Elsevier

Seminars in Neonatology

Volume 8, Issue 1, February 2003, Pages 29-38
Seminars in Neonatology

Inflammation and bronchopulmonary dysplasia

https://doi.org/10.1016/S1084-2756(02)00190-2Get rights and content

Abstract

Pulmonary inflammation is a key feature in the pathogenesis of bronchopulmonary dysplasia (BPD). This inflammatory process, induced by multiple risk factors, is characterized by the presence of inflammatory cells, cytokines and an arsenal of additional humoral mediators in the airways and pulmonary tissue of preterm infants with the condition. Several mediators have a direct detrimental effect on pulmonary structures by affecting cell integrity and inducing apoptosis. An imbalance between pro-inflammatory and anti-inflammatory factors can generally be considered to be a hallmark of lung injury. Intrauterine exposure to pro-inflammatory cytokines or antenatal infection may prime the fetal lung such that minimally injurious postnatal events provoke an excessive pulmonary inflammatory response that most certainly affects normal alveolization and pulmonary vascular development in preterm infants with BPD.

Introduction

It is now generally accepted that multiple risk factors that act additively or synergistically induce an injurious inflammatory response in the airways and pulmonary interstitium of preterm infants with bronchopulmonary dysplasia (BPD). This inflammatory response is characterized by an accumulation of neutrophils and macrophages as well as an arsenal of pro-inflammatory mediators. Besides pro-inflammatory cytokines, toxic oxygen radicals and lipid mediators, potent protease may be responsible for acute lung injury. In general an imbalance between pro- and anti-inflammatory factors may considerably affect normal alveolization and pulmonary vascular development in preterm infants with BPD. These aspects have been recently addressed in a number of review articles.1, 2, 3, 4, 5, 6 The current pathogenetic ideas on the possible role of inflammation in the evolution of BPD will be summarized in a condensed form in this review. However, we have to be cautious about these interpretations since the exact pathogenetic mechanisms underlying lung injury and inflammation, as well as repair mechanisms, are incompletely understood, and the molecular basis of these events has not yet been identified.

Section snippets

Risk factors

The principal risk factors for BPD that have been clearly identified are lung immaturity, oxygen toxicity, barotrauma and volutrauma, the initiation and duration of mechanical ventilation, prenatal and nosocomial infections, and increased pulmonary blood flow secondary to a patent ductusarteriosus.5 Antenatal glucocorticoid therapy, gentle ventilation techniques and surfactant treatment have definitely minimized the severity of lung injury in more mature infants with respiratory distress

Inflammatory cells

Soon after the initiation of mechanical ventilation, a large number of neutrophils can be detected in the lungs of premature animals,8 the appearance of neutrophils in bronchoalveolar lavage fluid being associated with a decrease in the level of circulating neutrophils and correlated with the extent of pulmonary edema formation and early indicators of lung injury. Most recently, it has been demonstrated that preterm infants with a decrease in the number of circulating neutrophils at a postnatal

Chemotaxis and endothelial adherence

The airway secretions of infants with BPD have been shown to contain a number of chemotactic and chemokinetic factors that are responsible for the recruitment of neutrophils and macrophages. The chemotactic activity was considerably higher in infants with BPD than in babies who recovered from RDS.12 Besides the anaphylatoxin C5a, leukotriene B4, tumor necrosis factor-alpha (TNFα) interleukin-8 (IL-8), platelet activating factor, intercellular adhesion molecule-1 (ICAM-1), fibronectin, elastin

Respiratory distress syndrome and systemic inflammatory response

There is growing evidence that compounds of the plasma protein system activated after the initiation of RDS are able to affect the alveolar–capillary membrane both directly and indirectly by the sequestration of activated neutrophils and platelets in the pulmonary vascular bed. In mechanically ventilated infants with RDS, a simultaneous activation of clotting, fibrinolysis, kinin kallikrein and the complement system has been observed.32, 33, 34 Early activation of inflammation and the clotting

Pro- and anti-inflammatory cytokines

During the inflammatory process, which is only partly understood, several mediators may have direct detrimental effects on lung tissue structures by affecting cell integrity and inducing apoptosis. Besides IL-8, other pro-inflammatory cytokines, such as TNFα, IL-1 and IL-6, are important mediators in the early inflammatory response. These cytokines are synthesized by alveolar macrophages, fibroblasts, type II pneumocytes and endothelial cells upon stimulation by hypoxia, hyperoxia, endotoxin,

Mechanical ventilation and intrauterine and postnatal infection

The initiation of mechanical ventilation in preterm animals causes a pro-inflammatory response, suggesting that any barotrauma or volutrauma of the immature lung may be injurious.49, 50, 51, 52 The effect of mechanical ventilation on the generation of various inflammatory and anti-inflammatory cytokines in an isolated rat lung model in the presence or absence of endotoxin-induced sepsis has recently been studied.53 The highest levels of inflammatory cytokines were seen with those ventilatory

Proteolytic damage and transforming growth factor-beta

Elastase, a powerful neutral proteinase stored in the azurophilic granules of neutrophils, is thought to play an essential role in the pathogenesis of acute and chronic lung disease in preterm infants. In normal circumstances, elastase is rapidly bound and inactivated by α1-proteinase inhibitor (α1-PI), which protects the alveolar–capillary unit (Fig. 2;comptd;;center;stack;;;;;6;;;;;width> ).71 Increased concentrations of free elastase and low α1-PI-activities have been detected in the airway

References (99)

  • L.J. Van Marter et al.

    Chorioamnionitis, mechanical ventilation, and postnatal sepsis as modulators of chronic lung disease in preterm infants

    J Pediatr

    (2002)
  • C.P. Speer et al.

    Elastase-alpha-1-proteinase inhibitor in early diagnosis of neonatal septicemia

    J Pediatr

    (1986)
  • C.E. Gerber et al.

    Presence of bleomycin-detectable free iron in the alveolar system of preterm infants

    Biochem Biophys Res Commun

    (1999)
  • M.H. Alnahhas et al.

    Elevated laminin concentrations in lung secretions of preterm infants supported by mechanical ventilation are correlated with radiographic abnormalities

    J Pediatr

    (1997)
  • S.H. Murch et al.

    Disruption of sulphated glycosaminoglycans in intestinal inflammation

    Lancet

    (1993)
  • M.S. Gaylord et al.

    Altered platelet-activating factor levels and acetylhydrolase activities are associated with increasing severity of bronchopulmonary dysplasia

    Am J Med Sci

    (1996)
  • J.O. Niu et al.

    Early increase in endothelin-1 in tracheal aspirates of preterm infants: correlation with bronchopulmonary dysplasia

    J Pediatr

    (1998)
  • P.J. Sime et al.

    Transfer of tumor necrosis factor-α to rat lung induces severe pulmonary inflammation and patchy interstitial fibrogenesis with induction of transforming growth factor- β1 and myofibroblasts

    Am J Pathol

    (1998)
  • S. Kotecha et al.

    Increase in the concentration of transforming growth factor-β1 in bronchoalveolar lavage fluid before the development of chronic lung disease of prematurity

    J Pediatr

    (1996)
  • M.R. Pierce et al.

    The role of inflammation in the pathogenesis of bronchopulmonary dysplasia

    Pediatr Pulmonol

    (1995)
  • J.J. Zimmermann

    Bronchoalveolar inflammatory pathophysiology of bronchopulmonary dysplasia

    Clin Perinatol

    (1995)
  • S. Kotecha

    Cytokines in chronic lung disease of prematurity

    Eur J Pediatr

    (1996)
  • C.P. Speer

    New insights into the pathogenesis of pulmonary inflammation in preterm infants

    Biol Neonate

    (2001)
  • C.P. Speer et al.

    Inflammatory mediators in neonatal lung disease

  • A.H. Jobe et al.

    Bronchopulmonary dysplasia

    Am J Respir Crit Care Med

    (2001)
  • D.P. Carlton et al.

    Role of neutrophils in lung vascular injury and edema after premature birth in lambs

    J Appl Physiol

    (1997)
  • T.A. Merritt et al.

    Elastase and α1-proteinase inhibitor activity in tracheal aspirates during respiratory distress syndrome

    J Clin Invest

    (1983)
  • S. Arnon et al.

    Pulmonary inflammatory cells in ventilated preterm infants: effect of surfactant treatment

    Arch Dis Child

    (1993)
  • P. Groneck et al.

    Association of pulmonary inflammation and increased microvascular permeability during the development of bronchopulmonary dysplasia: a sequential analysis of inflammatory mediators in respiratory fluids of high risk preterm infants

    Pediatrics

    (1994)
  • S. Kotecha et al.

    Increase in interleukin-8 and soluble intercellular adhesion molecule-1 in bronchoalveolar lavage of premature infants with chronic lung disease

    Arch Dis Child

    (1995)
  • B.E. Ogden et al.

    Neonatal lung neutrophils and elastase/proteinase inhibitor imbalance

    Am Rev Respir Dis

    (1984)
  • J.C. Jackson et al.

    Mechanisms for reduced total lung capacity at birth and during hyaline membrane disease in premature newborn monkeys

    Am Rev Respir Dis

    (1990)
  • A. Clement et al.

    Alveolar macrophage status in bronchopulmonary dysplasia

    Pediatr Res

    (1988)
  • M.S. Rindfleisch et al.

    Potential role of interleukin-1 in the development of bronchopulmonary dysplasia

    J Interferon Cytokine Res

    (1996)
  • S.H. Murch et al.

    Mucosal tumor necrosis factor-α production and extensive disruption of sulfated glycosaminglycans begin within hours of birth in neonatal respiratory distress syndrome

    Pediatr Res

    (1996)
  • P. Groneck et al.

    Levels of complement anaphylatoxin C5a in pulmonary effluent fluid of infants at risk for chronic lung disease and effects of dexamethasone treatment

    Pediatr Res

    (1993)
  • S.L. Kunkel et al.

    Interleukin-8 (IL-8): the major neutrophil chemotactic factor in the lung

    Exp Lung Res

    (1991)
  • K.R. Stenmark et al.

    Potential role of eicosanoids and PAF in the pathophysiology of bronchopulmonary dysplasia

    Am Rev Respir Dis

    (1987)
  • C.A. Jones et al.

    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

    Pediatr Res

    (1996)
  • B. Jónsson et al.

    Early increase of TNFα and IL-6 in tracheobronchial aspirate fluid indicator of subsequent chronic lung disease in preterm infants

    Arch Dis Child

    (1997)
  • C.P. Speer

    Inflammatory mechanisms in neonatal chronic lung disease

    Eur J Pediatr

    (1999)
  • S. Little et al.

    Role of elevated plasma soluble ICAM-1 and bronchial lavage fluid IL-8 levels as markers of chronic lung disease in premature infants

    Thorax

    (1995)
  • U.K. Munshi et al.

    Elevation of interleukin-8 and interleukin-6 precedes the influx ofneutrophils in tracheal aspirates from preterm infants who develop bronchopulmonary dysplasia

    Pediatr Pulmonol

    (1997)
  • J. Takasaki et al.

    Interleukin 8 and granulocyte elastase in the tracheobronchial aspirate of infants without respiratory distress syndrome or intrauterine infection and development of chronic lung disease

    Acta Paediatr Jpn

    (1997)
  • D.P. Inwald et al.

    High concentrations of GRO-α and MCP-1 in bronchoalveolar fluid of infants with respiratory distress syndrome after surfactant

    Arch Dis Child

    (1998)
  • S. Kotecha et al.

    Soluble L-selectin concentrations in bronchoalveolar fluid obtained from infants who develop chronic lung disease

    Arch Dis Child

    (1998)
  • P.L. Ramsay et al.

    Early clinical markers for the development of bronchopulmonary dysplasia: soluble E-Selectin and ICAM-1

    Pediatrics

    (1998)
  • F. Brus et al.

    Activation of the plasma clotting, fibrinolytic, and kinin-kallikrein system in preterm infants with severe idiopathic respiratory distress syndrome

    Pediatr Res

    (1994)
  • F. Brus et al.

    Activation of circulating polymorphonuclear leukocytes in preterm infants with severe idiopathic respiratory distress syndrome

    Pediatr Res

    (1996)
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