Published online March 17, 2008
PEDIATRICS (doi:10.1542/peds.2007-1697)
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ARTICLE

Serum Cytokine and Chemokine Profiles in Neonates With Meconium Aspiration Syndrome

Kaoru Okazaki, MDa, Masatoshi Kondo, MDa, Masahiko Kato, MDb, Ryota Kakinuma, MDa, Akira Nishida, MDa, Masahiro Noda, PhDc, Kiyosu Taniguchi, MDd and Hirokazu Kimura, PhDd

a Divisions of Neonatology, Tokyo Metropolitan Hachioji Children's Hospital, Tokyo, Japan
b Gunma Prefectural Institute of Public Health and Environmental Sciences, Gunma, Japan
c Department of Virology III
d Infectious Diseases Surveillance Center, National Institute of Infectious Diseases, Tokyo, Japan


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 
OBJECTIVES. Various inflammatory cytokines and chemokines are thought to be associated with the pathophysiology of meconium aspiration syndrome. To clarify any such association, we compared various serum cytokine and chemokine profiles in patients with and without meconium aspiration syndrome.

PATIENTS AND METHODS. Using a highly sensitive fluorescence microsphere method, 17 types of cytokines and chemokines in sera were measured in 11 neonatal patients with meconium aspiration syndrome, 16 neonatal patients without meconium aspiration syndrome, and 9 healthy children.

RESULTS. The concentrations of 8 types of proinflammatory cytokines and chemokines were significantly higher in the meconium aspiration syndrome group than in healthy controls: interleukin-1β, interleukin-6, interleukin-8, granulocyte-macrophage colony-stimulating factor, granulocyte colony-stimulating factor, interferon-{gamma}, macrophage inflammatory protein-1β, and tumor necrosis factor-{alpha}. Six types of proinflammatory cytokines and chemokines were significantly higher in the meconium aspiration syndrome group than in the nonmeconium aspiration syndrome group: interleukin-6, interleukin-8, granulocyte-macrophage colony-stimulating factor, granulocyte colony-stimulating factor, interferon-{gamma}, and tumor necrosis factor-{alpha}. Serum concentrations of interleukin-10 (anti-inflammatory cytokine) in the meconium aspiration syndrome group were higher than those in both the nonmeconium aspiration syndrome group and healthy children group (P = .007 and 0.001, respectively).

CONCLUSIONS. Most types of proinflammatory cytokines and chemokines in sera of neonates with meconium aspiration syndrome were higher than those without meconium aspiration syndrome, giving support to the suggestion that elevated levels are associated with the pathogenesis of meconium aspiration syndrome.

Key Words: cytokines • chemokines • MAS • neonates • inflammation • sera

Abbreviations: MAS—meconium aspiration syndrome • IL—interleukin • TNF—tumor necrosis factor • IFN—interferon • G-CSF—granulocyte colony-stimulating factor • GM-CSF—granulocyte-macrophage colony-stimulating factor • MIP—macrophage inflammatory protein • BALF—bronchoalveolar lavage fluid


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 
Meconium is reported to be a strong inducer of severe chemical pneumonitis in neonates, resulting in meconium aspiration syndrome (MAS).1 The major pathogenesis of chemical pneumonitis in MAS may be responsible for the transmigration and infiltration of inflammatory cells, including neutrophils and macrophages found in the alveoli, larger airways, and the lung parenchyma, as well as bacterial pneumonia.1–4 Moreover, Castellheim et al5 reported that meconium aspiration can lead to progressive systemic inflammatory responses syndrome in newborn piglets, involving granulocyte activation and interleukin (IL)-6 and IL-8 release. Thus, severe MAS can be life threatening because of multiple organ failure with devastating inflammation.4,6

Previous reports demonstrated that cytokines and chemokines as immunologic responders may be strongly linked to the various infectious lung diseases.7,8 Although MAS is not principally an infectious disease, its pathophysiology is similar in terms of the process of inflammatory response to pneumonia caused by various pathogens.2,3,9 Proinflammatory cytokines and chemokines may, therefore, be associated with the pathophysiology of MAS. Interestingly, de Beaufort et al10 suggested that meconium contains relatively high levels of certain types of proinflammatory cytokines and chemokine, such as IL-1β, IL-6, tumor necrosis factor (TNF)-{alpha}, and IL-8, directly leading to chemical pneumonitis in MAS. Moreover, it is suggested that leakage of aspirated meconium to the lung capillaries may induce systemic inflammation, such as the production of cytokines and chemokines and the activation of complements.11,12 Cytokines and chemokines certainly play pivotal roles in immunologic regulation, including proliferation and differentiation of most types of leukocytes.13,14 The cytokines and chemokines, such as IL-1β, IL-6, IL-8, IL-10, interferon (IFN)-{gamma}, and TNF-{alpha} are also involved in inflammatory responses in vivo. These cytokines and chemokines can activate inflammatory cells, such as neutrophils and monocytes or macrophages,13,14 which, in turn, may release toxic substances, such as reactive oxygen species, and toxic granules, including proteolytic enzymes and myeloperoxidase, resulting in cell and tissue injury.15 However, the exact role of these cytokines and chemokines in MAS remains unclear. Moreover, to the best of our knowledge, this role has not been extensively studied in the sera of neonates with MAS. To this end, in the present study we profiled 17 types of cytokines and chemokines in the sera of neonates with MAS and compared them with those obtained for neonates without MAS and for healthy children.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 
Subjects
A total of 27 neonates and 9 healthy children were the subjects of this study. All of the neonates with MAS were single births delivered between 37 and 41 weeks of gestation and admitted to the NICU of Tokyo Metropolitan Hachioji Children's Hospital between January 2005 and May 2006. MAS was defined as respiratory distress in an infant born through meconium-stained amniotic fluids, roentgenographic findings consistent with MAS, and symptoms that could not be otherwise explained.2 Exclusion criteria were congenital malformations, any apparent clinical sign of infection, trauma, coagulation disorders, and genetic disorders. Eleven neonates were diagnosed with MAS (MAS group). The 16 neonates without MAS (non-MAS group) were of normal vaginal delivery with no evidence of perinatal asphyxia or meconium-stained amniotic fluids. The 9 healthy children (healthy children group) ranged in age from 2 to 6 years (3.7 ± 1.3 years, mean ± SD).

To evaluate any differences in cytokines and chemokines in the serum during MAS at the neonatal stage, blood was drawn once from the umbilical artery or the radial artery of all of the neonates diagnosed with MAS within 6 hours after birth (3.5 ± 1.9 hours, mean ± SD). In the non-MAS group, blood samples were drawn once from a peripheral vein within 6 hours after birth. These samples were mainly collected to measure blood glucose and total bilirubin. In the healthy children group, blood samples were drawn from a peripheral vein for a preoperative examination of hernia repair.

Written informed consent was obtained from the parents of all of the subjects for the donation of 200 µL of blood, which was used in this analysis. The study protocol was approved by the ethics committee on human research of Tokyo Metropolitan Hachioji Children's Hospital.

Measurement of Cytokine and Chemokine Concentrations
The concentration of 17 types of cytokines and chemokines in a small volume (50 µL) of sera was measured using a highly sensitive fluorescence microsphere system (Bio-Plex suspension array system, Hercules, CA).16 The following cytokines and chemokines were measured: IL-1β, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12, IL-13, IL-17, granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), IFN-{gamma}, monocyte chemoattractant protein-1, macrophage inflammatory protein (MIP)-1β, and TNF-{alpha}. The detectable limit of each type of cytokine or chemokine was 0.1 to 0.3 pg/mL.16

Oxygenation Index
The oxygenation index was calculated according to the following formula: (mean airway pressure x fraction of inspired oxygen x 100)/arterial oxygen pressure.

Statistical Analysis
Data were analyzed using SPSS software (SPSS for Windows 10.0, SPSS Inc, Chicago, IL). All data are expressed as means ± SEs. Apgar score is expressed as the median and interquartile range. Statistical analysis of the cytokine and chemokine concentrations was performed using the Kruskal-Wallis and Bonferroni methods. A Mann-Whitney test was applied to compare the characteristics of the patients. Statistical significance was set at the level of P value <.05.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 CONCLUSIONS
 REFERENCES
 
Subjects
The detailed characteristics of the subjects with and without MAS are shown in Table 1. Significant differences in the 1- and 5-minute Apgar scores were seen between the MAS and non-MAS groups (P < .005). No significant difference was found for birth weight and gestational age. In the MAS group, none of the subjects had positive blood or tracheal aspirate cultures, abnormal C-reactive protein (<0.35 mg/dL), or immunoglobulin M elevation (<10 mg/dL). Total leukocyte counts ranged between 13 400 and 31 300 per µL.


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  		TABLE 1 Characteristics of Subjects in This Study

 
Among the 11 subjects in the MAS group, 8 required assisted ventilation, 5 of which were subjects with severe MAS, who required assisted ventilation for >48 hours.6 Only 1 subject was complicated by persistent pulmonary hypertension, and 7 subjects had multiple organ involvement, including central nerve, hepatic, cardiac, hematologic, and renal injury.17 However, there were no cases of poor outcome including neurologic sequelae and death in subjects with or without MAS.

Cytokine and Chemokine Concentrations in Serum of Neonates
We measured the 17 types of the cytokine and chemokine concentrations in the serum of all of the subjects. The data for each cytokine or chemokine are shown in Fig 1. Detailed statistical data with regard to cytokine and chemokine concentrations in sera are given in Table 2. Six types of proinflammatory cytokines in the sera of neonates in the MAS group were significantly higher than those in the healthy children: IL-1β, IL-6, IFN-{gamma}, TNF-{alpha}, G-CSF, and GM-CSF. The 2 chemokines of IL-8 and MIP-1β were significantly higher in the MAS group than in the healthy children. Next, 5 types of proinflammatory cytokines in the sera of the MAS group were found to be significantly higher than in the non-MAS group: IL-6, IFN-{gamma}, TNF-{alpha}, G-CSF, and GM-CSF. The chemokine IL-8 was also significantly higher in the sera of the MAS group than in the non-MAS group. Interestingly, a representative anti-inflammatory cytokine, IL-10, was drastically elevated in the MAS group compared with the non-MAS group. Only 1 cytokine, IL-7, in both the MAS and non-MAS groups was significantly lower than in the healthy children group. No significant difference in cytokine and chemokine levels in the sera was found between the non-MAS and the healthy children groups. Moreover, no significance differences between cytokine and chemokine concentrations in sera and the oxygenation index (1.5–18.7) were found among the MAS group (data not shown).


Figure 1
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  		FIGURE 1 Concentrations of various cytokines and chemokines in sera of healthy children, neonates without MAS, and neonates with MAS. Detailed subject data and procedures for the determination of cytokine concentrations in sera are described in Table 1 and the text. Vertical bars represent means ± SEs.

 

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  		TABLE 2 Various Cytokine and Chemokine Concentrations in Sera in Neonates With or Without MAS and in Healthy Children (pg/mL)

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
CONCLUSIONS
 REFERENCES
 
We found that most types of proinflammatory cytokines (IL-6, IFN-{gamma}, TNF-{alpha}, G-CSF, and GM-CSF) and chemokines (IL-8) in sera were significantly elevated in neonates with MAS compared with neonates without MAS. In addition, the anti-inflammatory cytokine IL-10 was also significantly elevated in the MAS group. It has been suggested that the levels of cytokines and chemokines in sera might reflect the production of cytokines and chemokines by inflammatory sites such as the lung, liver, and intestine.18–21 Our results suggest that proinflammatory cytokinemia and chemokinemia in MAS may indeed reflect exacerbation of pulmonary injuries because of excessive inflammation. This may also account for the simultaneously elevated IL-10 level, possibly to reduce the excessive inflammatory responses in MAS. Thus, imbalance of these immunologic responders (cytokines and chemokines) might, in part, be associated with the pathophysiology of chemical pneumonitis and systemic inflammation in MAS.22–24

The proinflammatory cytokines, that is, IL-1β, IL-6, IFN-{gamma}, TNF-{alpha}, G-CSF, and GM-CSF, and some chemokines, such as IL-8 and MIP1β, are strongly linked to various inflammatory diseases.23,25,26 These cytokines and chemokines directly induce complicated inflammatory responses, including cell proliferation, cell differentiation, and cell death. Moreover, these proinflammatory cytokines and chemokines activate cytotoxic T cells (natural killer cells and lymphokine activated killer cells) and phagocytes, such as granulocytes and monocytes or macrophages. These activated leukocytes, in turn, release toxic proteins (proteolytic enzymes and toxic granules) and active oxygen species, suggesting that these cells can induce excessive cellular or tissue damage in inflammatory lesions.27 For example, tissue injuries seen in lung disease, such as acute respiratory distress syndrome, may be responsible for these abnormal immunologic responses involving aberrant induction of proinflammatory cytokines and chemokines and activation or migration of leukocytes.28,29 In addition, the exacerbation of rheumatoid arthritis is believed to be because of the abnormal induction of TNF-{alpha}, and neutralizing monoclonal antibody is frequently used in treatment and is associated with remission.30,31 However, in MAS, the relationships between induction of cytokines and chemokines and pathophysiology are poorly understood, although levels of a few cytokines in sera of MAS patients have been investigated.4 The assessment of various cytokines and chemokines levels is, therefore, important to precisely understand the mechanisms of lung injuries in MAS.

IL-4, IL-10, and IL-13 act as anti-inflammatory cytokines and prevent abnormal inflammatory reactions in vivo.32,33 IL-10 is mainly secreted by lymphocytes and monocytes or macrophages as an anti-inflammatory cytokine and blocks inflammatory actions, including inhibition of IL-6 and TNF-{alpha} synthesis, and downregulates intercellular adhesion molecule-1 and matrix metalloproteinase.33–36 Garingo et al37 demonstrated the production of IL-10 by lung inflammatory cells from tracheal fluid collection in term neonates with MAS, suggesting that elevation of IL-10 levels may be induced mainly by lung injury or disseminated systemic inflammation because of meconium aspiration, thereby reducing the devastating inflammatory responses.11,38,39 In the present study, the presence of anti-inflammatory cytokine IL-10 in the serum of neonates with MAS was noted to be higher than in those without MAS, suggesting the possibility that elevated IL-10 levels in MAS play a role in preventing the exacerbation of pulmonary inflammation.

Meconium contains variable amounts of cytokines, chemokines, and other substances, including IL-1β, IL-6, IL-8, TNF-{alpha}, heme, phospholipase, bile acids, lipids, and polysaccharides,10,40 which are associated with the pathophysiology of MAS.4,10,38,40 For example, de Beaufort et al10 showed that the addition of meconium induces the production of IL-8 from A549 epithelial cells, and Zagariya et al24 demonstrated that mRNA for TNF-{alpha}, IL-6, and IL-8 is expressed in A549 epithelial cells stimulated by meconium. These results suggest that meconium itself is inducible for severe inflammatory responses. Thus, the various substances derived from meconium and host may synergistically affect lung inflammation in MAS.

Next, it may be important to address the origins of the high levels of cytokines and chemokines in serum with MAS, and some major origins have been suggested.10,38 Lindenskov et al12 showed that meconium leakage into circulating blood because of lung rupture may induce abnormal production of various cytokines and chemokines from blood cells through activation of complements, leading to cytokinemia or chemokinemia in MAS.38 Moreover, meconium exposure to lung cells, such as alveolar cells, epithelial cells, and immunologic cells, may induce overproduction of cytokines and chemokines from these cells.10,40,41 These cytokines and chemokines may mainly reflect their levels in not only bronchoalveolar lavage fluid (BALF) but also serum.12,42 Thus, it is possible that overproduction of cytokines and chemokines in the lung may reflect the cytokine and chemokine levels in serum with MAS, although we did not measure them in BALF with MAS. Together, high levels of cytokines and chemokines in serum with MAS may be mainly responsible for blood cell- and lung-derived cytokines and chemokines. Detailed studies focusing on the origin of cytokines and chemokines in serum with MAS may be needed.

We have demonstrated previously that 2 types of cytokines (IL-6 and IL-8) and the anti-inflammatory cytokine IL-10 in sera were higher in asphyxiated neonates without MAS than neonates with normal vaginal delivery.43 In the present study we have further shown that other cytokines and chemokines, including IFN-{gamma}, TNF-{alpha}, G-CSF, and GM-CSF, were higher in neonates with MAS than in those without MAS. It is suggested that meconium aspiration is a major risk factor for severity of asphyxia.44 Thus, these additionally elevated cytokines and chemokines induced by meconium aspiration may reflect the severity of MAS in asphyxiated neonates as a risk factor for exacerbation of pulmonary injury.

Substances including lactate, protein S-100 (a calcium-binding protein), and creatine kinase-BB (brain-specific creatine kinase) are useful markers for evaluating the severity of MAS and asphyxia,45 although we did not evaluate them in the present study. In addition, there may be an association between the oxygenation index and cytokine and chemokine levels in sera.12 However, no relationships between this index and any cytokine and chemokine levels in sera with MAS were found in the present study. This may be attributed to differences in experimental conditions including sampling time and samples (BALF or serum).12,42 To evaluate more precisely the severity of MAS, additional studies regarding the relationships between cytokines and chemokines and other markers may be needed.


   CONCLUSIONS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
REFERENCES
 
In conclusion, we found that most types of proinflammatory cytokines and some chemokines were significantly elevated in sera in patients with MAS. These inflammatory accelerators may be associated with aggravation of chemical pneumonitis and systemic inflammations in MAS, because elevated IL-10 (an anti-inflammatory cytokine) may reduce them. Thus, the pathophysiology of MAS may be partially explained by various significantly elevated proinflammatory cytokines, chemokines, and anti-inflammatory cytokines in serum. Monoclonal antibodies (eg, humanized monoclonal antibody) against proinflammatory cytokines, chemokines, and complement inhibitors may be applicable for MAS in the future.


   ACKNOWLEDGMENTS
 
We thank Taisei Ishioka for his skillful support.


   FOOTNOTES
 
Accepted Jul 31, 2007.

Address correspondence to Kaoru Okazaki, MD, Tokyo Metropolitan Hachioji Children's Hospital, 4-33-13 Daimachi, Hachioji, Tokyo 193-0931, Japan. E-mail: okazaki{at}chp.hachioji.tokyo.jp; or Hirokazu Kimura, PhD, Infectious Diseases Surveillance Center, National Institute of Infectious Diseases, 4-7-1 Gakuen, Musashimurayama, Tokyo 201-0011, Japan. E-mail: kimhiro{at}nih.go.jp

The authors have indicated they have no financial relationships relevant to this article to disclose.


What's Known on This Subject

We profiled cytokines and chemokines in sera with meconium aspiration syndrome. We found that various cytokines and chemokines were significantly elevated in meconium aspiration syndrome, suggesting that these inflammatory modulators may be associated with the pathophysiology of meconium aspiration syndrome.

 


What This Study Adds

The pathophysiology of meconium aspiration syndrome may be partially explained by significantly elevated proinflammatory cytokines, chemokines, and anti-inflammatory cytokines in serum. Monoclonal antibody against proinflammatory cytokines, chemokines, and complement inhibitors may be applicable for meconium aspiration syndrome in the future.

 


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 

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