A non-invasive, sustained release, polymeric nanoparticulate drug delivery system offers high retinal drug bioavailability so as to enable treatment of retinal complications effectively.

Idiopathic pulmonary fibrosis (IPF) is a fatal fibrotic lung disease associated with unremitting fibroblast activation including fibroblast-to-myofibroblast transformation (FMT), migration, resistance to apoptotic clearance, and excessive deposition of extracellular matrix (ECM) proteins in the distal lung parenchyma. Aberrant activation of lung-developmental pathways is associated with severe fibrotic lung disease; however, the mechanisms through which these pathways activate fibroblasts in IPF remain unclear. Sry-box transcription factor 9 (Sox9) is a member of the high-mobility group box family of DNA-binding transcription factors that are selectively expressed by epithelial cell progenitors to modulate branching morphogenesis during lung development. We demonstrate that Sox9 is upregulated via MAPK/PI3K-dependent signaling and by the transcription factor Wilms’ tumor 1 in distal lung-resident fibroblasts in IPF. Mechanistically, using fibroblast activation assays, we demonstrate that Sox9 functions as a positive regulator of FMT, migration, survival, and ECM production. Importantly, our in vivo studies demonstrate that fibroblast-specific deletion of Sox9 is sufficient to attenuate collagen deposition and improve lung function during TGF- α –induced pulmonary fibrosis. Using a mouse model of bleomycin-induced pulmonary fibrosis, we show that myofibroblast-specific Sox9 overexpression augments fibroblast activation and pulmonary fibrosis. Thus, Sox9 functions as a profibrotic transcription factor in activating fibroblasts, illustrating the potential utility of targeting Sox9 in IPF treatment.

Cardiac macrophages are broadly studied as two subtypes, tissue resident C-X3-C motif chemokine receptor 1 positive (CX3CR1 ⁺ ) that are also C-C motif chemokine receptor 2 negative (CCR2 ^– ), and monocyte derived CCR2 ⁺ . Previous systemic loss of function approaches suggested unique roles for each subtype in the heart with CCR2 ⁺ being inflammatory and CX3CR1 ⁺ being pro-healing. Here we employed a cardiac-specific gain of function approach to selectively enhance either macrophage subtype. A robust increase in basal CCR2 ⁺ macrophages in the heart by targeted C-C motif chemokine ligand 2 ( Ccl2 ) expression did not induce inflammation, cause fibroblast activation, or impair cardiac function. However, increased CCR2 ⁺ macrophages reciprocally diminished self-renewing tissue resident macrophages and worsened cardiac fibrosis due to pressure overload stimulation. Conversely, augmented expression of colony-stimulating factor-1 ( Csf1 ) in the heart promoted selective expansion of resident CX3CR1 ⁺ macrophages, which exerted no pathophysiological consequences at steady-state. However, pressure overload in these mice with expanded CX3CR1 ⁺ macrophages showed a CCR2 ⁺ macrophage-dependent inflammation leading to exacerbated cardiac dysfunction, simultaneously still protecting from adverse remodeling and cardiac fibrosis. In conclusion, cardiac-specific selective enrichment of macrophage subtypes shows their intricate interplay and unique functional roles in regulating myocardial inflammation and fibrosis during hypertrophy and at homeostasis.