The Presence of a Matrix-Derived Neutrophil Chemoattractant in Bronchiolitis Obliterans Syndrome after Lung Transplantation

Abstract

Lung transplantation is a therapeutic modality frequently utilized in end-stage lung disease. Unfortunately, lung transplant recipients have poor clinical outcomes, often due to the development of chronic rejection in the transplanted allograft. This process is characterized by neutrophil influx and extracellular matrix remodeling leading to luminal obstruction and airway inflammation. The molecular mechanisms underlying chronic rejection are poorly understood and disease-specific biomarkers are lacking. We report that in addition to increased levels of interleukin-8 (IL-8), the level of neutrophil chemoattractant proline-glycine-proline (PGP) is elevated in chronic rejection patient bronchoalveolar lavage (BAL) fluid and correlates with loss of lung function. The enzymes responsible for generating PGP, matrix metalloproteases-8 and -9 (MMP-8, -9) and prolyl endopeptidase (PE), are also elevated in chronic rejection samples. Together, IL-8 and PGP account for most of the neutrophil chemoattractant capacity seen in chronic rejection BAL fluid. Using specific neutralizing antibodies to both IL-8 and PGP, we demonstrate that PGP is the major neutrophil chemoattractant found in BAL fluid from individuals at the time of chronic rejection. These findings highlight the influence of a matrix-derived neutrophil chemoattractant in post-transplantation organ rejection and provide opportunities for the development of unique diagnostics and therapeutics to potentially improve disease outcomes.

A Potential Role for Acrolein in Neutrophil-Mediated Chronic Inflammation

“…Here, we provide a mechanism for acrolein-mediated neutrophilic inflammation through upregulation of the enzymes MMP-9 and PE at concentrations similar to those found in cigarette smoke. These enzymes are of particular importance because they are critical in the stepwise degradation of collagen to PGP [10,11] which may play a role in the pathogenesis and progression of COPD [29,32], CF [11], and bronchiolitis obliterans syndrome [33]. Additionally, the actions of acrolein selectively inhibit LTA4H aminopeptidase activity, preventing its normal function of degrading PGP [12] and resolution of acute inflammation thereby setting up a self-propagating inflammatory environment.…”

Bioactive extracellular matrix fragments in lung health and disease

“…The RTR antagonist (described above) abrogated PMN infiltration into mouse lungs in response to Ac-PGP exposure, and also prevented LPS-or cigarette smoke-induced neutrophilia, weakly suppressed in vitro IL-8-dependent neutrophil chemotaxis, and rescued emphysema after administration of either Ac-PGP or LPS (49,50). As was observed in COPD (51,52), PGP is upregulated in many other human lung diseases, including cystic fibrosis (CF) exacerbation (44), bronchiolitis obliterans syndrome (53), and acute respiratory distress syndrome (ARDS) (47,54). Notably, cigarette smoke (CS) influences PGP activity via LTA4H.…”

“…However, the diverse actions of HA are not fully explained by CD44 signaling, as some cells lacking CD44 (macrophages, epithelia, tumor cells, and others) respond to HA (80,85). Lowmolecular weight forms of HA induce cytokine production and a proinflammatory phenotype, whereas larger HA fragments maintain an epithelial protective phenotype via ligation of TLR4 and TLR2 (53), similar to the homeostatic epithelial TLR signaling in the gut, which maintains both appropriate inflammatory signaling and epithelial integrity (86). Based on these studies, there is an emerging paradigm in which multifaceted HA matrikine sig- Because the ECM functions as a scaffold for organ architectural stability and development, the interactions of various cell types with the molecules that make up the ECM are highly conserved and carefully orchestrated.…”

“…Mass spectrometry has been used to measure PGP peptides in clinical samples from patients with COPD (43, 51, 52), CF, bronchiolitis obliterans syndrome, and ARDS (44,53,54), with strong positive correlations seen between PGP levels and disease activity. PGP is now being measured as a dynamic biochemical readout in clinical trials involving patients with stable COPD and those suffering from CF exacerbation (52,102).…”

Direct Leukocyte Migration across Pulmonary Arterioles and Venules into the Perivascular Interstitium of Murine Lungs during Bleomycin Injury and Repair

“…[1][2][3][4][5][6][7][8][9][10][11] Although inflammation is a natural host response to infection and injury, excessive or unresolved inflammatory processes can play a role in cell injury and tissue remodeling with severe pathological consequences. For example, leukocytes such as neutrophils, eosinophils, and monocytes have been implicated as mediators of lung and vascular injury, [12][13][14][15][16][17] although the extent to which inflammatory cells and mediators directly cause lung cell injury or modulate development of fibrosis remains controversial.…”