MEK2 is a highly conserved mitogen-activated protein kinase whose pathway activation is increased in both acute respiratory distress syndrome (ARDS) and murine acute lung injury (ALI). We previously demonstrated that leukocyte-specific Mek2 -/- mice have accelerated recovery from ALI, including earlier restoration of alveolar barrier function, indicating that leukocyte MEK2 prolongs lung injury. Here, we tested the hypothesis that MEK2 suppresses reparative IL-4-driven macrophage function. Transcriptional profiling of WT and Mek2 -/- bone marrow-derived macrophages (BMDM) revealed that MEK2 inhibits a subset of IL-4-dependent gene expression, including those enriched in wound repair pathways. Mechanistically, MEK2 is required for IL-4-induced ERK1/2 phosphorylation and the suppression of PPARγ levels. Pharmacologic inhibition of PPARγ abolished the enhanced IL-4-dependent gene expression observed in Mek2 -/- BMDMs, identifying PPARγ as a key mediator by which MEK2 restrains reparative macrophage polarization. To determine the functional relevance of these findings, we evaluated macrophage-supported alveolar epithelial type II (AT2) cell growth using an alveolar organoid model. IL-4-polarized macrophages enhanced AT2 proliferation in a PPARγ-dependent manner, whereas MEK2 suppressed this reparative effect. Together, these findings identify MEK2 as a negative regulator of reparative macrophage programming via suppression of PPARγ. Targeting MEK2 may represent a novel therapeutic strategy to accelerate repair of lung injury via enhancement of PPARγ activity in reparative macrophages.
Macrophage involvement in the human response to ozone remains poorly defined. In this human crossover exposure study, we characterized ozone-induced changes in airway macrophage populations at 24, 48, and 72 h post-exposure. Ozone exposure caused immediate declines in pulmonary function, which improved 24–72 h later; recovery was associated with increases in airway monocyte-derived macrophage-to-neutrophil and monocyte-derived macrophage-to-monocyte ratios. These findings highlight coordinated, time-related macrophage dynamics that may contribute to recovery from ozone-induced lung injury.
The airway epithelium serves as a critical barrier against pathogens, allergens, and other environmental insults. Disruption of this barrier contributes to respiratory diseases such as chronic obstructive pulmonary disease, making rapid epithelial repair essential for maintaining lung function. Basal cells (BCs), the primary regenerative cell population of the proximal airway epithelium, drive repair through coordinated collective cell migration rather than isolated cellular behaviors. This process is closely linked to dynamic transitions between jammed and unjammed tissue states that regulate migratory capacity and tissue remodeling. Emerging evidence identifies extracellular matrix (ECM) remodeling, Wnt, and transforming growth factor-β (TGF-β) signaling as key regulators of these multicellular responses. ECM remodeling establishes the mechanical substrate for migration, while non-canonical Wnt signaling promotes cytoskeletal reorganization, cell polarity, and coordinated BC movement. TGF-β signaling acts as a context-dependent regulator of BC migration, differentiation, epithelial jamming, and cytoskeletal remodeling through canonical and non-canonical pathways. ECM-integrin signaling links the extracellular environment to cytoskeletal dynamics and collective migration, while inflammatory and mechanical cues modify these responses. Integrin αvβ5/αvβ6-mediated interactions with the ECM connect mechanical forces to focal adhesion signaling and activation of latent TGF-β, linking tissue mechanics to epithelial repair. Together, integration of inflammatory, biochemical, and biomechanical signals that coordinate collective migration and epithelial restoration. This mini-review highlights recent advances supporting a model where coordinated ECM remodeling, Wnt signaling, and TGF-β signaling regulate BC migration and restore epithelial barrier integrity following injury, and examines how disruption of these processes contributes to abnormal repair in chronic lung disease.
Early to midgestational testosterone (T) excess adversely programs lung development in a sex-specific manner, with effects extending from fetal life into adulthood. Fetal lung transcriptomics reveal distinct sex-specific molecular responses to prenatal T exposure. Together, these findings suggest that prenatal androgen excess may represent a developmental mechanism linking fetal lung programming to persistent pulmonary remodeling in adulthood.
