    • 1
  • Bo Sun
    • 1
  • Chao Chen
    • 1
  • Yun Cao
    • 1
  1. 1.Departments of Pediatrics, Children’s Hospital, The Institute of Biomedical SciencesFudan UniversityShanghaiPeople’s Republic of China

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