Early Treatment with Oral Pirfenidone Improves Bladder Function after Contusive Spinal Cord Injury in Mice
Spinal cord injury (SCI) disrupts innervation to the lower urinary tract, resulting in bladder dysfunction that predisposes to urinary infections and renal impairment. While inflammation is central to bladder pathology after SCI, the molecular events linking acute to chronic remodeling are poorly defined. We hypothesized that early treatment with pirfenidone, an anti-inflammatory and…
A study reveals that early treatment with oral pirfenidone can enhance bladder function in mice after a contusive spinal cord injury. Spinal cord injury disrupts nerve signals to the lower urinary tract, leading to bladder dysfunction that increases the risk of urinary infections and kidney damage. Although the molecular mechanisms connecting acute to chronic bladder remodeling are not fully understood, pirfenidone was hypothesized to mitigate bladder issues after SCI.
Adult female C57BL/6J mice were subjected to contusive SCI or sham surgery, and their bladders were analyzed at 2, 7, 16, and 45 days post-injury. Immediately following SCI, the bladder exhibited hypertrophy, edema, hemorrhage, neutrophil infiltration, cell proliferation, and reduced voiding function. Gene expression profiling at this stage revealed activation of inflammatory and cytokine pathways, such as those involving TNF-alpha, IL-6, the complement cascade, and TGF-beta.
While bladder function partially recovered by day 7, inflammatory pathways persisted and extracellular matrix (ECM) remodeling programs became evident. By day 16, a robust activation of ECM-remodeling pathways was observed in all bladders.
Treating mice with pirfenidone during the initial inflammatory phase (days 2-7) decreased bladder hypertrophy and suppressed the expression of pro-fibrotic, inflammatory, and neuroplasticity-associated genes, including Bdnf and Chrm2, which encodes muscarinic receptor 2 (M2). Pirfenidone worked by inhibiting TGF-beta signaling, as demonstrated by decreased levels of phosphoSmad2 protein in the bladders and reduced M2 receptor expression in the urothelium.
These molecular changes were linked to improved bladder function in the treated mice, characterized by fewer voiding events and larger urine volumes up until 45 days after SCI. The study concludes that early treatment with pirfenidone limits inflammation and fibrosis, normalizes neural signaling, and improves bladder function after spinal cord injury.
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