The role of neutrophil apoptosis in the resolution of acute lung injury in newborn infants

S Kotecha; R J Mildner; L R Prince; J R Vyas; A E Currie; R A Lawson; M K B Whyte

doi:10.1136/thorax.58.11.961

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Paediatric lung disease

The role of neutrophil apoptosis in the resolution of acute lung injury in newborn infants

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Delayed Neutrophil Apoptosis in Newborn Infants
Sailesh Kotecha
Published on: 4 January 2005
Delayed neonatal neutrophil apoptosis and chronic lung disease: perinatal influences
Eleanor J Molloy
Published on: 3 August 2004

Published on: 4 January 2005
Delayed Neutrophil Apoptosis in Newborn Infants
- Sailesh Kotecha, Senior Lecturer
- Other Contributors:
  Moira Whyte
Dear Editor
We would like to thank Dr Molloy for her interest in our recent paper showing delayed neutrophil apoptosis in infants who progressed to chronic lung disease prematurity (CLD) and indeed in those infants who do not survive their course of extracorporeal membrane oxygenation (ECMO) for severe respiratory failure.[1] Having established the association, we are now exploring the potential mechanisms that mi...
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Dear Editor
We would like to thank Dr Molloy for her interest in our recent paper showing delayed neutrophil apoptosis in infants who progressed to chronic lung disease prematurity (CLD) and indeed in those infants who do not survive their course of extracorporeal membrane oxygenation (ECMO) for severe respiratory failure.[1] Having established the association, we are now exploring the potential mechanisms that might result in delayed neutrophil apoptosis in infants who develop CLD. Dr Molloy mentions in her letter a number of important clinical factors that might influence rates of neutrophil apoptosis in new born children. The principal aim of our study, however, was to determine whether or not there were differences in neutrophil apoptosis between CLD babies and those who recover from RDS. We refrained from over analysing the data, since far greater numbers would need to be studied to establish the effects of other co-morbidities, maternal factors and ventilatory parameters on the outcomes we measured. Nonetheless we entirely agree with Dr Molloy that many of the factors she mentions, both perinatal factors such as chorioamnionitis and mode of delivery, and post natal factors such as mechanical ventilation have the potential to influence pulmonary inflammation and neutrophil apoptosis. Ultimately, whether any of these factors have a direct causal role might need to be addressed in other systems such as animal models.
The small amounts of BAL obtained from the babies studied limited the cytokine analyses we were able to perform. We did not measure IL-6 in this cohort. Measurements of GCSF were available in a proportion of the babies. Although GCSF levels were raised in some of the babies there was no clear association with development of CLD.
Sailesh Kotecha
Child Health, University of Leicester
Moira Whyte
Respiratory Medicine, University of Sheffield
Reference
S Kotecha, R J Mildner, L R Prince, J R Vyas, A E Currie, R A Lawson, and M K B Whyte. The role of neutrophil apoptosis in the resolution of acute lung injury in newborn infants. Thorax 2003; 58: 961-967.
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Conflict of Interest:
None declared.
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Published on: 3 August 2004
Delayed neonatal neutrophil apoptosis and chronic lung disease: perinatal influences
- Eleanor J Molloy, Neonatology Fellow
Dear Editor
The paper by Kotecha et al reveals the important association between delayed pulmonary neutrophil apoptosis and neonatal chronic lung disease. This paper also raises several questions. Did the authors analyse the effect of labour on the neutrophil counts? It would be useful to know the mode of delivery as several papers have shown an effect on systemic neutrophil function and survival. Neutrophil coun...
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Dear Editor
The paper by Kotecha et al reveals the important association between delayed pulmonary neutrophil apoptosis and neonatal chronic lung disease. This paper also raises several questions. Did the authors analyse the effect of labour on the neutrophil counts? It would be useful to know the mode of delivery as several papers have shown an effect on systemic neutrophil function and survival. Neutrophil counts are higher in infants born following vaginal delivery compared with elective caesarean section with no labour [1-4]. In addition, several studies indicate that neonatal neutrophil function is activated by labour [5-7]. Gender may be an additional confounding factor [8] as in females neutrophil apoptosis is delayed compared with males. Differential neutrophil counts would also be useful as there may be increased immature neutrophils associated with both prematurity and steroids [9,10]. Progenitor neutrophils may have delayed apoptosis, extrapolating from research in HL-60 cells [11]. Premature infants also have more inflammatory conditions (e.g. necrotising enterocolitis, sepsis) therefore details of co-morbidity would be interesting. In addition, duration of ventilation and mean PIP, PEEP and MAP at one week would assess the severity of the respiratory illness. In adults, the systemic inflammatory response is associated with delayed neutrophil apoptosis [12]. Therefore, the presence of maternal infection such as chorioamnionitis may be relevant as infants may have altered neutrophil survival at birth associated with a fetal inflammatory response [13]. In this patient group were systemic and pulmonary neutrophil counts inversely correlated? The systemic neutrophil counts in parallel with the BAL results may give important information on the transmigration of neutrophils in RDS and CLD [14]. Did infants with low Apgars, acidotic cord pH or need for resuscitation have deranged neutrophil apoptosis? The data on Apgars and cord pH would be interesting as the delay in apoptosis is an early response and may be related to peripartum events [15,16]. Finally, measurement of IL-6 and GCSF would be relevant in this study group as they have been shown to delay neutrophil apoptosis and both are elevated in RDS [17,18].
References:
(1) Chirico G, Gasparoni A, Ciardelli L, Martinotti L, Rondini G. Leukocyte counts in relation to the method of delivery during the first five days of life. Biol Neonate. 1999;75(5):294-9
(2) Thilaganathan B, Meher-Homji N, Nicolaides KH. Labor: an immunologically beneficial process for the neonate. Am J Obstet Gynecol. 1994 ;171(5):1271-2
(3) Herson VC, Block C, Eisenfeld LI, Maderazo E, Krause PJ. Effect of labor and delivery on neonatal polymorphonuclear leukocyte number and function. Am J Perinatol. 1992 ;9(4):285-8
(4) Hasan R, Inoue S, Banerjee A. Higher white blood cell counts and band forms in newborns delivered vaginally compared with those delivered by cesarean section. Am J Clin Pathol. 1993;100(2):116-8
(5) Gessler P, Dahinden C. Increased respiratory burst and increased expression of complement receptor-3 (CD11b/CD18) and of IL-8 receptor-A in neutrophil granulocytes from newborns after vaginal delivery. Biol Neonate. 2003;83(2):107-12
(6) Weinschenk NP, Farina A, Bianchi DW. Neonatal neutrophil activation is a function of labor length in preterm infants. Pediatr Res. 1998 ;44(6):942-5
(7) Molloy EJ, O'Neill AJ, Grantham JJ, Sheridan-Pereira M, Fitzpatrick JM, Webb DW, Watson RW. Labor Promotes Neonatal Neutrophil Survival and Lipopolysaccharide Responsiveness. Pediatr Res 2004, Jul;56(1):99-103
(8) Molloy EJ, O’Neill AJ, Grantham J, Sheridan-Pereira M, Fitzpatrick JM, Webb DW, Watson RWG. Gender-specific alterations in neutrophil apoptosis: the role of estradiol and progesterone. Blood. 2003, 102:2653-2659
(9) Mouzinho A, Rosenfeld CR, Sanchez PJ, Risser R. Revised reference ranges for circulating neutrophils in very-low-birth-weight neonates. Pediatrics. 1994 Jul;94(1):76-82
(10) Peng CT, Lin HC, Lin YJ, Tsai CH, Yeh TF. Early dexamethasone therapy and blood cell count in preterm infants. Pediatrics. 1999 Sep;104(3 Pt 1):476-81
(11) Doyle BT, O'Neill AJ, Fitzpatrick JM, Watson RW. Differentiation- induced HL-60 cell apoptosis: a mechanism independent of mitochondrial disruption? Apoptosis. 2004 May;9(3):345-52
(12) Jimenez, M.F. et al. 1997. Dysregulated expression of neutrophil apoptosis in the systemic inflammatory response syndrome (SIRS). Arch. Surg. 132:1263-1270
(13) Gomez R, Romero R, Ghezzi F, Yoon BH, Mazor M, Berry SM. The fetal inflammatory response syndrome. Am J Obstet Gynecol. 1998 Jul;179(1):194- 202
(14) Sarafidis K, Drossou-Agakidou V, Kanakoudi-Tsakalidou F, Taparkou A, Tsakalidis C, Tsandali C, Kremenopoulos G.Evidence of early systemic activation and transendothelial migration of neutrophils in neonates with severe respiratory distress syndrome. Pediatr Pulmonol. 2001 Mar;31(3):214 -9
(15) Drossou V, Kanakoudi F, Tzimouli V, Sarafidis K, Taparkou A, Bougiouklis D, Petropoulou T, Kremenopoulos G. Impact of prematurity, stress and sepsis on the neutrophil respiratory burst activity of neonates. Biol Neonate. 1997;72(4):201-9
(16) Stanton K, Alam HB, Rhee P, Llorente O, Kirkpatrick J, Koustova E.Human polymorphonuclear cell death after exposure to resuscitation fluids in vitro: apoptosis versus necrosis. J Trauma. 2003 Jun;54(6):1065- 74; discussion 1075-6
(17) McLoughlin RM, Witowski J, Robson RL, Wilkinson TS, Hurst SM, Williams AS, Williams JD, Rose-John S, Jones SA, Topley N. Interplay between IFN- gamma and IL-6 signaling governs neutrophil trafficking and apoptosis during acute inflammation. J Clin Invest. 2003 Aug;112(4):598-607
(18) Munshi UK, Niu JO, Siddiq MM, Parton LA. Elevation of interleukin-8 and interleukin-6 precedes the influx of neutrophils in tracheal aspirates from preterm infants who develop bronchopulmonary dysplasia. Pediatr Pulmonol. 1997 Nov;24(5):331-6
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Conflict of Interest:
None declared.
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