Novel Noninvasive Spinal Neuromodulation Strategy Facilitates Recovery of Stepping after Motor Complete Paraplegia.

It has been suggested that neuroplasticity-promoting neuromodulation can restore sensory-motor pathways after spinal cord injury (SCI), reactivating the dormant locomotor neuronal circuitry. We introduce a neuro-rehabilitative approach that leverages locomotor training with multi-segmental spinal cord transcutaneous electrical stimulation (scTS). We hypothesized that scTS neuromodulates spinal networks, complementing the neuroplastic effects of locomotor training, result in a functional progression toward recovery of locomotion. We conducted a case-study to test this approach on a 27-year-old male classified as AIS A with chronic SCI. The training regimen included task-driven non-weight-bearing training (1 month) followed by weight-bearing training (2 months). Training was paired with multi-level continuous and phase-dependent scTS targeting function-specific motor pools. Results suggest a convergence of cross-lesional networks, improving kinematics during voluntary non-weight-bearing locomotor-like stepping. After weight-bearing training, coordination during stepping improved, suggesting an important role of afferent feedback in further improvement of voluntary control and reorganization of the sensory-motor brain-spinal connectome.

Prolonged Targeted Cardiovascular Epidural Stimulation Improves Immunological Molecular Profile: A Case Report in Chronic Severe Spinal Cord Injury.

In individuals with severe spinal cord injury (SCI), the autonomic nervous system (ANS) is affected leading to cardiovascular deficits, which include significant blood pressure instability, with the prevalence of systemic hypotension and orthostatic intolerance resulting in an increased risk of stroke. Additionally, persons with SCI rostral to thoracic vertebral level 5 (T5), where sympathetic nervous system fibers exit the spinal cord and innervate the immune system, have clinically significant systemic inflammation and increased infection risk. Our recent studies show that lumbosacral spinal cord epidural stimulation (scES), applied at the lumbosacral level using targeted configurations that promote cardiovascular stability (CV-scES), can safely and effectively normalize blood pressure in persons with chronic SCI. Herein we present a case report in a female (age 27 years) with chronic clinically motor complete cervical SCI demonstrating that 97-sessions of CV-scES, which increased systemic blood pressure, improved orthostatic tolerance in association with increased cerebral blood flow velocity in the middle cerebral artery, also promoted positive immunological changes in whole-blood gene expression. Specifically, there was evidence of the down-regulation of inflammatory pathways and the up-regulation of adaptative immune pathways. The findings of this case report suggest that the autonomic effects of epidural stimulation, targeted to promote cardiovascular homeostasis, also improves immune system function, which has a significant benefit to long-term cardiovascular and immunologic health in individuals with long-standing SCI. Clinical Trial Registration: www.ClinicalTrials.gov, identifier NCT02307565.

Heart rate and blood pressure response improve the prediction of orthostatic cardiovascular dysregulation in persons with chronic spinal cord injury.

Unstable blood pressure after spinal cord injury (SCI) is not routinely examined but rather predicted by level and completeness of injury (i.e., American Spinal Injury Association Impairment Scale AIS classification). Our aim was to investigate hemodynamic response to a sit-up test in a large cohort of individuals with chronic SCI to better understand cardiovascular function in this population. Continuous blood pressure and ECG were recorded from individuals with SCI (n = 159) and non-injured individuals (n = 48). We found orthostatic hypotension occurred within each level and AIS classification (n = 36). Moreover, 45 individuals with chronic SCI experienced a drop in blood pressure that did not meet the criteria for orthostatic hypotension, but was accompanied by dramatic increases in heart rate, reflecting orthostatic intolerance. A cluster analysis of hemodynamic response to a seated position identified eight distinct patterns of interaction between blood pressure and heart rate during orthostatic stress indicating varied autonomic responses. Algorithmic cluster analysis of heart rate and blood pressure is more sensitive to diagnosing orthostatic cardiovascular dysregulation. This indicates blood pressure instability cannot be predicted by level and completeness of SCI, and the consensus statement definition of orthostatic hypotension is insufficient to characterize the variability of blood pressure and heart rate responses during orthostatic stress. Both blood pressure and heart rate responses are needed to characterize autonomic function after SCI.

Cardiovascular Autonomic Dysfunction in Spinal Cord Injury: Epidemiology, Diagnosis, and Management.

Spinal cord injury (SCI) disrupts autonomic circuits and impairs synchronistic functioning of the autonomic nervous system, leading to inadequate cardiovascular regulation. Individuals with SCI, particularly at or above the sixth thoracic vertebral level (T6), often have impaired regulation of sympathetic vasoconstriction of the peripheral vasculature and the splanchnic circulation, and diminished control of heart rate and cardiac output. In addition, impaired descending sympathetic control results in changes in circulating levels of plasma catecholamines, which can have a profound effect on cardiovascular function. Although individuals with lesions below T6 often have normal resting blood pressures, there is evidence of increases in resting heart rate and inadequate cardiovascular response to autonomic provocations such as the head-up tilt and cold face tests. This manuscript reviews the prevalence of cardiovascular disorders given the level, duration and severity of SCI, the clinical presentation, diagnostic workup, short- and long-term consequences, and empirical evidence supporting management strategies to treat cardiovascular dysfunction following a SCI.

Respiratory muscle activation patterns during maximum airway pressure efforts are different in women and men.

Maximum inspiratory and expiratory pressure values (PImax and PEmax) are indirect measures of respiratory muscle strength that, in healthy adults, are known to be significantly lower in women compared to men. In part, sex differences in breathing kinematics, lung size, body composition, muscle mass, and muscle fiber composition are thought to be responsible for these effects. However, it is not known whether respiratory muscle activation during maximum respiratory efforts is also sex-specific. In this study, we addressed whether respiratory multi-muscle activation patterns during PImax and PEmax efforts are different between healthy women and men. Forced vital capacity (FVC), forced expiratory volume in one second (FEV1), PImax, PEmax, and surface electromyographic (sEMG) activity recorded from respiratory muscles during these maximum airway pressure efforts were obtained in 13 women and 11 men. Percent predicted values of FVC and FEV1 were not significantly different in these two groups (women vs. men: 112 ± 14 vs. 105 ± 15%, p = 0.29; and 92 ± 12 vs. 93 ± 13, p = 0.82, Mean ± SD, respectively), while PImax and PEmax measures were significantly lower in women compared to men (68 ± 16 vs. 88 ± 19 cmH2O, p = 0.011; and 69 ± 13 vs. 94 ± 17, p = 0.0004, respectively). Using vector-based methodology, by calculating the Similarity Index (SI) as measure of the resemblance between two sEMG patterns and the Magnitude (Mag) representing the overall amount sEMG during motor task, we have found that although the Mag values for both PImax and PEmax tasks were not significantly different in two groups, the SIs revealed significant sex-dependent differences in muscle activation patterns (0.89 ± 0.08 vs. 0.97 ± 0.02, p = 0.016; and 0.77 ± 0.11 vs. 0.92 ± 0.04, p = 0.0006, respectively). During the PImax effort, presented as the percentage of total sEMG amplitude, activity of upper trapezius muscle was significantly larger (p = 0.001) while activation of rectus abdominus, oblique, and lower paraspinal muscles were significantly smaller (p = 0.002, p = 0.040, p = 0.005, respectively) in women when compared to the men (50 ± 21 vs. 22 ± 11%; 2 ± 2 vs. 8 ± 7; 4 ± 3 vs. 9 ± 7, 2 ± 3 vs. 7 ± 6, respectively). During PEmax effort, the percentage of sEMG activity were significantly larger in upper and lower trapezius, and intercostal muscles (p = 0.038, p = 0.049, p = 0.037, respectively) and were significantly smaller in pectoralis, rectus abdominus, and oblique muscles (p = 0.021, p < 0.0001, p = 0.048, respectively) in women compared to men (16 ± 10 vs. 9 ± 4%; 16 ± 9 vs. 8 ± 5; 36 ± 12 vs. 25 ± 9; 6 ± 3 vs. 15 ± 5; 14 ± 5 vs. 20 ± 7, respectively). These findings indicate that respiratory muscle activation patterns during maximum airway pressure efforts in healthy individuals are sex-specific. This information should be considered during respiratory motor control evaluation and treatment planning for people with compromised respiratory motor function.

Epidural Spinal Cord Stimulation of Lumbosacral Networks Modulates Arterial Blood Pressure in Individuals With Spinal Cord Injury-Induced Cardiovascular Deficits.

Disruption of motor and autonomic pathways induced by spinal cord injury (SCI) often leads to persistent low arterial blood pressure and orthostatic intolerance. Spinal cord epidural stimulation (scES) has been shown to enable independent standing and voluntary movement in individuals with clinically motor complete SCI. In this study, we addressed whether scES configured to activate motor lumbosacral networks can also modulate arterial blood pressure by assessing continuous, beat-by-beat blood pressure and lower extremity electromyography during supine and standing in seven individuals with C5-T4 SCI. In three research participants with arterial hypotension, orthostatic intolerance, and low levels of circulating catecholamines (group 1), scES applied while supine and standing resulted in increased arterial blood pressure. In four research participants without evidence of arterial hypotension or orthostatic intolerance and normative circulating catecholamines (group 2), scES did not induce significant increases in arterial blood pressure. During scES, there were no significant differences in electromyographic (EMG) activity between group 1 and group 2. In group 1, during standing assisted by scES, blood pressure was maintained at 119/72 ± 7/14 mmHg (mean ± SD) compared with 70/45 ± 5/7 mmHg without scES. In group 2 there were no arterial blood pressure changes during standing with or without scES. These findings demonstrate that scES configured to facilitate motor function can acutely increase arterial blood pressure in individuals with SCI-induced cardiovascular deficits.

Strategies for the Integration of Cough and Swallow to Maintain Airway Protection in Humans.

PURPOSE: Airway protective behaviors, like cough and swallow, deteriorate in many populations suffering from neurologic disorders. While coordination of these behaviors has been investigated in an animal model, it has not been tested in humans. METHODS: We used a novel protocol, adapted from previous work in the cat, to assess cough and swallow independently and their coordination strategies in seven healthy males (26 ± 6 years). Surface electromyograms of the submental complex and external oblique complex, spirometry, and thoracic and abdominal wall kinematics, were used to evaluate the timing of swallow, cough, and breathing as well as lung volume (LV) during these behaviors. RESULTS: Unlike the cat, there was significant variability in the cough-swallow phase preference; however, there was a targeted LV range in which swallow occurred. CONCLUSION: These results give insight into the differences between the cat and human models in airway protective strategies related to the coordination of cough and swallow behaviors, allowing for better understanding of dystussia and dysphagia.

Effects of Respiratory Training on Heart Rate Variability and Baroreflex Sensitivity in Individuals With Chronic Spinal Cord Injury.

OBJECTIVE: To evaluate the effects of pressure threshold respiratory training (RT) on heart rate variability and baroreflex sensitivity in persons with chronic spinal cord injury (SCI). DESIGN: Before-after intervention case-controlled clinical study. SETTING: SCI research center and outpatient rehabilitation unit. PARTICIPANTS: Participants (N=44) consisted of persons with chronic SCI ranging from C2 to T11 who participated in RT (n=24), and untrained control subjects with chronic SCI ranging from C2 to T9 (n=20). INTERVENTIONS: A total of 21±2 RT sessions performed 5 days a week during a 4-week period using a combination of pressure threshold inspiratory and expiratory devices. MAIN OUTCOME MEASURES: Forced vital capacity (FVC), forced expiratory volume in 1 second (FEV1), and beat-to-beat arterial blood pressure and heart rate changes during the 5-second-long maximum expiratory pressure maneuver (5s MEP) and the sit-up orthostatic stress test, acquired before and after the RT program. RESULTS: In contrast to the untrained controls, individuals in the RT group experienced significantly increased FVC and FEV1 (both P<.01) in association with improved quality of sleep, cough, and speech. Sympathetically (phase II) and parasympathetically (phase IV) mediated baroreflex sensitivity both significantly (P<.05) increased during the 5s MEP. During the orthostatic stress test, improved autonomic control over heart rate was associated with significantly increased sympathetic and parasympathetic modulation (low- and high-frequency change: P<.01 and P<.05, respectively). CONCLUSIONS: Inspiratory-expiratory pressure threshold RT is a promising technique to positively affect both respiratory and cardiovascular dysregulation observed in persons with chronic SCI.

Respiratory functional and motor control deficits in children with spinal cord injury.

Children with spinal cord injury (SCI) are at high risk for developing complications due to respiratory motor control deficits. However, underlying mechanisms of these abnormalities with respect to age, development, and injury characteristics are unclear. To evaluate the effect of SCI and age on respiratory motor control in children with SCI, we compared pulmonary function and respiratory motor control outcome measures in healthy typically developing (TD) children to age-matched children with chronic SCI. We hypothesized that the deficits in respiratory functional performance in children with SCI are due to the abnormal and age-dependent respiratory muscle activation patterns. Fourteen TD (age 7±2 yrs., Mean±SD) and twelve children with SCI (age 6±1 yrs.) were evaluated by assessing Forced Vital Capacity (FVC); Forced Expiratory Volume in 1sec (FEV1); and respiratory electromyographic activity during maximum inspiratory and maximum expiratory airway pressure measurements (PImax and PEmax). The results indicate a significant reduction (p<.01) of FVC, FEV1 and PEmax values in children with SCI compared to TD controls. During PEmax assessment, children with SCI produced significantly decreased (p<.01) activation of respiratory muscles below the neurological level of injury (rectus abdominous and external oblique muscles). In addition, children with SCI had significantly increased (p<.05) compensatory muscle activation above the level of injury (upper trapezius muscle). In the TD group, age, height, and weight significantly (p<.05) contributed towards increase in FVC and FEV1. In children with SCI, only age was significantly (p<.05) correlated with FVC and FEV1 values. These findings indicate the degree of SCI-induced respiratory functional and motor control deficits in children are age-dependent.

Baroreceptor reflex during forced expiratory maneuvers in individuals with chronic spinal cord injury.

Pulmonary and cardiovascular dysfunctions are leading causes of morbidity and mortality in patients with chronic Spinal Cord Injury (SCI). Impaired respiratory motor function and decreased Baroreflex Sensitivity (BS) are predictors for the development of cardiopulmonary disease. This observational case-controlled clinical study was undertaken to investigate if respiratory motor control deficits in individuals with SCI affect their ability to perform the Valsalva maneuver, and to determine if a sustained Maximum Expiratory Pressure (MEP) effort can serve as an acceptable maneuver for determination of the BS in the event that the Valsalva maneuver cannot be performed. The BS outcomes (ms/mmHg) were obtained using continuous beat-to-beat arterial blood pressure (BP) and heart rate (HR) recordings during Valsalva or MEP maneuvers in thirty nine individuals with chronic C3-T12 SCI. Twenty one participants (54%) reported signs of intolerance during the Valsalva maneuver and only 15 individuals (39%) were able to complete this task. Cervical level of injury was a significant risk factor (p=0.001) for failing to complete the Valsalva maneuver, and motor-complete injury was a significant risk factor for symptoms of intolerance (p=0.04). Twenty eight participants (72%) were able to perform the MEP maneuver; the other 11 participants failed to exceed the standard airway pressure threshold of 27cm H2O. Neither level nor completeness of injury were significant risk factors for failure of MEP maneuver. When the required airway pressure was sustained, there were no significant differences between BS outcomes obtained during Valsalva and MEP maneuvers. The results of this study indicate that individuals with high-level and motor-complete SCI are at increased risk of not completing the Valsalva maneuver and that baroreflex-mediated responses can be evaluated by using sustained MEP maneuver when the Valsalva maneuver cannot be performed.

Respiratory motor training and neuromuscular plasticity in patients with chronic obstructive pulmonary disease: A pilot study.

The objective of this study was to examine the feasibility of a full-scale investigation of the neurophysiological mechanisms of COPD-induced respiratory neuromuscular control deficits. Characterization of respiratory single- and multi-muscle activation patterns using surface electromyography (sEMG) were assessed along with functional measures at baseline and following 21±2 (mean±SD) sessions of respiratory motor training (RMT) performed during a one-month period in four patients with GOLD stage II or III COPD. Pre-training, the individuals with COPD showed significantly increased (p<0.05) overall respiratory muscle activity and disorganized multi-muscle activation patterns in association with lowered spirometrical measures and decreased fast- and slow-twitch fiber activity as compared to healthy controls (N=4). Following RMT, functional and respiratory sEMG activation outcomes during quite breathing and forced expiratory efforts were improved suggesting that functional improvements, induced by task-specific RMT, are evidence respiratory neuromuscular networks re-organization.

Respiratory Training Improves Blood Pressure Regulation in Individuals With Chronic Spinal Cord Injury.

OBJECTIVE: To investigate the effects of respiratory motor training (RMT) on pulmonary function and orthostatic stress-mediated cardiovascular and autonomic responses in individuals with chronic spinal cord injury (SCI). DESIGN: Before-after intervention case-controlled clinical study. SETTING: SCI research center and outpatient rehabilitation unit. PARTICIPANTS: A sample of (N=21) individuals with chronic SCI ranging from C3 to T2 diagnosed with orthostatic hypotension (OH) (n=11) and healthy, noninjured controls (n=10). INTERVENTIONS: A total of 21±2 sessions of pressure threshold inspiratory-expiratory RMT performed 5d/wk during a 1-month period. MAIN OUTCOME MEASURES: Standard pulmonary function test: forced vital capacity, forced expiratory volume in one second, maximal inspiratory pressure, maximal expiratory pressure, beat-to-beat arterial blood pressure, heart rate, and respiratory rate were acquired during the orthostatic sit-up stress test before and after the RMT program. RESULTS: Completion of RMT intervention abolished OH in 7 of 11 individuals. Forced vital capacity, low-frequency component of power spectral density of blood pressure and heart rate oscillations, baroreflex effectiveness, and cross-correlations between blood pressure, heart rate, and respiratory rate during the orthostatic challenge were significantly improved, approaching levels observed in noninjured individuals. These findings indicate increased sympathetic activation and baroreflex effectiveness in association with improved respiratory-cardiovascular interactions in response to the sudden decrease in blood pressure. CONCLUSIONS: Respiratory training increases respiratory capacity and improves orthostatic stress-mediated respiratory, cardiovascular, and autonomic responses, suggesting that this intervention can be an efficacious therapy for managing OH after SCI.

Respiratory motor function in seated and supine positions in individuals with chronic spinal cord injury.

This case-controlled clinical study was undertaken to investigate to what extent pulmonary function in individuals with chronic spinal cord injury (SCI) is affected by posture. Forced vital capacity (FVC), forced expiratory volume in one second (FEV1), maximal inspiratory pressure (PImax) and maximal expiratory pressure (PEmax) were obtained from 27 individuals with chronic motor-complete (n=13, complete group) and motor-incomplete (n=14, incomplete group) C2-T12 SCI in both seated and supine positions. Seated-to-supine changes in spirometrical (FVC and FEV1) and airway pressure (PImax and PEmax) outcome measures had different dynamics when compared in complete and incomplete groups. Patients with motor-complete SCI had tendency to increase spirometrical outcomes in supine position showing significant increase in FVC (p=.007), whereas patients in incomplete group exhibited decrease in these values with significant decreases in FEV1 (p=.002). At the same time, the airway pressure values were decreased in supine position in both groups with significant decrease in PEmax (p=.031) in complete group and significant decrease in PImax (p=.042) in incomplete group. In addition, seated-to-supine percent change of PImax was strongly correlated with neurological level of motor-complete SCI (ρ=-.77, p=.002). These results indicate that postural effects on respiratory performance in patients with SCI can depend on severity and neurological level of SCI, and that these effects differ depending on respiratory tasks. Further studies with adequate sample size are needed to investigate these effects in clinically specific groups and to study the mechanisms of such effects on specific respiratory outcome measures.

Quality of residual neuromuscular control and functional deficits in patients with spinal cord injury.

STUDY DESIGN: Prospective cohort study. OBJECTIVE: This study examined the relationship between motor control and clinical function outcomes after spinal cord injury (SCI). SETTING: University of Louisville, Louisville, KY, USA. MATERIALS: Eleven persons with SCI and 5 non-injured subjects were included in this study. METHODS: The ASIA Impairment Scale (AIS) was used to categorize injury level and severity. Multi-muscle, surface EMG (sEMG) recording, was carried out using a protocol of reflex and volitional motor tasks and was analyzed using a vector-based tool that calculates index values that relate a distribution of multi-muscle activation pattern of each SCI subject to the prototype obtained from non-injured subject group and presents overall magnitude as a separate value. Functional Independence Measure motor sub-scale, Spinal Cord Injury Independence Measure (SCIM-III), and Walking Index for Spinal Cord Injury (WISCI) scale scores were compared to neurophysiological parameters. RESULTS: AIS category and injury level correlated significantly with the WISCI and SCIM mobility sub-scales. sEMG-derived parameters were significantly correlated with SCIM and WISCI scores but only for examinations carried out 48 or more days post-injury. CONCLUSION: These results supported the hypothesis that clinically relevant function after SCI is related to the degree to which functional organization within the central nervous system is disrupted. Further, due likely to the constraints placed on the expression of functional ability by early post-injury immobilization and hospitalization, neurophysiological assessment of motor function may provide better sensitivity and reliability than can be obtained using the clinical function scales examined here within the early period after injury.

Evaluation of respiratory muscle activation using respiratory motor control assessment (RMCA) in individuals with chronic spinal cord injury.

During breathing, activation of respiratory muscles is coordinated by integrated input from the brain, brainstem, and spinal cord. When this coordination is disrupted by spinal cord injury (SCI), control of respiratory muscles innervated below the injury level is compromised leading to respiratory muscle dysfunction and pulmonary complications. These conditions are among the leading causes of death in patients with SCI. Standard pulmonary function tests that assess respiratory motor function include spirometrical and maximum airway pressure outcomes: Forced Vital Capacity (FVC), Forced Expiratory Volume in one second (FEV1), Maximal Inspiratory Pressure (PImax) and Maximal Expiratory Pressure (PEmax). These values provide indirect measurements of respiratory muscle performance(6). In clinical practice and research, a surface electromyography (sEMG) recorded from respiratory muscles can be used to assess respiratory motor function and help to diagnose neuromuscular pathology. However, variability in the sEMG amplitude inhibits efforts to develop objective and direct measures of respiratory motor function. Based on a multi-muscle sEMG approach to characterize motor control of limb muscles, known as the voluntary response index (VRI), we developed an analytical tool to characterize respiratory motor control directly from sEMG data recorded from multiple respiratory muscles during the voluntary respiratory tasks. We have termed this the Respiratory Motor Control Assessment (RMCA). This vector analysis method quantifies the amount and distribution of activity across muscles and presents it in the form of an index that relates the degree to which sEMG output within a test-subject resembles that from a group of healthy (non-injured) controls. The resulting index value has been shown to have high face validity, sensitivity and specificity. We showed previously that the RMCA outcomes significantly correlate with levels of SCI and pulmonary function measures. We are presenting here the method to quantitatively compare post-spinal cord injury respiratory multi-muscle activation patterns to those of healthy individuals.

Respiratory motor control disrupted by spinal cord injury: mechanisms, evaluation, and restoration.

Pulmonary complications associated with persistent respiratory muscle weakness, paralysis, and spasticity are among the most important problems faced by patients with spinal cord injury when lack of muscle strength and disorganization of reciprocal respiratory muscle control lead to breathing insufficiency. This review describes the mechanisms of the respiratory motor control and its change in individuals with spinal cord injury, methods by which respiratory function is measured, and rehabilitative treatment used to restore respiratory function in those who have experienced such injury.

Differential effects of nitric oxide synthesis on pulmonary vascular function during lung ischemia-reperfusion injury.

Lung ischemia-reperfusion (IR) injury causes alveolar, epithelial and endothelial cell dysfunction which often results in decreased alveolar perfusion, characteristic of an acute respiratory distress syndrome. Nitric oxide (NO) from endothelium-derived NO synthase (eNOS) helps maintain a low pulmonary vascular resistance. Paradoxically, during acute lung injury, overproduction of NO via inducible NO synthase (iNOS) and oxidative stress lead to reactive oxygen and nitrogen species (ROS and RNS) formation and vascular dysfunction. RNS potentiate vascular and cellular injury by oxidation, by decreasing NO bioavailability, and by regulating NOS isoforms. RNS potentiate their own production by uncoupling NO production through eNOS by oxidation and disruption of Akt-mediated phosphorylation of eNOS. This review focuses on effects of NO which cause vascular dysfunction in the unique environment of the lung and presents a hypothesis for interplay between eNOS and iNOS activation with implications for development of new strategies to treat vascular dysfunction associated with IR.

Lung ischemia-reperfusion injury: implications of oxidative stress and platelet-arteriolar wall interactions.

Pulmonary ischemia-reperfusion (IR) injury may result from trauma, atherosclerosis, pulmonary embolism, pulmonary thrombosis and surgical procedures such as cardiopulmonary bypass and lung transplantation. IR injury induces oxidative stress characterized by formation of reactive oxygen (ROS) and reactive nitrogen species (RNS). Nitric oxide (NO) overproduction via inducible nitric oxide synthase (iNOS) is an important component in the pathogenesis of IR. Reaction of NO with ROS forms RNS as secondary reactive products, which cause platelet activation and upregulation of adhesion molecules. This mechanism of injury is particularly important during pulmonary IR with increased iNOS activity in the presence of oxidative stress. Platelet-endothelial interactions may play an important role in causing pulmonary arteriolar vasoconstriction and post-ischemic alveolar hypoperfusion. This review discusses the relationship between ROS, RNS, P-selectin, and platelet-arteriolar wall interactions and proposes a hypothesis for their role in microvascular responses during pulmonary IR.

3-Deazaadenosine mitigates arterial remodeling and hypertension in hyperhomocysteinemic mice.

Chronic hyperhomocysteinemia (HHcy) is an important factor in development of arterial hypertension. HHcy is associated with activation of matrix metalloproteinases (MMPs); however, it is unclear whether HHcy-dependent extracellular matrix (ECM) accumulation plays a role in arterial hypertrophy and hypertension. We tested the hypothesis that in HHcy the mechanism of arterial hypertension involves arterial dysfunction in response to ECM accumulation between endothelial and arterial smooth muscle cells and subsequent endothelium-myocyte (E-M) uncoupling. To decrease plasma Hcy, dietary supplementation with 3-deazaadenosine (DZA), the S-adenosylhomocysteine hydrolase inhibitor, was administered to cystathionine beta-synthase (CBS) knockout (KO) mice. Mice were grouped as follows: wild type (WT; control), WT+DZA, CBSKO, and CBSKO+DZA (n = 4/group). Mean aortic blood pressure and heart rate were monitored in real time with a telemetric system before, during, and after DZA treatment (6 wk total). In vivo aorta function and morphology were analyzed by M-mode and Doppler echocardiography in anesthetized mice. Aorta MMP activity in unfixed cryostat sections was measured with DQ gelatin. Aorta MMP-2, MMP-9, and connexin 43 expression were measured by RT-PCR and Western blot analyses, respectively. HHcy caused increased aortic blood pressure and resistance, tachycardia, and increased wall thickness and ECM accumulation in aortic wall vs. control groups. There was a linear correlation between aortic wall thickness and plasma Hcy levels. MMP-2, MMP-9, and connexin 43 expression were increased in HHcy. In the CBSKO+DZA group, aortic blood pressure and levels of MMP and connexin 43 were close to those found in control groups. However, removal of DZA reversed the aortic lumen-to-wall thickness ratio in CBSKO mice, suggesting, in part, a role of vascular remodeling in the increase in blood pressure in HHcy. The results show that arterial hypertension in HHcy mice is, in part, associated with arterial remodeling and E-M uncoupling in response to MMP activation.