The airway epithelium is a direct source of matrix degrading enzymes in bronchiolitis obliterans syndrome

doi:10.1016/j.healun.2011.06.007

The Journal of Heart and Lung Transplantation

Volume 30, Issue 10, October 2011, Pages 1175-1185

https://doi.org/10.1016/j.healun.2011.06.007 Get rights and content

Background

Long-term survival after lung transplantation is hindered by the development of bronchiolitis obliterans syndrome (BOS), and recent evidence suggests that dysregulated epithelial repair may underlie its development. Because matrix metalloproteinase (MMP) -2 and MMP-9 secretion is integral to repair, we hypothesized that airway epithelial cells from patients with BOS would over-express these matrix-degrading enzymes.

Methods

Cells obtained from bronchial and bronchiolar brushings from patients with and without BOS (without acute rejection or infection) were analyzed via quantitative polymerase chain reaction and immunocytochemistry for MMP-2, and MMP-9 gene and protein expression. The expression of tissue inhibitor of metalloproteinase (TIMP)2 and TIMP1 was also assessed. MMP activity in bronchoalveolar lavage was determined via gelatin zymography.

Results

MMP-2 and MMP-9 production was significantly higher in bronchoalveolar lavage (3.85- and 11.59-fold, p < 0.001) and airway epithelium (MMP-2 bronchial: 6.33-fold, bronchiolar: 3.57-fold, both p < 0.001; MMP-9 bronchial: 32.55-fold, p < 0.001; bronchiolar: 8.60-fold, p = 0.01) in patients with BOS, but expression in patients without BOS was not different from healthy controls. TIMP expression was similar in patients with and without BOS. Immunostaining confirmed that the airway epithelium was a direct source of MMP-2 and MMP-9 expression in patients with BOS.

Conclusion

In patients with BOS, the airway epithelium over-expresses MMPs, even in the absence of acute rejection or infection. Dysregulated epithelial repair may be a key feature of BOS.

Section snippets

Materials and methods

The study was approved by the Royal Perth Hospital and the Prince Charles Hospital Human Research and Ethics Committees. Please refer to the online supplement for full details.

Results

MMP-2 and MMP-9 activity in BAL from patients with BOS was significantly higher compared with those without (3.85-fold higher for MMP-2 [p < 0.001], and 11.59-fold higher for MMP-9 [p < 0.001] and healthy controls [p < 0.001 for MMP-2 and MMP-9]; Figure 1), but there was no difference between patients without BOS and healthy controls (p = 0.07 for MMP-2 and p = 0.52 for MMP-9; Figure 1). A significant up-regulation in the gene expression of MMP-9 (32.55-fold [p < 0.001] for bronchial and

Discussion

We have demonstrated that the bronchial and bronchiolar epithelium are a direct source of MMP-2 and MMP-9, the matrix-degrading enzymes that orchestrate airway remodelling in BOS. In contrast, epithelial MMP expression in patients with normal allograft function is no different from healthy controls (Figure 2). We also found that the increased expression of MMP-2 and MMP-9 was unchecked because there was no corresponding increase in the expression of the associated tissue inhibitors of MMPs,

Disclosure statement

This work was supported by an Ada Bartholomew Medical Research Trust Grant, the WA Heart & Lung Transplant Foundation, the Alcock Brown-Neaves Foundation, the RPH Medical Research Foundation, and a UWA Research Development Award. Stephen M. Stick is a National Health and Medical Research Council (NHMRC) Practitioner Fellow.

None of the authors has a financial relationship with a commercial entity that has an interest in the subject of the presented manuscript or other conflicts of interest do

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Original pre-clinical scienceThe airway epithelium is a direct source of matrix degrading enzymes in bronchiolitis obliterans syndrome

Background

Methods

Results

Conclusion

Section snippets

Materials and methods

Results

Discussion

Disclosure statement

J Heart Lung Transplant

Am J Transplant

J Heart Lung Transplant

J Heart Lung Transplant

J Heart Lung Transplant

J Biol Chem

Am J Transplant

Am J Transplant

J Biol Chem

Bronchiolitis Obliterans after Human Lung Transplantation

Am J Respir Crit Care Med

Increased gelatinolytic activity in bronchoalveolar lavage fluid in stable lung transplant recipients

Am J Respir Crit Care Med

Matrix metalloproteinase-9 in bronchiolitis obliterans syndrome after lung transplantation

Eur Respir J

The presence of a matrix-derived neutrophil chemoattractant in bronchiolitis obliterans syndrome after lung transplantation

J Immunol

Pathogenesis of COPDPart I. The role of protease-antiprotease imbalance in emphysema

Int J Tuberc Lung Dis

Airway neutrophilia in stable and bronchiolitis obliterans syndrome patients following lung transplantation

Thorax

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

Transplant Infect Dis

Successful establishment of primary small airway cell cultures in human lung transplantation

Respir Res

The use of non-bronchoscopic brushings to study the paediatric airway

Respir Res

Original pre-clinical science
The airway epithelium is a direct source of matrix degrading enzymes in bronchiolitis obliterans syndrome