33 - Pathophysiology After Spinal Cord Injury Is Nonuniform Along the Gastrointestinal Tract

Poster Board Number: 33
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Co-authors:

Gerrgory Holmes - Penn State College of Medicine; Prashant Nighot - Penn State College of Medicine

Abstract Body : Following spinal cord injury (SCI), many individuals develop systemic inflammatory response syndrome (SIRS), a life-threatening condition. While a mechanistic understanding of SIRS following SCI is incomplete, clinical and preclinical evidence have implicated gastrointestinal (GI) epithelial barrier compromise as a driving factor. In a physiologic state, the GI epithelial tight junction (TJ) barrier excludes luminal antigens. Disruption of the TJ barrier increases permeability of antigens, leading to inflammation. Previous studies in neurally intact mice found the proximal intestine displays a heightened sensitivity to hypoxia, owing to differences in metabolic demands and local physiological factors. An increase in GI barrier permeability has been found following SCI using an oral tracer, however, these results did not specify segmental permeability of the GI tract. It is well established that systemic hypotension develops after SCI, which results in GI hypoperfusion. We sought to investigate if post-SCI GI barrier pathophysiology develops uniformly in the foregut, midgut, and hindgut. We hypothesize that after SCI, the proximal intestine is the primary site of GI barrier pathophysiology.

Male Wistar rats (n=40) were administered a T3 spinal contusion injury, or control surgical procedure. GI tissue (duodenum, proximal colon, and distal colon) was explanted 3 days or 3 weeks post-SCI. Full thickness samples were mounted in Ussing chambers to measure permeability ex-vivo. Radiotracers ([¹⁴C]urea, 60 g/mol; [³H]inulin, 5000 g/mol) were used to probe the paracellular pathway. In the duodenum, urea (p< 0.05) and inulin (p< 0.05) flux were elevated in the SCI group vs control. In the proximal colon, only urea flux was elevated following SCI compared to control (p< 0.05). Mucosal TJ proteins claudin-2 and occludin were measured via western blot. Claudin-2 was significantly elevated in duodenum (p< 0.05) and proximal colon (p< 0.01) at 3 days post-SCI vs control. Mucosal reactive oxygen species (ROS) was measured using the superoxide indicator dihydroethidium. Mean fluorescent intensity was significantly elevated in duodenum (p< 0.05) at 3 days post-SCI vs control. Together, these data indicate that barrier disruption develops nonuniformly along the GI post-following SCI. Specifically, T3-SCI transiently disrupts barrier permeability in the proximal intestine, irrigated by the SMA, (duodenum & proximal colon), while the irrigation territories of the IMA (distal colon) remain unaffected. These findings suggest that regional physiology plays a larger role in post-SCI GI barrier pathophysiology than has been previously reported, and that the proximal intestine may be a new target for investigating GI pathophysiology post-SCI.