Fig. 1

Representative figure of the distal alveolus for healthy control, IPF, and COVID-19 patient samples. Distal aberrant changes in early lungs. A Distal airway and alveolus from a healthy control lung. Several epithelial cell types can be found in the bronchiole epithelium, including club cell, ciliated cell, and basal cell. Basal cells are the airway epithelial progenitor. The alveoli are located in the respiratory bronchioles as scattered outpockets, extending from their lumens. Each lung contains approximately 150 million alveoli providing a surface of gas exchange of forty square meters. Each alveolus is wrapped in a fine mesh of capillaries covering about 70% of its area and composed of endothelial and venule cells. There are three major types of alveolar cells. Two types of pneumocytes or pneumonocytes are known as type 1 (AT1) and type 2 (AT2) cells that are found in the alveolar wall, and a large phagocytic cell known as an alveolar macrophage that moves about in the lumens of the alveoli and the connective tissue. AT1 cells are thin and are involved in the process of gas exchange between the alveoli and blood. AT2 cells are cuboidal and produce surfactant, a lipoprotein that reduced the alveolar tension. AT2 cells also serve as the local alveolar epithelial progenitor. The alveolar fibroblasts are located in the interstitial compartment and are the main source of ECM proteins like collagen and elastin that allow the alveoli to stretch when they fill with air during inhalation. B In IPF, repeated injuries of a senescent alveolar epithelium and bronchiole can lead to the loss of alveolar resident AT1 and AT2 cells, and an increase in airway epithelial cells, such as club cells, basal cells, ciliated cells suggesting “proximalization” of the distal lung. In the vascular compartment, there is a loss in alveolar capillary cells corresponding to gCAP and aerocytes with a concomitant ectopic increase in venous ECs (COL15A1^pos) in the lung parenchyma. Immunohistochemistry (IHC) confirmed their presence in fibrotic and bronchiolized areas in IPF lungs paralleling the proximalization of the distal lung observed in the epithelium. In addition to changes in these well-described lung resident cell populations, a new subpopulation of cells distinct was identified and called aberrant basaloid cells. Regarding the immune cells, monocyte-derived macrophages also contribute to fibrosis through increased recruitment and extravasation of these cells, as well as their secreted molecules that also lead to a profibrotic environment. The change of the cellular composition of the epithelial, immune, and endothelial compartments lead to an abnormal secretion of profibrotic mediators such as TGF-β and MMP7 and to the differentiation of alveolar fibroblasts into myofibroblasts. These cells are postulated as the main source of aberrant production of ECM deposition in the interstitial space, ultimately leading to the destruction of the alveolar space and to fibrosis of the lung. C During end-stage COVID-19 lung infection, a similar but different process occurs. SARS-Cov-2 preferentially infects AT2 and AT1 cells, monocyte-derived macrophages, and endothelial cells, causing apoptosis of AT1, AT2, and endothelial cells. To compensate for ATI and ATII cell loss, KRT5 + basal progenitors proliferate and migrate into the alveolus. The injury of the alveolar epithelium also leads to the differentiation of alveolar fibroblasts into myofibroblasts. These cells may contribute to the deposition of the extracellular proteins in the interstitial space. It is unclear what happens to endothelial cell proportions, though it has been postulated that these cells decrease. Viral infection load also correlates directly with gCAPs and aerocytes proportions. There is also an increase in the recruitment and extravasation of macrophages as well as an increase in activated T cells