Recommendations from the INHAND Apoptosis/Necrosis Working Group

Abstract

Historically, there has been confusion relating to the diagnostic nomenclature for individual cell death. Toxicologic pathologists have generally used the terms single cell necrosis and apoptosis interchangeably. Increased research on the mechanisms of cell death in recent years has led to the understanding that apoptosis and necrosis involve different cellular pathways and that these differences can have important implications when considering overall mechanisms of toxicity, and, for these reasons, the separate terms of apoptosis and necrosis should be used whenever differentiation is possible. However, it is also recognized that differentiation of the precise pathway of cell death may not be important, necessary, or possible in routine toxicity studies and so a more general term to indicate cell death is warranted in these situations. Morphological distinction between these two forms of cell death can sometimes be straightforward but can also be challenging. This article provides a brief discussion of the cellular mechanisms and morphological features of apoptosis and necrosis as well as guidance on when the pathologist should use these terms. It provides recommended nomenclature along with diagnostic criteria (in hematoxylin and eosin [H&E]-stained sections) for the most common forms of cell death (apoptosis and necrosis). This document is intended to serve as current guidance for the nomenclature of cell death for the International Harmonization of Nomenclature and Diagnostic Criteria Organ Working Groups and the toxicologic pathology community at large. The specific recommendations are: Use necrosis and apoptosis as separate diagnostic terms. Use modifiers to denote the distribution of necrosis (e.g., necrosis, single cell; necrosis, focal; necrosis, diffuse; etc.). Use the combined term apoptosis/single cell necrosis when There is no requirement or need to split the processes, or When the nature of cell death cannot be determined with certainty, or When both processes are present together. The diagnosis should be based primarily on the morphological features in H&E-stained sections. When needed, additional, special techniques to identify and characterize apoptosis can also be used

Toxicogenomic module associations with pathogenesis: a network-based approach to understanding drug toxicity

“…Mechanism can be inferred from enriched GO terms, for example, hypertrophy and 'glutathione metabolic process' for module 42m or single-cell necrosis and 'MAPK signaling' for module 29 (Table 1). Modules 70 (enriched with cell cycle arrest genes, including Ddit3) and 29 (enriched for MAPK signaling consistent with apoptosis processes in liver 27 ) were associated with single-cell necrosis, but not with necrosis (non-programmed cell death; single-cell necrosis is synonymous with programmed cell death or apoptosis in histological evaluation 28 ). Thus, clustering on p-adj revealed distinct module associations with distinct forms of cell death not observed when clustering on effect size.…”

NAD + repletion produces no therapeutic effect in mice with respiratory chain complex III deficiency and chronic energy deprivation

“…Quantification of staining was performed according to our published method (19). Apoptotic and necrotic cells (single-cell necrosis) were counted from hematoxylin and eosin-stained sections, based on characteristic morphologic features, such as condensed hypereosinophilic cytoplasm, cell swelling, and condensed, fragmented, or dissolved nucleus (24). For quantification of ductular reactions, we included all ductules outside portal triads and those portal ductules that exceeded the typical 2 duct-like structures visible per portal triad cross section.…”

Detection of apoptosis and matrical degeneration within the intervertebral discs of rats due to passive cigarette smoking

“…Changes were accompanied by decreases in type II collagen and PG in the NP, leading to destruction of the NP architecture. Apoptosis was suggested by the detection of chondrocytes that were positive for ssDNA; however, definitive morphological features of apoptosis were not observed in this study [41]. Therefore, further studies are needed to elucidate the extent of true apoptosis within this region of the IVD in rats exposed to passive cigarette smoking.…”