Relevance of granulocyte apoptosis to resolution of inflammation at the respiratory mucosa

Abstract

The respiratory mucosa is responsible for gas exchange and is therefore, of necessity, exposed to airborne pathogens, allergens, and foreign particles. It has evolved a multi-faceted, physical and immune defense system to ensure that in the majority of instances, potentially injurious invaders are repelled. Inflammation, predominantly mediated by effector cells of the granulocyte lineage including neutrophils and eosinophils, is a form of immune defense. Where inflammation proves unable to remove an inciting stimulus, chronic inflammatory disease may supervene because of the potential for tissue damage conferred by the presence of large numbers of frustrated, activated granulocytes. Successful recovery from inflammatory disease and resolution of inflammation rely on the clearance of these cells. Ideally, they should undergo apoptosis prior to phagocytosis by macrophage, dendritic, or epithelial cells. The outcome of inflammation can have serious sequelae for the integrity of the respiratory mucosa leading to disease. Therapeutic strategies to drive resolution of inflammation may be directed at the induction of granulocyte apoptosis and the enhancement of granulocyte clearance.

Figure 1

Diagram showing both resolution and failure of resolution of eosinophil- and neutrophil-dominant inflammatory processes. Neutrophilia at the respiratory mucosa is resolved by apoptosis of infiltrating neutrophils and phagocytic clearance by macrophages. It fails to resolve where neutrophils are in great excess or are not efficiently cleared and undergo secondary necrosis following apoptosis. This leads to alveolar damage and destruction followed by fibrotic healing. Histology on the right-hand side of the diagram shows neutrophil-dominant inflammation. Eosinophil-dominant inflammation is resolved by the same mechanisms and fails to resolve for the same reasons. The effects of eosinophil-dominant inflammation in the asthmatic airway are depicted and an example of the histology demonstrated on the left-hand side of the diagram. Histology was kindly provided by William Wallace (Pathology Department, Edinburgh Royal Infirmary). PowerPoint slide

Figure 2

Neutrophil apoptosis. The intrinsic and extrinsic pathways are shown along with some examples of pro and antiapoptotic signaling. Proinflammatory signaling pathways may directly influence transcription of survival proteins e.g., NF-κB promotes transcription of XIAP or increase protein stability e.g., ERK (of the MAPK family) maintains XIAP levels. TNF-α may have both early proapoptotic action and late antiapoptotic effects. TNFR is the TNF receptor. DISC refers to the death-inducing signaling complex, which is composed of TNFR-associated death domain protein (TRADD), Fas-associated death domain protein (FADD), and procaspase-8. MOMP is mitochondrial outer membrane permeabilization. ERK, extracellular signal-regulated kinase; LMP, Lysosomal membrane permeabilisation; NF-κB, nuclear factor-κB; TNF-α, tumor necrosis factor-α; TNFR, tumor necrosis factor receptor. PowerPoint slide