Systemic disease or local injury initiates the inflammatory response with the recruitment and activation of effector cells, predominate^ the polymorphonuclear neutrophil (PMN). Exudation of plasma proteins into the alveolar space and the release of pro-inflammatory cytokines result from damage to the pulmonary capillary endothelium and epithelium. Other cells, including macrophages, influx into the lungs playing a role in the down-regulation of the inflammatory response with the release of the anti-inflammatory mediators. The balance of these two processes is important for the reestablishment of normal tissue function and structure, because if the reparative process is not controlled, fibrosis can result.
Cytokines are mediators that interact within this complex process to coordinate the inflammatory response and repair. They are low molecular weight soluble proteins compartmentalized in both the alveolar and tissue compartments of the lung and are synthesized and released in response to an inflammatory stimulus. Cytokines are produced by various cell types and regulate cell function either locally or distally eliciting physiological and biochemical responses in critically ill patients. Interference in postnatal alveolarization and vascular development in the very preterm lung by cytokines has been suggested as a cause of chronic lung disease. Cytokines may also play a role in premature infants with secondary respiratory decompensation, inhibiting surfactant function, contributing to acute respiratory decompensation and increasing fibroblast activity.
Macrophages activated by the release of endotoxin initiate the release of pro-inflammatory mediators early in the course of disease. Inflammatory cytokines include IL- lβ, IL-6 and TNF-α, and along with CXCL8 are mediators of the early inflammatory response. IL-lβ and TNF-α are both produced by mononuclear phagocytes, initiate the inflammatory response and actually begin the process that leads to recognition, recruitment, removal and repair of tissue injury in the cytokine cascade. Interleukin-1 is stimulated by bacteria cell walls and induces IL-6, CXCL8 and TNF-α. It is an acute-phase reaction and elevation causes leucopenia, hypotension and myocardial depression, similar to septic shock. High concentrations of TNF-α and IL-1β have been found in the bronchoalveolar fluid (BAL) at the onset of acute respiratory distress syndrome, with higher levels in ARDS patients who die. High IL-1β has also been found in infants in the first week of life who later develop Chronic Lung Disease (CLD). Following endotoxin stimulation, monocytes and macrophages secrete TNF-α activating IL-1β, IL-6 and CXCL8. TNF-α is a critical inflammatory mediator in septic shock, and has been shown to cause capillary leak, ARDS, hypotensive shock, acute renal failure, DIC and neutropenia.
Interleukin-6 is produced by macrophages, endothelial cells, smooth muscle cells and fibroblasts when exposed to TNF-α and IL-1β. As with many other cytokines, it has both pro-inflammatory and anti-inflammatory properties. IL-6 induces acute-phase protein synthesis in hepatocytes and is increased in sepsis and severe disease. The anti-inflammatory properties act through inhibition in the production of TNF-α and IL-1β. High levels of IL-6 have been found in infants at risk for CLD and patients with ARDS.
Chemokines are a large family of cytokines, induced by other cytokines, as well as endotoxin and are chemotactic for neutrophils and monocytes. CXCL8 is an example of a chemokine produced locally by alveolar macrophages, monocytes, type II alveolar cells, and endothelial cells and is important in mediating pulmonary neutrophil recruitment. It promotes vascular leak and is elevated in patients with septic shock. High sustained levels of CXCL8 has been found to be important as a mediator of lung disease in adults, children and have been associated with an increased risk for CLD in neonates. In tracheal aspirates and lung lavage fluid from preterm infants, elevated CXCL8 is a predictor of poor outcome. CXCL8 levels have been reported to be increased in extremely premature infants, preterm infants (> 32 weeks) and term infants. However, there was a faster response seen in term infants, which may indicate a developmental inflammatory response.
The balance of cytokine production is complex and critical in protecting against the effects of the pro-inflammatory mediators. Prolonged or increased production of the pro-inflammatory mediators has been linked in the pathophysiology of septic shock. The compensatory anti-inflammatory response releases substances to limit the effects of the pro-inflammatory mediators. Interleukin-10 is a powerful anti-inflammatory cytokine that down regulates the inflammatory process by decreasing production of TNF-α, IL-1β and CXCL8 by macrophages and monocytes. In one study of ventilated preterm infants, CXCL8 levels increased in B AL fluid over the first 5 days of life, followed by an increase in IL-10 levels. This early, significant increase in both cytokines was seen in infants who were developing or dying of chronic lung disease.