Epigenomics of Idiopathic Pulmonary Fibrosis

Abstract

In this study, using sLC and CD11b-DTR techniques, monocytes were depleted from both peripheral blood by 70-95% and spleen by 50-70%. Administration of MC21 mAb removed 45% of the PBMs. Whether or not the three techniques have an influence on monocytes and neutrophils in the bone marrow was not reported. It is crucial to cautiously choose depletion strategies because monocytes are able to migrate among different pools (the peripheral blood, spleen, and bone marrow) during inflammation. Monocytes also play a requisite role in regulating the resolution of inflammation by different mechanisms. Otherwise, it is very difficult to interpret the experimental findings. This notion is supported by the following findings: (1) bone marrow can release Ly6C high CCR2 1 monocytes to the blood stream in response to the LPS challenge (12); (2) the spleen is a storage site that contains 50% of monocytes (Ly6C high ) in the body, and splenic monocytes can be rapidly mobilized toward the peripheral blood and inflamed site during inflammation and injury (13); (3) the splenic monocytes are indispensable elements forming immune reflex, which controls production of systemic proinflammatory cytokines (for example, TNF-a) (14) through the cholinergic-a7nAChR pathway; (4) alternatively activated monocytes (M2) in the peripheral blood and spleen might be involved in the resolution of inflammation (15); and (5) activation of CD11b in monocytes is able to limit TLR4dependent proinflammatory cytokine production (16).Alveolar flooding is a hallmark of ALI and ARDS. It should be mentioned that the magnitude of lung injury in this study is not equivalent to the clinical conditions because the dosages of LPS (0.4 mg/kg) and bacteria (10 25 cfu) used in the experiments were relatively low. In the meantime, a clear link among PBM depletion, alveolar neutrophilia, and pulmonary edema has not been established. Alveolar neutrophilia and the slight increase of lung vascular permeability are not parallel to the formation of pulmonary edema. Therefore, the conclusion drawn from the current study should be verified in more severe conditions and the other ALI animal models that are neutrophil dependent, for example, acid aspiration, transfusion-related acute lung injury, and ventilator-induced lung injury. Nevertheless, this study contributes importantly to ongoing research on how neutrophils are guided to the airspaces of the lung to mediate lung inflammation and injury.

Single-cell RNA sequencing identifies diverse roles of epithelial cells in idiopathic pulmonary fibrosis

“…Coexpression of normally relatively restricted AT1 (HOPX) with AT2 (ABCA3 and HTII-280) marker genes and frequent coexpression of SP-B with MUC5B are consistent with loss of region-specific cellular identities in IPF (Figure 7). Prediction of EZH2 as a candidate regulator of altered fate in IPF epithelial cells (Supplemental Figure 2) may reflect changes in epigenetic states associated with widespread and dramatic changes in gene expression, a concept previously supported by methylation studies in IPF (37)(38)(39).…”

Pathogenesis of Idiopathic Pulmonary Fibrosis

“…Epigenetic changes include alterations in DNA methylation, histone modification, or microRNA expression (121, 122). Exposure to environmental stresses such as tobacco smoke (123, 124), air pollution (125), and aging (126) can lead to epigenetic DNA changes.…”

Blue Journal Conference. Aging and Susceptibility to Lung Disease

“…For example, changes in histone acetylation have been suggested to increase the risk of pulmonary fibrosis and alter the response to therapy in patients with COPD (35)(36)(37). Epigenomic studies of other age-related chronic lung diseases are underway, with more recent studies reporting the results of global DNA methylation in patients with IPF (38)(39)(40). Understanding the impact of these epigenetic changes on functional networks in the lung and determining whether reversing them could delay lung aging or age-associated lung diseases is an active area of investigation.…”