Decreased efferocytosis and mannose binding lectin in the airway in bronchiolitis obliterans syndrome

Abstract

Short running title: Decreased efferocytosis and MBL in BOSwith BOS) and 14 healthy controls. Abstract & Manuscript 2Results: In plasma, MBL levels were highly variable (0-17.538 g/mL), but increased in infected subjects vs control (p=0.09) or stable groups (p=0.003). There was a similar increase in UC4 in infected patients and a significant correlation between MBL and UC4. There was no correlation between MBL and time post-transplant. In BAL, MBL levels were less variable (0-73.3 ng/mL) and significantly reduced in patients with BOS vs controls and stable groups. 3Lung transplantation is now recognized as an effective treatment option for a variety of end-stage lung diseases and is associated with improvements in life expectancy and quality of life. However the five-year survival is currently only around 60%, the worst of any solid organ transplant, with death beyond the acute phase being largely due to progressive and treatment refractory airway remodeling (obliterative bronchiolitis, OB) manifest clinically as bronchiolitis obliterans syndrome (BOS). BOS is thought to follow persistent alloreactive, infective, and non-specific epithelial injury with dysregulated epithelial repair 1 . Although the predominant histopathologic finding in patients with OB is of fibro-proliferative small airway obliteration, large airways are also affected with the eventual development of bronchiectasis, leading directly to patient morbidity and mortality.The well-ordered process of apoptosis is important for regulation and maintenance of normal tissue homeostasis. During resolution of airway inflammation, apoptotic epithelial cells are removed by phagocytosis by alveolar macrophages (a process termed 'efferocytosis'). The pathological concept of failed efferocytosis has been described in regard to a number of lung diseases including pulmonary fibrosis 2 , cystic fibrosis 3 chronic granulomatous disease 4 smokers and patients chronic obstructive pulmonary disease (COPD) 5-8 .It is considered that the failed efferocytosis results in a net increase in apoptotic material that may lead to secondary necrosis of this material resulting in increased tissue damage and chronic inflammation. This was clearly shown in our studies of COPD where we found evidence of secondary necrosis (increased lactate dehydrogenase in BAL) and that the increased numbers of apoptotic bronchial epithelial cells negatively correlated with efferocytosis 6,9 . In lung transplant recipients we have also described an accumulation of apoptotic material associated with an increase in the cytotoxic mediator granzyme b in the airways 10,11 .Mannose binding lectin (MBL) is a key mediator of both innate immunity and efferocytosis and is thus likely to be important in protecting against lung tissue damage. In other inflammatory chronic lung diseases including COPD, we have shown reduced levels of MBL that correlated with a defect in the 4 ability of alveolar macrophages to phagocytose apoptotic bronchial epithelial cells (efferocytosis) 8 . We further showed that treatm...

Oxidative Stress Decreases Functional Airway Mannose Binding Lectin in COPD

“…We have also demonstrated impaired phagocytosis of bacteria in COPD; an important finding given the increased bacterial colonization and increased susceptibility to infectious exacerbations in these patients [6], [7]. These defects are not isolated to COPD, as we have also reported increased numbers of apoptotic bronchial epithelial cells and defective efferocytosis in the airways in other chronic lung diseases including severe asthma and chronic lung transplant rejection [8], [9]. Importantly, these defects could be substantially overcome using macrophage-targeted therapies [6], [10]–[14].…”

“…Presence of MBL in bronchoalveolar lavage (BAL) of children with airway infections but not controls suggests its role in pulmonary defence [18]. We have extensively investigated MBL in lung diseases, in particular in smokers and COPD patients and in a smoke-exposed mouse model [8], [12]. Our data showed significantly reduced levels of functional MBL in the airway of COPD subjects and healthy smokers compared to non-COPD controls, and further demonstrated a positive correlation between efferocytosis and MBL in the airway [8].…”

Mannan-Binding Lectin in Cardiovascular Disease

“…Its higher levels in plasma of recipients were associated with development of bronchiolitis obliterans syndrome (BOS) and poorer long-term outcome [56, 57]. Immunohistochemistry revealed the presence of MBL in lung tissue from patients with BOS and at the time of ischaemia [57]. Moreover, Carroll et al [58] observed a significant increase of MBL concentration in plasma at 3, 6, and 12 months after transplantation.…”

“…Interestingly, the presence of MBL in bronchoalveolar lavage (BAL) (3 and 6 months after transplant) was associated with later BOS development [58]. In contrast, Hodge et al [57] found no correlation between blood MBL levels and time after transplantation. They found lower MBL concentrations in BAL from recipients who developed BOS, in comparison with controls and patients with stable graft function.…”

Effects of Hypercapnia in Lung Tissue Repair and Transplant

“…Such a delay in clearance of cellular debris can results in poor healing following lung injury. In fact, there is now evidence to support that defective macrophage function and reduced ability to clear apoptotic cells can lead to progressive pulmonary fibrosis both in native lungs [26] and transplanted lung allografts [27].…”