TNF-induced necroptosis of uninfected ATII cells. A, Graphic showing TNF, downstream necroptosis pathway components, and NINJ1 are initially expressed in latticework bodies. Activation of the pathway generates a porous latticework composed initially of darker staining latticework bodies that stain with decreasing intensity as pathway and cell contents are progressively emptied. In the process, the cells enlarge and are eventually disrupted, releasing the pores and porous latticework into alveolar space. Because ATII cells proliferate in the reparative response to lung injury, alveoli are lined and filled by contiguous ATII cells. Activation of the necroptotic pathway fuses adjacent cells to amplify and shape the cytopathology, giving rise to multinucleated giant cells, syncytia, and residual cell membranes lining and detached from alveolar walls. B, Brown-stained TNF⁺ cells and structures, and hematoxylin counterstain. Fused syncytial mass of TNF⁺ cells lining alveolar wall (traced). Arrow points to a trinucleate cell with “owl's eye” appearance created by residual clumped chromatin in a largely emptied nucleus. Asynchronous emptying results in variable clearing with the most extensive clearing in the nucleus at the top of the cell. C, Red-stained RIPK3⁺ cells and structures and hematoxylin counterstain. Alveolar space lined and filled by fused RIPK3⁺ cells. Line traces a RIPK3⁺ syncytium in which the latticework pores retain RIPK3 staining (red arrowhead) or are largely emptied (outlined white arrowhead) The black arrowhead points to residual cell membranes. D, Brown-stained cells and structures and hematoxylin counterstain. Trinucleate cell with latticework at various stages of emptying from early darkly staining latticework to later stages in which the intensity of staining decreases as NINJ1 and cell content empty. Abbreviations: AT, alveolar type; TNF, tumor necrosis factor; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.