Diaphragmatic Activity and Respiratory Function Following C3 or C6 Unilateral Spinal Cord Contusion in Mice

Abstract

The majority of spinal cord injuries (SCIs) are cervical (cSCI), leading to a marked reduction in respiratory capacity. We aimed to investigate the effect of hemicontusion models of cSCI on both diaphragm activity and respiratory function to serve as preclinical models of cervical SCI. Since phrenic motoneuron pools are located at the C3–C5 spinal level, we investigated two models of preclinical cSCI mimicking human forms of injury, namely, one above (C3 hemicontusion—C3HC) and one below phrenic motoneuron pools (C6HC) in wild-type swiss OF-1 mice, and we compared their effects on respiratory function using whole-body plethysmography and on diaphragm activity using electromyography (EMG). At 7 days post-surgery, both C3HC and C6HC damaged spinal cord integrity above the lesion level, suggesting that C6HC potentially alters C5 motoneurons. Although both models led to decreased diaphragmatic EMG activity in the injured hemidiaphragm compared to the intact one (−46% and −26% in C3HC and C6HC, respectively, both p = 0.02), only C3HC led to a significant reduction in tidal volume and minute ventilation compared to sham surgery (−25% and −20% vs. baseline). Moreover, changes in EMG amplitude between respiratory bursts were observed post-C3HC, reflecting a change in phrenic motoneuronal excitability. Hence, C3HC and C6HC models induced alteration in respiratory function proportionally to injury level, and the C3HC model is a more appropriate model for interventional studies aiming to restore respiratory function in cSCI.

Therapeutic Strategies Targeting Respiratory Recovery after Spinal Cord Injury: From Preclinical Development to Clinical Translation

“…Instead, a key feature of these strategies is that they rely on spared tissue, cells, and axonal pathways. To test these therapeutics for respiratory recovery, two preclinical models of cervical SCIs were used: contusion injury-often at mid-cervical levels [75][76][77][78][79][80][81][82]-and high cervical hemisection-usually at the second cervical segment [83][84][85][86][87][88][89][90][91][92]. Contusion paradigms better model human pathophysiology but are often associated with greater variability in anatomical and functional outcomes.…”

Treadmill training improves lung function and inhibits alveolar cell apoptosis in spinal cord injured rats

“…The increased mortality rate is due to secondary complications from SCI, encompassing respiratory tract and urinary tract infections, among others 3 . Respiratory complications emerge as a predominant contributor to post-SCI mortality, with varying degrees of respiratory dysfunction observed following cervical and upper thoracic SCI 4 , 5 . Despite this, pulmonary function tests in patients with SCI displaying lower injury segments remain suboptimal, leading to secondary lung injuries such as pulmonary hemorrhage, edema, and inflammatory infiltrates in the early stages of lower thoracic SCI with intact major respiratory muscles, suggesting that intricate mechanisms underlie SCI-induced respiratory complications 6 , 7 .…”