Bronchiolitis obliterans syndrome in lung transplant recipients is associated with increased neutrophil activity and decreased antioxidant status in the lung

Abstract

Long-term survival of lung transplant recipients is limited by the advent of obliterative bronchiolitis and irreversible airways obstruction, e.g. bronchiolitis obliterans syndrome (BOS). This study investigated whether inflammatory cells and their activation markers were increased in bronchoalveolar lavage (BAL) and transbronchial biopsies (TBB) from patients with BOS. Levels of antioxidants in BAL fluid were also assessed. BAL fluid and TBB from six single-lung, two bilateral-lung, and five heart-lung transplanted patients with diagnosis of BOS were compared with 13 transplant recipients without BOS. BAL fluid levels of myeloperoxidase (MPO), eosinophil cationic protein (ECP) and interleukin (IL)-8 were used as markers for the activation and attraction of neutrophils and eosinophils, respectively. Immunohistochemical staining of TBB with monoclonal antibodies to MPO and ECP (EG2) was performed. Significantly increased BAL percentages of neutrophils and levels of MPO were found in patients with BOS. The findings correlated well with the degree of monoclonal staining for MPO in TBB. BAL levels of ECP and IL-8 were significantly increased in BOS patients. BAL concentrations of the water-soluble antioxidants ascorbate, urate and glutathione were generally lower in BOS patients. The results indicate that neutrophil infiltration and activation, as well as oxidative stress, may play a role in the development and/or progression of bronchiolitis obliterans syndrome. Markers for neutrophil activation could have a potential role in monitoring disease activity in patients with this syndrome.

Persistent high BAL fluid granulocyte activation marker levels as early indicators of bronchiolitis obliterans after lung transplant

“…DIGIOVINE et al [10] performed chemotactic studies in which IL-8 appeared to account for the neutrophil presence, and IL-8 was also found in the peribronchial region of their transbronchial biopsy specimens. Furthermore, in a cross-sectional study evidence was recently found of neutrophil granulocyte activation in the form of increased BAL fluid levels and degree of immunohistochemical staining of MPO in TBBs from BOS patients compared to matching controls [9].…”

“…In contrast, patients with manifest BOS proved to have significantly increased levels of both IL-8 and MPO, as well as neutrophil percentages, in BAL fluid compared to matched controls without BOS [9]. Furthermore, DIGIOVINE et al [10] reported from neutrophil chemotaxis experiments that IL-8 accounted for a significant amount of the neutrophil chemotactic activity found in lung transplant recipients with BOS.…”

Tissue remodelling in chronic bronchial diseases: from the epithelial to mesenchymal phenotype

“…Other pro-inflammatory cytokines, such as IL-8, TNF-a and IL-1b, are also highly expressed in BO patients [127,148,165]. This inflammatory environment could contribute to EMT in BO.…”

“…Studies in the inflammatory environment of BO have shown that TGF-b is one of the most important factors involved in the fibrotic process and high levels of TGF-b are found in the BAL from BO patients [148,[161][162][163][164][165]. Other pro-inflammatory cytokines, such as IL-8, TNF-a and IL-1b, are also highly expressed in BO patients [127,148,165].…”

“…BO results from an allogeneic mechanism in which allo-antigens are presented to T-lymphocytes from the recipient [148,149]. Even though the immune response plays a role in the development of BO, the respiratory epithelium also contributes to the fibrotic phenomenon.…”