The role of inflammation in hyperoxia-induced lung injury

Abstract

The development of acute (HMD) and chronic (BPD) lung disease in premature human neonates is characterised, in part, by pulmonary inflammation. One of the pathophysiological determinants of lung injury includes exposure to high inspired concentrations of oxygen. Due to the practical and ethical problems associated with the study of these diseases a guinea pig (GP) model of prematurity has been developed. In this thesis the role of inflammation, following exposure to oxygen in the development of acute and chronic lung disease was investigated using the GP model of prematurity.
Delivery of preterm GP’s (3 days premature) by Caesarian section in to air (21% oxygen), results in lung injury, evidenced by an alteration in the permeability of the lung which leads to an increase in lung wet weight and bronchoalveolar fluid (BALF) protein. BALE phospholipase A₂ activity was also raised and suggests that pro-inflammatory lipids may be present in the lung. Following an acute period of oxygen exposure, lung injury and mortality increased. The presence of activated neutrophils (PMN’s) and leukotriene B₄ (LTB₄) in BALF indicated an on going inflammation which was investigated further.
Neutrophils have the potential to cause extensive tissue injury through the generation of superoxide. Although BALF cells from both preterm and term animals exposed to 95% oxygen generated significantly less superoxide than air exposed animals. As it proved difficult to isolate and study alveolar neutrophils, superoxide production from peritoneal PMN’s of term and preterm pups was studied. No significant difference between term and preterm PMN superoxide generation was found. To further study the relationship between PMN’s and lung injury, a specific antisera to GP PMN’s was used to deplete these cells from the circulation. However, PMN depletion did not alter the degree of lung injury or survival. The role of PAF and LTB₄ in HMD in oxygen-induced lung injury was investigated using specific receptor antagonists. Treatment with the PAF antagonist, WEB2086, blunted inflammation and injury. However, no reduction in survival was observed. A similar observation was attained using the LTB₄ antagonist, U75302, although this was attributed to the possible antioxidant effects of the vehicle. These observations suggest that injury to the lung probably involves a number of different mediators.
The role of inflammation in prolonged (28 days) hyperoxic exposure was also studied. Qualitative microscopic analysis of premature GP’s exposed to 28 days 85% oxygen demonstrated changes similar to those observed in human infants with BPD. Although inflammation was present through out the exposure period, the observed induction of antioxidants may have contributed to reduction in lung injury that occurred between days 14 and 28. This thesis reports a description of the GP model of prematurity and the role of particular inflammatory mediators in the development of HMD and BPD.

More information

Identifiers

Catalogue record

Export record