Oxygen radicals, cytokines, adhesion molecules and lung injury in neonates

Abstract

Chronic lung disease of preterm infants (CLD) has a multifactorial aetiology. Pulmonary immaturity, oxygen toxicity and mechanical injury (barotrauma) as well as additional factors such as infections with Ureaplasma urealyticum and other micro-organisms may contribute to pulmonary damage. The mechanisms of acute lung injury observed during the initial stage of respiratory distress syndrome are incompletely understood. There is growing evidence, however, that an inflammatory pulmonary reaction following lung injury may be an early event in the development of CLD, finally leading to lung fibrosis. CLD is associated with a significant inflammatory response of the airways and the interstitium of the lungs; besides neutrophils, macrophages immunoreactive for tumour necrosis factor α are found in large numbers. Phagocyte influx is possibly mediated by chemotactic factors present in the alveolar secretions. Leukotriene B 4 , C5a, interleukin 8, elastin fragments and other factors may contribute to the high chemotactic activity. Intercellular adhesion molecule 1, which has been detected in bronchoalveolar secretions of infants with CLD, may promote neutrophil diapedesis. Furthermore, a number of lipid mediators including leukotrienes, prostacyclin and platelet-activating factor were found to be elevated in bronchoalveolar lavage fluid. These and other mediators which are mainly released by macrophages and pulmonary cells exert various effects on the airways and the vascular system by increasing the microvascular permeability; this increased alveolar-capillary leakage is one of the most important pathophysiological factors of early CLD. Neutrophils and macrophages attracted to the site of injured tissue can cause severe lung damage by release of potent proteases (elastase, collagenase), pro-inflammatory cytokines and by generation of toxic oxygen radicals. The presence of free elastase activity and oxidative inactivation of α 1 -proteinase inhibitor which protects the alveolar-capillary unit from autolytic proteolysis has been well documented. The protease-antiprotease imbalance as well as toxic oxygen radicals released by phagocytes or generated by tissue bound xanthine oxidase may play a central role in lung injury. In fact, increased concentrations of products of elastolytic fibre degradation and other structural components of lung tissue as well as of oxygen radical mediated lipid peroxidation were detected in infants with CLD; antioxidant activity of preterm infants seems to be insufficient to deal with free oxygen radicals. The complex interaction between mediators of inflammation and fibrosis has not been defined yet.