2P-S5-2

 

NEW INSIGHTS INTO THE PATHOGENESIS OF CHRONIC LUNG DISEASE

Speer CP

University Children’s Hospital Würzburg/Germany

 

Chronic lung disease is associated with a significant inflammatory response of the airways and the interstitium of the lungs; besides neutrophils, macrophages immunoreactive for tumor necrosis factor-a (TNF-α) are found in large numbers. Phagocyte influx is possibly mediated by chemotactic and chemokinetic factors present in the alveolar secretions. Leukotriene B4, C5a, Interleukin-8 (IL-8), elastin fragments and other factors may contribute to the high chemotactic activity. IL 8 which is probably the most important chemotactic factor in the lung is produced by alveolar macrophages, fibroblasts, type II pneumocytes and endothelial cells upon stimulation by hypoxia, hyperoxia, endotoxin and other factors. Monocyte chemotactic protein-I, macrophage inflammatory protein-1α and other chemokines may induce migration of monocytes and macrophages. Intercellular adhesion molecule-1 and selectins which have been detected in bronchoalveolar secretions of infants with chronic lung disease (CLD) may promote neutrophil diapedesis. Besides IL-8 other proinflammatory cytokines such as TNF-α, Interleukin-1 (IL-1) and Interleukin-6 (IL-6) seem to be important mediators in the early inflammatory response by activating inflammatory cells. Production of these proinflammatory cytokines is regulated in part by the antiinflammatory cytokine Interleukin-10 (IL-10). The increased levels and enhances mRNA-expression of proinflammatory cytokines present in the airways and the pulmonary tissue may reflect an inability to regulate inflammation through an adequate expression of the antiinflammatory cytokine IL-10. 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.

Epidemiological data suggest a strong association between chorioamnionitis and the development of CLD. In a subset of infants, increased concentrations of cytokines in amniotic fluid including TNF-a, IL-1, IL-6 and IL-8 were clearly identified as risk factors of CLD. In addition, elevated levels of IL-6 in fetal cord blood at birth were shown to be an independent risk factor for the development of CLD. These data support the concept that – at least in some infants – the injury responsible for CLD may begin before birth. Moreover, our most recent findings indicate that chorioamnionitis is associated with an intrauterine inflammatory response of the fetal lung characterised by a marked infiltration of neutrophils and macrophages as well as an increased expression of IL-8 mRNA.

Neutrophils and macrophages attracted to the site of injured tissue can cause severe lung damage by release of potent proteases (elastase, collagenase), proinflammatory cytokines and by generation of toxic oxygen radicals. The presence of free elastase activity and oxidative inactivation of a1-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. Due to high concentrations of free iron detected in airway samples of infants with respiratory distress syndrome hydroxil-radicals are generated during release of toxic oxygen metabolites by phagocytes and tissue-bound xanthine oxidase. In fact, increased concentrations of products of elastolytic fiber 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 still to be defined. However, there is growing evidence that the inflammatory process may affect normal alveolization and pulmonary vascular development in preterm infants with CLD.