The role of neutrophils in the pathogenesis of obliterative bronchiolitis after lung transplantation

Abstract

Obliterative bronchiolitis (OB) represents the most important long-term complication after lung transplantation. Elevated numbers of neutrophils within the airways are a hallmark of OB. It is unclear what causes the recruitment and activation of neutrophils in the airways of patients with OB: the process of chronic rejection itself or infection, which may (especially in latent virus infection) often be overlooked by the currently applied diagnostic procedures. It is well known that besides their physiologic functions in the clearance of invading micro-organisms, activated neutrophils have a remarkable potential to cause damage to lung tissue. This is attributable to their capability to generate reactive oxygen species and to release potentially toxic proteases. It has been shown that the increased numbers of neutrophils in bronchoalveolar lavage fluid of patients with bronchiolitis obliterans syndrome (BOS) after lung transplantation are associated with elevated levels of interleukin-8, the predominant neutrophil chemotactic factor in the lung. As evidence for the impact of neutrophils on the pathogenesis of BOS, there is significant oxidative stress within the airways of patients with BOS. In addition, the milieu within the airways is characterized by an imbalance between neutrophil elastase (NE) and molecules that inhibit NE as a result of an increased burden of NE released by neutrophils. A defective antiprotease shield due to the loss of secretory leukoprotease inhibitor could be demonstrated in BOS. These mechanisms may provide possible targets to develop new therapeutic strategies that either prevent neutrophil sequestration and activation, or inhibit neutrophil products in order to prevent or attenuate airway damage.