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.