Inflammation and bronchopulmonary dysplasia
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
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