Undetectable Interleukin (IL)-10 and Persistent IL-8 Expression Early in Hyaline Membrane Disease: A Possible Developmental Basis for the Predisposition to Chronic Lung Inflammation in Preterm Newborns

Abstract

We are interested in determining whether premature birth alters expression of counterregulatory cytokines which modulate lung inflammation. Production of proinflammatory cytokines tumor necrosis factor alpha. IL-1 beta, and IL-8 is regulated in part by the antiinflammatory cytokine IL-10. For preterm newborns with hyaline membrane disease, deficiencies in the ability of lung macrophages to express antiinflammatory cytokines may predispose to chronic lung inflammation. We compared the expression of pro- and antiinflammatory cytokines at the mRNA and protein level in the lungs of preterm and term newborns with acute respiratory failure from hyaline membrane disease or meconium aspiration syndrome. Four sequential bronchoalveolar lavage (BAL) samples were obtained during the first 96 h of life from all patients. All patients rapidly developed an influx of neutrophils and macrophages. Over time, cell populations in both groups became relatively enriched with macrophages. The expression of proinflammatory cytokine mRNA and/or protein was present in all samples from both patient groups. In contrast, IL-10 mRNA was undetectable in most of the cell samples from preterm infants and present in the majority of cell samples from term infants. IL-10 concentrations were undetectable in lavage fluid from preterm infants with higher levels in a few of the BAL samples from term infants. These studies demonstrate that 1) IL-10 mRNA and protein expression by lung inflammatory cells is related to gestational age and 2) during the first 96 h of life neutrophil cell counts and IL-8 expression decrease in BAL from term infants, but remain unchanged in BAL samples from preterm infants.

Pulmonary inflammation and bronchopulmonary dysplasia

“…26,33 -35 Cellular IL-10 mRNA was undetectable in most airway samples of preterm infants with RDS, but it was expressed in all cell samples of term infants with meconium aspiration syndrome. 26 However, lung inflammatory cells of preterm infants exposed to IL-10 in vitro responded with a reduced expression of proinflammatory cytokines. 36 An imbalance between proinflammatory and anti-inflammatory cytokines can be considered as an important feature of lung injury.…”

Studies of meconium-induced lung injury: inflammatory cytokine expression and apoptosis

“…Jones et al 4 demonstrated increased production of inflammatory cytokines in preterm infants with MAS. Castelheim 10 showed compliment activation in human monocytes culture of MAS model.…”

“…17 Now we describe the pathways of induction of inflammatory response following cell influx. 4 Preterm and term newborns Production of TNFa, IL1b, and IL8 is regulated by IL-10; IL-10 not detected in preterm infants with or without MAS de Beaufort et al 8 Newborn infants Overexpression of IL-8 in MAS in vitro; increased migration of neotrophils; anti-IL-8 antibodies inhibit neutrophil migration Uotila and Kaapa 9 Human monocytes In culture increase of cycloxygenase-2 expression in vitro Castellheim et al 10 Human monocytes in culture Complement activation in MAS Animal models of MAS Tyler et al 3 Animal models Surfactant inactivation, chemical pneumonitis, airway obstruction, direct toxic damage of animal lung tissues Zagariya et al 6 Rabbit pups Intense inflammatory reactions involved in meconium-induced injury in vivo; expression of endothelin 1 in MAS Davey et al 11 Piglets Acute decrease in gas exchange and dynamic lung compliance; increase of total lung protein; inhibition of surfactant Holopainen et al 12 Piglets Inflammation, airway epithelium targeted, necrotic changes, phospholipase 2 activity increased. Mollnes et al 13 Animal models Complement activation in MAS Khan et al 14 Mice Increase of IL-13 expression in MAS in vivo; lymphocytic and eosinophilic inflammation Zagariya et al 15 Rabbit pups Phospholipase A2 activates apoptosis, influx of T-lymphocytes and macrophages in vivo; increase of TNFa, IL-1b, IL-6 and IL-8 in MAS in vivo Zagariya et al 16 Rabbit pups Cell death by apoptosis, influx of neutrophils and macrophages in vivo Tessler et al 17 Newborn infants Reactive oxygen species in vitro…”

“…10 Meconium itself may stimulate neutrophil chemotaxis and it supposedly induces the lung inflammatory cells to produce proinflammatory chemotactic cytokines. 4,8,10,18 Ex vivo studies using a piglet model show that moderate and high concentrations of aspirated meconium rapidly activate circulating neutrophils. 19 Experimental study in piglet model suggests that meconium-induced inflammation is localized in the meconium-contaminated areas of the lungs with no generalized inflammatory injury.…”

“…There is emerging evidence from different animal models that intense inflammatory reaction may be central to the initial progression of MAS and associated severe pulmonary hypertension. [3][4][5] Investigators using animal models have shown the presence of inflammatory-induced cell death through apoptotic process in meconium-instilled lungs. 6,7 There is increased interest to better understand complex mechanisms of inducing meconium-induced lung cell apoptosis.…”