Simvastatin attenuates release of neutrophilic and remodeling factors from primary bronchial epithelial cells derived from stable lung transplant recipients

Abstract

Obliterative bronchiolitis (OB), the major cause of chronic lung allograft dysfunction, is characterized by airway neutrophilia, inflammation, and remodeling, with progressive fibroproliferation and obliteration of small airways that ultimately leads to patient death. Statins have potential anti-inflammatory effects and have been demonstrated to confer a survival advantage in lung transplant patients. We postulated that the beneficial effects of simvastatin in lung transplantation are in part due to inhibition of the epithelial production of key mediators of neutrophil chemotaxis, inflammation, and airway remodeling. Our objective was to assess the effect of simvastatin on a unique population of primary bronchial epithelial cells (PBECs) derived from stable lung allografts, with specific reference to airway neutrophilia and remodeling. PBEC cultures were stimulated with IL-17 or transforming growth factor (TGF)-beta, with and without simvastatin. Supernatant levels of factors critical to driving airway neutrophilia and remodeling were measured. IL-17 upregulated IL-8, IL-6, granulocyte colony-stimulating factor, granulocyte-macrophage colony-stimulating factor (GM-CSF), and VEGF, whereas TGF-beta increased IL-6, GM-CSF, matrix metalloproteinase (MMP)-2, and MMP-9. Simvastatin attenuated effects of both IL-17 and TGF-beta. We have demonstrated the ability of simvastatin to attenuate release of airway neutrophilic and remodeling mediators and to inhibit their upregulation by TGF-beta and IL-17. These data illustrate the potential of simvastatin to alleviate neutrophilic airway inflammation and remodeling in the transplanted lung and may have additional relevance to other neutrophilic airway conditions, such as chronic obstructive pulmonary disease.

Systemic manifestations and comorbidities of COPD

“…Statins also prevent elastase-mediated emphysema in mice and are associated with evidence for proliferation and regeneration of alveolar epithelial cells [184]. At a cellular level, statins inhibit the effects of IL-17 and TGF-b in stimulating mediator release from primary airway epithelial cells, indicating their potential to modulate the inflammatory response and small airway fibrosis in COPD [185]. Statins also stimulate the uptake of apoptotic neutrophils by alveolar macrophages (efferocytosis), an effect that is mediated via inhibition of the prenylation and activation of RhoA, which is involved in the phagocytosis of apoptotic cells [186].…”

Pharmacological actions of statins: potential utility in COPD

“…Studies have shown that statins reduce neutrophil influx in the lung which might have a strong effect on attenuating the downstream inflammatory events, such as macrophage influx, lymphocyte activation and inhibition of cytokine release, in particular IL-8 that appears central to the neutrophil inflammation of the lung [67][68][69][70][71][72][73][74][75][76][77][80][81][82][83][84][85][86][87][88]. The inhibition of IL-6, IL-8 and GM-CSF expression by statins has been shown in cell cultures of human BEC [65,70]. Statins have also been shown to modify airway inflammation in animal models and matrix remodelling, notably inhibiting emphysema formation [73][74][75].…”

“…Further support for the protective role of statins on lung inflammation comes from lung transplant studies that show concomitant use of statins reduces post-transplant bronchiolitis and improves lung function compared to patients not receiving statins [70,76,82,121]. This is an inflammatorybased complication of lung transplantation with over lapping pathology with COPD, including small airway inflammation dominated by airway fibrosis (bronchiolitis obliterans).…”

Interleukin-17 and T Helper 17 Cells in Mucosal Immunity of the Lung

“…IL-17 seems to be an important mediator of linking activated T cells to accumulation of neutrophils, although solid data on T helper cells and neutrophils are lacking. In vitro work confirmed that IL-17 orchestrated neutrophilic influx by the production of CXCL8 (IL-8), CXCL1 (GRO-a), and granulocyte-macrophage colony stimulating factor (GM-CSF) in airway epithelial cells, smooth muscle cells, endothelial cells, and fibroblasts (Murphy et al 2008). So, the importance of Th17 cells in neutrophilic inflammation lies in the ability of IL-17 to induce granulopoiesis, neutrophil chemotaxis, and the anti-apoptotic properties of G-CSF (Kolls and Linden 2004;Ouyang, Kolls, and Zheng 2008).…”