Jennifer C. Fleming

α4β1 integrin blockade after spinal cord injury decreases damage and improves neurological function

The extent of disability caused by spinal cord injury (SCI) relates to secondary tissue destruction arising partly from an intraspinal influx of neutrophils and monocyte/macrophages after the initial injury. The integrin alpha4beta1, expressed by these leukocytes, is a key to their activation and migration into/within tissue. Therefore, blocking this integrins functions may afford significant neuroprotection. Rats were treated intravenously with a blocking monoclonal antibody (mAb) to the alpha4 subunit of alpha4beta1 at 2 and 24 h after thoracic clip-compression SCI. Anti-alpha4beta1 treatment significantly decreased neutrophil and monocyte/macrophage influx at 3 d by 47% and 53%, respectively, and decreased neutrophil influx by 61% at 7 d after SCI. Anti-alpha4beta1 treatment also significantly reduced oxidative activity in injured cord homogenates at 3 d. For example, myeloperoxidase activity decreased by 38%, inducible nitric oxide by 44%, dichlorofluorescein (marking free radicals) by 33% and lipid peroxidation (malondialdehyde) by 42%. At 2-8 weeks after SCI, motor function improved by up to 2 points on an open-field locomotor scale. Treated rats supported weight with their hind paws instead of sweeping. At 2-4 weeks after SCI, anti-alpha4beta1 treatment decreased blood pressure responses during autonomic dysreflexia by as much as 43% and, at 2-8 weeks, decreased mechanical allodynia elicited from the trunk and hind paw by up to 54% and 40%, respectively. This improved functional recovery correlated with spared myelin-containing white matter and >10-fold more bulbospinal serotonergic axons below the injury than were in controls. The significant neurological improvement offered by this neuroprotective strategy underscores the potential for an anti-integrin treatment for SCI.

A Selective Phosphodiesterase-4 Inhibitor Reduces Leukocyte Infiltration, Oxidative Processes, and Tissue Damage after Spinal Cord Injury

We tested the hypothesis that a selective phosphodiesterase type 4 inhibitor (PDE4-I; IC486051) would attenuate early inflammatory and oxidative processes following spinal cord injury (SCI) when delivered during the first 3 days after injury. Rats receiving a moderately severe thoracic-clip-compression SCI were treated with the PDE4-I (0.5, 1.0, and 3.0 mg/kg IV) in bolus doses from 2-60 h post-injury. Doses at 0.5 mg/kg and 1.0 mg/kg significantly decreased myeloperoxidase (MPO) enzymatic activity (neutrophils), expression of a neutrophil-associated protein and of ED-1 (macrophages), and estimates of lipid peroxidation in cord lesion homogenates at 24 h and 72 h post-injury by 25-40%. The 3.0 mg/kg dose had small or no effects on these measures. The PDE4-I treatment (0.5 or 1.0 mg/kg) reduced expression of the oxidative enzymes gp91(phox), inducible nitric oxide synthase, and cyclooxygenase-2, and diminished free radical generation by up to 40%. Treatment with 0.5 mg/kg PDE4-I improved motor function (as assessed by the Basso-Beattie-Bresnahan scale) significantly from 4-8 weeks after SCI (average difference 1.3 points). Mechanical allodynia elicited from the hindpaw decreased by up to 25%. The PDE4-I treatment also increased white matter volume near the lesion at 8 weeks after SCI. In conclusion, the PDE4-I reduced key markers of oxidative stress and leukocyte infiltration, producing cellular protection, locomotor improvements, and a reduction in neuropathic pain. Early inhibition of PDE4 is neuroprotective after SCI when given acutely and briefly at sufficient doses.

Predicting the need for tracheostomy in patients with cervical spinal cord injury.

BACKGROUND Approximately 75% of hospitalized patients with a cervical spinal cord injury (CSCI) will require intubation and mechanical ventilation (MV) because of compromised respiratory function. It is difficult to predict those CSCI patients who will require prolonged ventilation and therefore will most benefit from early tracheostomy. This study intended to show the benefits of tracheostomy, particularly early, and to identify predictors of prolonged MV after CSCI. METHODS A retrospective review of patients aged 16 years and older with acute CSCI admitted to London Health Science Center from 1991 to 2010 was performed. Demographic data and clinical parameters were extracted from medical records and the trauma registry. Regression analysis was used to identify predictors of prolonged MV. RESULTS There were 66 eligible patients of which 42 (62%) had a tracheostomy performed. Five patients (7.6%) remained ventilator dependent and seven (10.6%) died more than 7 days after injury secondary to sepsis. After adjusting for the number of ventilator days after injury, patients who had a tracheostomy had fewer pulmonary complications than those who did not have a tracheostomy (p = 0.001). Early tracheostomy resulted in fewer days on the ventilator and a shorter hospital stay. Clinical parameters that predicted MV to be required longer than 7 days were Injury Severity Score > 32, complete SCI, and a PAO2/FIO2 ratio < 300 3 days after MV was initiated. CONCLUSION We recommend early tracheostomy if the Injury Severity Score is >32, the patient has a complete SCI, and the PAO2/FIO2 ratio is <300 3 days after MV was initiated. LEVEL OF EVIDENCE Prognostic study, level III.

Disordered cardiovascular control after spinal cord injury

Damage to the spinal cord disrupts autonomic pathways, perturbing cardiovascular homeostasis. Cardiovascular dysfunction increases with higher levels of injury and greater severity. Disordered blood pressure control after spinal cord injury (SCI) has significant ramifications as cord-injured people have an increased risk of developing heart disease and stroke; cardiovascular dysfunction is currently a leading cause of death among those with SCI. Despite the clinical significance of abnormal cardiovascular control following SCI, this problem has been generally neglected by both the clinical and research community. Both autonomic dysreflexia and orthostatic hypotension are known to prevent and delay rehabilitation, and significantly impair the overall quality of life after SCI. Starting with neurogenic shock immediately after a higher SCI, ensuing cardiovascular dysfunctions include orthostatic hypotension, autonomic dysreflexia and cardiac arrhythmias. Disordered temperature regulation accompanies these autonomic dysfunctions. This chapter reviews the human and animal studies that have furthered our understanding of the pathophysiology and mechanisms of orthostatic hypotension, autonomic dysreflexia and cardiac arrhythmias. The cardiovascular dysfunction that occurs during sexual function and exercise is elaborated. New awareness of cardiovascular dysfunction after SCI has led to progress toward inclusion of this important autonomic problem in the overall assessment of the neurological condition of cord-injured people.

Remote inflammatory response in liver is dependent on the segmental level of spinal cord injury.

BACKGROUND: Traumatic spinal cord injury (SCI) triggers a systemic inflammatory response (SIR) that contributes to a high incidence of secondary organ complications, particularly after a cervical or high-level thoracic injury. Because liver plays a key role in initiating and propagating the SIR, the aim of this study was to assess the effects that SCI at differing segmental levels has on the intensity of the inflammatory response in the liver. METHODS: Using male Wistar rats, clip compression SCI was performed at the 4th thoracic (T4 SCI; high-level SCI) or the 12th thoracic (T12 SCI; low-level SCI) spinal cord segment. Sham-injured rats had a partial laminectomy, but no SCI. Leukocyte recruitment to the liver, hepatic blood flow, and hepatocellular injury/death were assessed using intravital microscopy and histology. Chemokine and cytokine concentrations were assessed in the liver. Outcomes were measured at 1.5 hours, 12 hours, and 24 hours after SCI. RESULTS: At 12 hours after injury, T4 SCI caused a threefold increase in hepatic leukocyte recruitment compared with T12 SCI (p < 0.05). T4 SCI induced 50% more hepatocyte injury than T12 SCI at 12 hours (p < 0.05). Hepatic blood flow decreased after SCI, but not after sham injury, and stayed decreased only after T4 SCI at 24 hours after injury. The T4 SCI-induced changes were accompanied by increases in the hepatic concentrations of interleukin-1&bgr;, leptin, interleukin 10, and cytokine-induced neutrophil chemoattractant-1 at 1.5 hours. CONCLUSIONS: Our findings indicate that traumatic SCI triggers an acute SIR that contributes to hepatocellular injury. SCI-induced remote injury/dysfunction to the liver appears to be transient and is more robust after an upper thoracic SCI compared with a lower thoracic SCI.