Transepithelial Migration, Necrosis and Apoptosis as Silent and Pro- Inflammatory Fates of Airway Granulocytes

Abstract

In inflammatory airway diseases, granulocytes such as eosinophils and neutrophils infiltrate the tissue where they are thought to exert pathogenic activities. To avoid a catastrophic accumulation of activated granulocytes, their recruitment must be balanced by efficient cell clearance mechanisms. In this regard, the focus has been on elimination through apoptosis and subsequent engulfment of apoptotic cells by phagocytes. However, novel data suggest that in the airways, powerful non-apoptotic mechanisms are also critically involved in cell clearance. One such mechanism is transepithelial migration into the airway lumen where the mucociliary escalator executes the final elimination. The physiological clearance of tissue granulocytes is normally silent, but can under certain situations shift to become a pro-inflammatory event. For example, apoptotic cells that escape phagocytosis, disintegrate in a pro-inflammatory process called secondary necrosis. In other situations, granulocytes are triggered to undergo an active and violent cytolytic death. This delicate balance in vivo, between silent and violent properties of granulocyte demise, complicates the design of pro-apoptotic pharmacological interventions. On the other hand, this insight may also open possibilities to new exciting treatment strategies. In this context, promoting transepithelial migration, prevention of secondary necrosis, and boosting the macrophage phagocytic system appear as exciting treatment avenues.

Direct evidence of secondary necrosis of neutrophils during intense lung inflammation

“…Several fundamental questions therefore remain regarding the nature of secondary necrosis in the lung. For example, it is still unclear which cell types actually undergo secondary necrosis, and are therefore the source of the LDH found in BAL, and if/how this release relates to modes of cell death, such as primary necrosis [13]. Furthermore, until now, virtually nothing has been known about when and where in the inflammatory process secondary necrosis takes place.…”

“…neutrophils with granule alterations and/or phagosomes) and death were quantified using set and previously validated criteria (table 1; fig. 1) [10][11][12][13]. At least 90 neutrophils per time-point were counted, with the exception being controls for which a very limited number of neutrophils were found, and the results were expressed as percentage of the total number of cells.…”

Secondary necrosis in multicellular animals: an outcome of apoptosis with pathogenic implications

“…In a mechanism of clearance, neutrophils and eosinophils in lung tissue can be removed through egression across the epithelial lining into the airway lumen where they may undergo apoptosis with engulfment by scavengers or progress to secondary necrosis [142,143]. These granulocytes or their remnants are eventually eliminated with airway mucus and expectoration.…”

“…Released proteinases overcome the activity of natural anti-proteases [194] and impair the anti-microbial activity of neutrophils [220]. Besides egression to the airway lumen [142,143], an efficient mechanism for removal of neutrophils accumulated in the inflamed lung is through neutrophil apoptosis and removal by macrophages [76,191]. Alveolar macrophages from patients with COPD are deficient in the capacity to engulf apoptotic cells [221], deficiency that is aggravated by smoking [222].…”

Apoptosis in the lung: induction, clearance and detection

“…An additional complexity in attempts to pigeonhole the different processes of PCD is that they also are often not temporally discreet. Thus, if an apoptotic cell is not removed by the normally efficient clearance mechanisms, it undergoes secondary changes, often called secondary necrosis or cytolysis, which eventually result in liberation of cell contents into the environment (13,35). In the context of this review and the discussion of apoptotic cell detection in the lung, we will focus primarily on caspasemediated apoptosis.…”