Impairment of phagocytosis of apoptotic cells and its role in chronic airway diseases

Abstract

Phagocytosis of dying cells is a complex and dynamic process coordinated by the interaction of many surface molecules, adaptors, and chemotactic molecules, and it is controlled at multiple levels. This well regulated clearance process is of utmost importance for the development and homeostasis of organisms because defective or inefficient phagocytosis may contribute to human pathologies. In this review we discuss recent advances in the knowledge of the molecular interactions involved in recognition and clearance of apoptotic cells and how derangement of these processes can contribute to the pathogenesis of chronic airway diseases such as chronic obstructive pulmonary disease, cystic fibrosis and asthma. We will briefly consider how different types of macrophages are implicated in chronic airway diseases. Finally, we will address possible therapeutic strategies, such as the use of macrolide antibiotics and statins, for modulating apoptotic cell clearance.

Insulin-Dependent Phosphatidylinositol 3-Kinase/Akt and ERK Signaling Pathways Inhibit TLR3-Mediated Human Bronchial Epithelial Cell Apoptosis

“…Interestingly, development of acute renal failure in critically ill patients in intensive care units was reduced by intensive insulin treatment, which was mediated mainly through a nonmetabolic effect of insulin (28), which may be due to the involvement of a direct antiapoptotic mechanism. The widespread induction of apoptosis by multiple mechanisms, such as viral infections and oxidative stress, which might overwhelm the capacity of epithelial cell repopulation and apoptotic cellular clearance in the airway and lung, plays an integral part in the underlying mechanisms for progression of idiopathic pulmonary fibrosis, bronchial asthma, and chronic obstructive pulmonary disease, including the setting of exacerbations (8)(9)(10)29). Therefore, manipulating excessive apoptosis in epithelial cells is required for the prevention of disease deteriorations.…”

“…Apoptosis is tightly regulated by activation of effector caspases. However, excessive apoptosis in the airway from noxious environmental stimuli may overwhelm apoptotic cellular clearance mechanisms and contribute to airway pathology in asthma and chronic obstructive pulmonary disease (8)(9)(10). Recent studies elucidated plausible pathologic implications of activation of innate immunity and cytokine secretion by TLR recognition in airway disease (11,12).…”

“…Among the TLR family, TLR3 mainly recognizes viral-associated dsRNA. Recognition of dsRNA byproducts released from apoptotic and necrotic cells is a recently proposed mechanism for the enhancement of injury (13), suggesting a pivotal participation of TLR3 in viral infection, as well as in apoptosis-related illness, including tobacco and allergen-induced airway disease, especially in the setting of exacerbations (8)(9)(10)(11)(12). Furthermore, the inducible expression of TLR3 was demonstrated by treatment with polyinosinic-polycytidylic acid (poly-IC), a dsRNA analog, in lung epithelial cells (14), further indicating the amplifying link between dsRNA and TLR3 recognition as part of the pathogenic sequence in apoptosis-related illness progression.…”

Genetic variation associates with susceptibility for cigarette smoke-induced neutrophilia in mice

“…Moreover, in COPD patients it has been shown that both apoptosis as well as the efficient phagocytosis of apoptotic cells is disturbed in the airways (27). Further research is needed to determine the role of disturbed cell death pathways in CS-induced airway inflammation and COPD.…”

CD36, but not G2A, modulates efferocytosis, inflammation, and fibrosis following bleomycin-induced lung injury

“…Furthermore, defective apoptotic cell clearance in CD36 Ϫ / Ϫ mice ( Fig. 1A, B ) could result in the amplifi cation and/or protraction of infl ammation ( 28,29 ). To address these issues, we measured bronchoalveolar infl ammatory cell composition in WT, G2A Ϫ / Ϫ mice 2 days following bleomycin instillation ( Fig.…”