Transcriptional profiling of lung macrophages during pulmonary injury induced by nitrogen mustard

Abstract

Nitrogen mustard (NM) and sulfur mustard are cytotoxic alkylating agents that cause severe and progressive damage to the respiratory tract. Evidence indicates that macrophages play a key role in the acute inflammatory phase and the later resolution/profibrotic phase of the pathogenic response. These diverse roles are mediated by inflammatory macrophages broadly classified as M1 proinflammatory and M2 anti-inflammatory that sequentially accumulate in the lung in response to injury. The goal of the present study was to identify signaling mechanisms contributing to macrophage activation in response to mustards. To accomplish this, we used RNA sequencing to analyze the gene expression profiles of lung macrophages isolated 1 and 28 days after intratracheal exposure of rats to NM (0.125 mg/kg) or phosphate-buffered saline control. We identified 641 and 792 differentially expressed genes 1 and 28 days post-NM exposure, respectively. These genes are primarily involved in processes related to cell movement and are regulated by cytokines, including tumor necrosis factor-α, interferon-γ, and interleukin-1β. Some of the most significantly enriched canonical pathways included STAT3 and NF-κB signaling. These cytokines and pathways may represent potential targets for therapeutic intervention to mitigate mustard-induced lung toxicity.

ROS-responsive liposomes as an inhaled drug delivery nanoplatform for idiopathic pulmonary fibrosis treatment via Nrf2 signaling

“…Innate and adaptive immune cells have been proven to widely participate in fibroblast-to-myofibroblast transition. As one of the most important types of innate immune cells in lung tissue, macrophages have been found to accumulate in the fibrotic area and are widely involved in fibrosis development [9][10][11]. In the early phase of fibrosis, macrophages mainly manifest the classically activated phenotype (M1), which generates various proinflammatory cytokines to exacerbate the recurrent microinjury of alveolar epithelial cells [12].…”

“…In the injury healing and fibrosis phase, macrophages undergo phenotypic transformation from the M1 type to the M2 type under the stimulation of Th2 cytokines such as interleukin (IL)-4 and IL-13 and produce a range of cytokines such as transforming growth factor-β (TGF-β), platelet derived growth factor (PDGF), chemokine ligand 17, and chemokine ligand 18 [13,14]. TGF-β is a typical "profibrotic" cytokine that induces fibroblast differentiation into myofibroblasts and promotes collagen production in lung tissue [9,15]. Moreover, reactive oxygen species (ROS) produced by macrophages are considered to be key factors in the pathogenesis of pulmonary fibrosis [16,17].…”

Senescence in Pulmonary Fibrosis: Between Aging and Exposure

“…Exposure to the warfare agent, nitrogen mustard is accompanied by early pro-inflammatory macrophage activation, followed by transition to a pro-resolution/pro-fibrotic phenotype (238). While identification of a senescent phenotype was beyond the scope of these studies, RNA-sequencing analysis of lung macrophages at a time coordinated with fibrosis found features consistent with senescence, including apoptosis, p53, and cell cycle signaling, paired with morphologically aberrant appearance (foamy) (239,240). In the context of biological aging, tissueresident macrophages persist in the lung without input from bone marrow-derived monocytes.…”

Role of CCR2+ Myeloid Cells in Inflammation Responses Driven by Expression of a Surfactant Protein-C Mutant in the Alveolar Epithelium

“…Our understanding of the phenotype and function of resident and monocyte-derived macrophages and infiltrating monocytes in the context of chronic injury and fibrosis has been revolutionized in the past decade (8,(10)(11)(12)(13)(14)(15)(16). As a result, a growing research area is now dedicated to comprehend the interplay between ontogeny and polarization from birth to adulthood, in healthy and disease state (16)(17)(18)(19).…”