Hyperbaric oxygen therapy: a novel treatment option in complex regional pain syndrome and other chronic pain conditions.

Fibrosis is characterized by persistent fibroblast activation, resulting in excess extracellular matrix (ECM) deposition, and is the common endpoint of chronic injury across organs. Fibrosis accounts for a large proportion of global disease burden, contributing to roughly 45% of all deaths in developed nations. Excess ECM stiffens tissues, impairs organ function, and ultimately leads to organ failure. Resolution of the wound-healing program is normally mediated through apoptosis of activated myofibroblasts; however, inflammatory cues — delivered by neutrophils, macrophages, and other immune cells — can persist, subsequently further activating fibroblasts into myofibroblasts that continue to secrete ECM. This dysregulation or “wound healing gone awry” concept can be provoked by diverse insults (infection, toxins, metabolic stress, malignancy, or genetic mutations) and be perpetuated by cytokines such as TGF-β, PDGF, and IL-1β. While altered wound healing presents as organ-specific manifestations, such as cirrhosis, glomerulosclerosis, and interstitial lung disease, the mechanisms of fibrosis across organs appear to be similarly reflected by an inflammatory/fibrotic cascade (–). Fibrosis is traditionally viewed as irreversible scarring, but recent studies demonstrate that fibrotic tissues are dynamic and, under certain conditions, reversible. In lung fibrosis, for example, lipofibroblasts (LIFs) are programmed into activated myofibroblasts (aMYFs) during injury; however, pharmacologic agents have been shown to reverse this transition, promoting aMYF-to-LIF conversion and leading to fibrosis resolution (). This paradigm shift is supported by the observation that abnormal ECM, which becomes the scaffold of a persistently fibrotic niche, can undergo remodeling during successful repair. Unfortunately, the success of therapeutic strategies that promote ECM remodeling remains confined largely to idiopathic pulmonary fibrosis (IPF), where two antifibrotic drugs, nintedanib and pirfenidone, are approved for use in patients. However, these drugs only slow down functional decline rather than reversing established fibrosis and show limited benefit when repurposed for dermal or systemic sclerosis–associated fibrosis. Thus, in general, no disease-modifying, antifibrotic therapies are currently available for fibrosis in most other organs, underscoring the need for new conceptual frameworks and treatments. A unifying theme in fibrosis across organs is the dynamic interplay between stromal cells and the immune system (, ). Macrophages are recruited to sites of injury and secrete cytokines, including TGF-β, PDGF, and IL-1β, that induce fibroblast activation and differentiation. Activated fibroblasts subsequently produce chemokines, cytokines, and ECM components that modulate immune cell recruitment and polarization. Multiple signaling pathways, including TGF-β/SMAD, ERK, PI3K/AKT, and Wnt/Notch, integrate these inputs and govern the transition between repair and fibrosis. Together, these observations support a conceptual model in which fibrosis emerges from a dynamic inflammatory/stromal circuit. Tissue injury triggers innate immune activation and recruitment of monocytes, which differentiate into macrophage subsets that instruct stromal progenitors to adopt myofibroblast phenotypes. The resulting ECM remodeling further reinforces immune activation through mechanical and biochemical feedback signals. Importantly, this inflammatory/fibrotic circuit appears to be conserved across organs, suggesting that common cellular programs govern both the initiation and potential reversibility of fibrosis (). Understanding how these circuits are disrupted or restored in specific disease contexts therefore provides a framework for therapeutic intervention (, ).