Apoptosis and Cell Death: Relevance to Lung

Abstract

In multicellular organisms, cell death plays an important role in development, morphogenesis, control of cell numbers, and removal of infected, mutated, or damaged cells. The term apoptosis was first coined in 1972 by Kerr et al.1 to describe the morphologic features of a type of cell death that is distinct from necrosis and is today considered to represent programmed cell death. In fact, the evidence that a genetic program existed for physiologic cell death came from the developmental studies of the nematode Caenorhabditis elegans.2 As time has progressed, however, apoptotic cell death has been shown to occur in many cell types under a variety of physiologic and pathologic conditions. Cells dying by apoptosis exhibit several characteristic morphologic features that include cell shrinkage, nuclear condensation, membrane blebbing, nuclear and cellular fragmentation into membrane-bound apoptotic bodies, and eventual phagocytosis of the fragmented cell (Figure 4.1). Figure 4.1Morphologic features of cell death. Necrosis: Cells die by necrosis, and their organelles are characteristically swollen. There is early membrane damage with eventual loss of plasma membrane integrity and leakage of cytosol into extra-cellular space. Despite early clumping, the nuclear chromatin undergoes lysis (karyolysis). Apoptosis: Cells die by type I programmed cell death (also called apoptosis); they are shrunken and develop blebs containing dense cytoplasm. Membrane integrity is not lost until after cell death. Nuclear chromatin undergoes striking condensation and fragmentation. The cytoplasm becomes divided to form apoptotic bodies containing organelles and/or nuclear debris. Terminally, apoptotic cells and fragments are engulfed by phagocytes or surrounding cells. Autophagy: Cells die by type II programmed cell death, which is characterized by the accumulation of autophagic vesicles (autophagosomes and autophagolysosomes). One feature that distinguishes apoptosis from autophagic cell death is the source of the lysosomal enzymes used for most of the dying-cell degradation. Apoptotic cells use phagocytic cell lysosomes for this process, whereas cells with autophagic morphology use the endogenous lysosomal machinery of dying cells. Paraptosis: Cells die by type III programmed cell death, which is characterized by extensive cytoplasmic vacuolization and swelling and clumping of mitochondria, along with absence of nuclear fragmentation, membrane blebbing, or apoptotic body formation. Autoschizis: In this form of cell death, the cell membrane forms cuts or schisms that allow the cytoplasm to leak out. The cell shrinks to about one-third of its original size, and the nucleus and organelles remain surrounded by a tiny ribbon of cytoplasm. After further excisions of cytoplasm, the nuclei exhibit nucleolar segregation and chromatin decondensation followed by nuclear karyorrhexis and karyolysis.