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• W2092778514 abstract "Must not all things at the last be swallowed up in death? (Plato (427–347 BCE), Dialogues, Phaedo (360 BCE)). A true understanding of granulocyte contributions to airway inflammatory pathology remains elusive. These cells undoubtedly have an impact on inflammatory disease with correlations existing between disease severities and their presence at inflammatory sites [1]. Eosinophils are associated with asthma and allergy and their presence is known to correlate with disease severity. They have well-documented cytotoxic potential resulting in damage to the epithelium while their release of lipid mediators such as cysteinyl leukotrienes can obstruct airflow [2, 3]. Two recently developed eosinophil-deficient mouse models, although yielding differing results, have provided strong support for eosinophil involvement in asthma [4, 5]. Divergence between the models may have reflected differing mouse backgrounds, i.e. Balb/c vs. B6 mice, but taken together a predominant role for eosinophils in airway remodelling and disease severity was suggested [6]. Balzar et al. [7] reinforced this view by showing that transforming growth factor (TGF)-β2, secreted primarily by tissue eosinophils, is the predominant isoform in severe asthma and is associated with augmented pro-fibrotic responses. With approximately 50% of asthma attributed to eosinophils, neutrophil-mediated asthma could represent a major subset of asthma pathology [8, 9]. After allergen challenge it is neutrophils that infiltrate the lung first and their high numbers in nocturnal asthma correlate with disease severity [10]. Mucus secretion has also been linked to neutrophil elastase's potent secretagogue capacity on airway epithelial cells and submucosal gland cells and it has been postulated that neutrophil-driven goblet cell metaplasia is a key facet of neutrophilic asthma [11]. Although we know much of their ingression mechanisms, recruited granulocyte fate remains unresolved. The where, when and why of apoptosis induction and phagocytic clearance are crucial facets required for our understanding of airway inflammation. Peripheral blood granulocytes are recruited under the influence of chemokines and cytokines, such as IL-5 and GM-CSF, which also promote their survival. Tissue transmigration also involves interactions with endothelial cells, extracellular matrix (ECM) and epithelial cells. While the close proximity of granulocytes with the endothelium brings them in contact with endothelial-derived survival-enhancing factors, such as the one(s) identified by Brazil et al. [12] in the current issue of Clinical and Experimental Allergy, the role of direct cell–cell contact is yet to be fully elucidated. This too may impart anti-apoptotic signals to the migrating granulocytes. LPS-stimulated neutrophils migrating through an endothelial cell line exhibited delayed apoptosis [13] and neutrophils migrating through a bilayer of human lung endothelial cells and epithelial cells exhibited reduced apoptosis [14]. The bilayer study highlighted that despite enhanced survival the cells remained susceptible to further apoptotic stimuli such as anti-Fas monoclonal antibody ligation and TNF-α treatment. This may be important as phagocytosis of apoptotic cells can result in Fas-L release from macrophages and apoptosis of bystander leucocytes [15]. Interestingly, Brazil et al.'s [12] uncharacterized survival factor(s) for neutrophils remained present even when neutrophil numbers began to diminish suggesting that neutrophil longevity may have been perturbed by non-soluble factors in the epithelial lining fluid. Indeed, we have demonstrated that freshly isolated human eosinophils left in cell–cell contact with primary human small airway epithelial cells for up to 24 h were induced to undergo apoptosis above constitutive levels and that this apoptosis was not rescued by concomitant co-culture with IL-5 at levels known to prolong eosinophils survival in vitro [16]. Unfortunately transmigrated cells in the bilayer study [14] went into suspension rather than maintaining cell–cell contact with the epithelium so the impact of this mode of interaction was not ascertained. Transmigration also results in ECM interactions. These can impart pro-survival signals to interacting eosinophils [17, 18]. Neutrophil data, however, suggest that ECM interactions are more complicated with apoptosis induction or survival depending on the activation state/physiochemical exposure of the neutrophils [19, 20]. Physiochemical properties such as low pH and hypoxia at inflammatory sites can, for example, exert survival enhancement in granulocytes [21-24]. The complexities of granulocyte interactions with other cells, ECM and cytokines mean that reductionist in vitro experiments while providing key insights into specific granulocyte interactions fail to provide information on the ultimate fate of granulocytes in a particular in vivo situation. Once recruited clearance of granulocytes can be attained by lymphatic drainage [25, 26], systemic re-circulation [27, 28] or phagocytosis following apoptosis or necrosis [29]. Hughes et al. [27] found that while neutrophil clearance from inflamed glomeruli involved phagocytosis of apoptotic PMN by intraluminal macrophages, approximately 80% of infiltrating neutrophils emigrated from the inflamed glomeruli back into the circulation. Could this also explain the decreased neutrophil numbers seen by Brazil et al. in the airway lumen despite sustained levels of survival factors? With variable phagocytic avarice reported for in vitro cultured macrophages [30, 31] and others reporting relatively poor alveolar macrophage clearance of apoptotic cells [32] other mechanisms may be requisite for efficient removal of cells in vivo. Luminal entry has also been proffered for eosinophil clearance [33-35]. Several papers from the same group have highlighted eosinophil efflux to the airway lumen in the absence of tissue apoptosis. This mechanism does not preclude granulocyte apoptosis in the airway lumen and subsequent clearance by macrophage [36, 37] or airway epithelial cells [30, 38, 39] but does question the significance of tissue apoptosis observed by others [40]. Corry et al. [41] suggest that while phagocytosis of apoptotic cells during quiescent periods is an important process, transepithelial egression is a necessary second means of removal during inflammation in their mouse model. While it is also known that subsets of eosinophils traffic to lymph nodes in their capacity as antigen-presenting cells [25] and others may be cleared by mucocilliary clearance, it is not a question of whether phagocytosis occurs but, as observed with neutrophils in inflamed glomeruli, what contribution it makes. The notion of vestigial phagocytosis does not seem feasible but rather that if phagocytosis is only a minor contributor to cell clearance then its maintenance in the body reflects an evolutionary preserved feedback mechanism capable of limiting continued inflammation, making it a crucial facet of inflammation resolution. The question remains, however, where do granulocytes die? In vivo data is crucial to encompass the myriad competing signals manipulating granulocyte apoptosis. A shortfall in this area of research, however, is a lack of stringent and consistent tools for ascertaining the apoptotic state of a cell in vivo. Granulocyte apoptosis in the tissues has been documented by several groups [40, 42]; yet, these studies have been questioned by those espousing luminal entry as a sole mechanism for granulocyte disposal [33-35]. TUNEL and morphology are not comprehensive tools for discerning the apoptotic status of a cell, as both features are downstream markers of the effects of caspases and are not always components of cell death (paraptosis for example does not exhibit nuclear condensation or DNA laddering [43]). Indeed, others have shown that TNF-α-induced cell death in neutrophils can occur independent of caspases and results in no DNA cleavage or other morphological markers of apoptosis [44]. This observation may, however, be attributed to the toxic side-effects of z-VAD-fmk [45]. Cell surface receptor changes on apoptotic cells also precede gross morphological changes and thus the body's phagocytes would identify and clear these early apoptotic cells rapidly. Lagasse and Weissman [46] describe bcl-2 expressing neutrophils, which survived longer in culture but were phagocytosed in vitro by macrophages. This suggested an uncoupling between manifest morphological signs of apoptosis and the cell surface changes utilized by phagocytes. This is reinforced by Kurosaka et al.'s [47] demonstration of macrophage clearance of very early apoptotic cells, exhibiting no morphological changes. Despite these limitations completely ingested cells in vivo, should be identifiable within phagocytes as they are in bronchoalveolar lavage samples [12, 48] or in sputum [49]. The paper in this issue by Brazil et al. [12] provides a kinetic model for examining a self-limiting and resolving inflammation in vivo which should highlight the innate mechanisms involved in the influx and clearance of neutrophils from the airway. It highlights alveolar macrophage phagocytosis of apoptotic neutrophils occurring in vivo in the airway lumen but may also, in future, elucidate the contribution of tissue apoptosis in a resolving inflammatory situation." @default.
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• W2092778514 title "Airway inflammation resolution" @default.
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