Respiratory Center Research Articles

Higher protein intake may benefit in patients with prolonged mechanical ventilation.

Patients with prolonged mechanical ventilation (PMV) is usually associated with muscle wasting and diaphragm weakness, resulting in high medical costs and mortality. Adequate energy and protein intake were beneficial in sarcopenia patients. We aimed to investigate the impact of protein intake in weaning parameters in patients with PMV. We enrolled patients with PMV (mechanical ventilation ≥6 h/day for ≥21 days) from a respiratory care center (RCC) of a tertiary medical center from December 2020 to October 2022, and classified them into weaning success and weaning failure groups. The patients' characteristics, nutrition records, weaning parameters and outcomes were analyzed. A total of 289 patients were included (mean age 73.5 years). Of the 289 patients, 149 were weaned successfully and 140 were not. The average protein intake was higher in the weaning success group than in the weaning failure group (1.22 ± 0.320 versus 0.99 ± 0.332 g/kg/day, p < 0.001). No significant differences were noted in the average calorie intake and whey protein intake between the two groups. RSBI <90 breaths/min/L (OR = 2.38, p = 0.045), serum albumin at 4th week ≥3 g/dL (OR = 2.89, p = 0.027), daily protein intake ≥1.01 g/kg/day (OR = 8.10, p < 0.001), PaO2/FiO2 (PF) ratio ≥ 300 (OR = 2.56, p = 0.027) were independent predictors for weaning from ventilator. Weak positive correlations were found between average protein intake with PF ratio (r = 0.1576, p = 0.0227) and PaO2 (r = 0.13359, p = 0.0497). Daily protein intake had positively correlated with PF ratio and had independently benefit for weaning in patients with PMV.

Brainstem opioid peptidergic neurons regulate cough reflexes in mice

Cough is a vital defensive reflex for expelling harmful substances from the airway. The sensory afferents for the cough reflex have been intensively studied. However, the brain mechanisms underlying the cough reflex remain poorly understood. Here, we developed a paradigm to quantitatively measure cough-like reflexes in mice. Using this paradigm, we found that prodynorphin-expressing (Pdyn+) neurons in the nucleus of the solitary tract (NTS) are critical for capsaicin-induced cough-like reflexes. These neurons receive cough-related neural signals from Trpv1+ vagal sensory neurons. The activation of Pdyn+ NTS neurons triggered respiratory responses resembling cough-like reflexes. Among the divergent projections of Pdyn+ NTS neurons, a glutamatergic pathway projecting to the caudal ventral respiratory group (cVRG), the canonical cough center, was necessary and sufficient for capsaicin-induced cough-like reflexes. These results reveal that Pdyn+ NTS neurons, as a key neuronal population at the entry point of the vagus nerve to the brainstem, initiate cough-like reflexes in mice.

Prevalence and Clinico-sociodemographic Factors of Asthmatic Children Aged 1 to 14 Years: A Prospective Descriptive Cross-sectional Study in Gandaki Province, Nepal

Introduction Pediatric asthma poses a significant public health challenge, impacting children’s health and quality of life. As asthma prevalence continues to rise globally, understanding its epidemiology is crucial for developing effective management strategies. This study aims to investigate the prevalence and associated demographic, socioeconomic, and clinical characteristics of pediatric asthma among children aged 1 to 14 years. Methods This study employed a prospective descriptive cross-sectional design. Data were collected from a diagnosed asthmatic children attending pediatric department of the GP Koirala National Respiratory Centre and Hospital, Tanahun, Ganaki, Nepal over three months from April 20, 2023 by assessing demographic factors (age, gender, residence), socioeconomic status, clinical history (family history and comorbid conditions), and asthma severity. Data were analyzed with SPSS version 23 using descriptive statistics. Results Prevalence rate of pediatric asthma was 3.08%. The demographic analysis revealed that most participants were aged 1-5 years (53%), predominantly male (64.9%), and resided in urban areas (59.6%). Socioeconomic data indicated that 59.6% came from low-income households, suggesting a potential link between socioeconomic status and asthma prevalence. Clinically, 53% had a family history of asthma, with 26.3% presenting with comorbid allergic rhinitis. Asthma severity assessments showed that 50% had mild asthma, 33.33% had moderate asthma, and 16.67% had severe asthma. Conclusion This study highlights a low prevalence of asthma in the pediatric population at GP Koirala National Respiratory Centre and Hospital, yet emphasizes the burden faced by younger children, especially those from low-income backgrounds. The correlations between asthma prevalence, socioeconomic status, and comorbid conditions underscore the need for targeted public health interventions and comprehensive management strategies. Further research is warranted to deepen understanding and enhance healthcare services for affected children.

Bronchoscopic Interventional Treatment of Mixed Squamous Cell and Glandular Papilloma of Diffuse Trachea: A Case Report and Literature Review

Pulmonary mixed squamous cell and glandular papilloma (MSCGP) is a subtype of pulmonary papilloma, which can be classified as central type and peripheral type based on its site of development. The central type is the most common. The clinical manifestations of pulmonary MSCGP are mainly related to the location of the tumor. Surgery is the main treatment for this disease. Bronchoscopic interventional treatment for the MSCGP in the central trachea could receive satisfactory effect. We reported a patient suffered from diffuse tracheal MSCGP who was treated by bronchoscopic interventional treatment in Respiratory Disease Center, Dongzhimen Hospital of Beijing University of Chinese Medicine, aiming to enhance the recognition of the clinical features and provide clinical references for the diagnosis and treatment of such disease. .

Identification of a histone deacetylase inhibitor as a therapeutic candidate for congenital central hypoventilation syndrome

Congenital central hypoventilation syndrome (CCHS), a rare genetic disease caused by heterozygous PHOX2B mutations, ischaracterized by life-threatening breathing deficiencies. PHOX2B is a transcription factor required for the specification of the autonomic nervous system, which contains, in particular, brainstem respiratory centers. In CCHS, PHOX2B mutations lead to cytoplasmic PHOX2B protein aggregations, thus compromising its transcriptional capability. Currently, the only available treatment for CCHS is assisted mechanical ventilation. Therefore, identifying molecules with alleviating effects on CCHS-related breathing impairments is of primary importance. A transcriptomic analysis of cells transfected with different PHOX2B constructs was used to identify compounds of interest with the CMap tool. Using fluorescence microscopy and luciferase assay, the selected molecules were further tested invitro for their ability to restore the nuclear location and function of PHOX2B. Finally, an electrophysiological approach was used to investigate exvivo the effects ofthe most promising molecule on respiratory activities of PHOX2B-mutant mouse isolated brainstem. The histone deacetylase inhibitor SAHA was found to have low toxicity invitro, to restore the proper location and function of PHOX2B protein, and to improve respiratory rhythm-relatedparameters exvivo. Thus, our results identify SAHA as a promising agent to treat CCHS-associated breathing deficiencies.

Impact Of Inhalational Anesthetics On Respiratory System

Inhalational anaesthetics, commonly used in general anaesthesia, profoundly impact respiratory function and lung mechanics. These agents depress the central nervous system, including the respiratory centres in the brainstem, leading to reduced breathing rate and depth. This suppression results in diminished tidal volume, reduced inspiratory and expiratory reserve volumes, and potentially decreased functional residual capacity. The central nervous system depression also weakens airway reflexes such as coughing, gagging, and swallowing, increasing the risk of airway obstruction and aspiration. Additionally, inhalational anaesthetics can impair gas exchange, causing lower oxygen levels (hypoxemia) and elevated carbon dioxide levels (hypercapnia). Respiratory complications during surgery may include hypoxia, bronchospasm, and impaired ventilation, especially in patients with pre-existing respiratory conditions. To manage these risks, continuous monitoring of respiratory parameters, preoperative assessment, and effective airway management are crucial. This paper reviews the effects of inhalational anaesthetics on respiratory function and outlines strategies for minimising associated risks during surgical procedures

Correlation of sputum inflammatory markers with severity and blood inflammatory markers in bronchiectasis.

As a disease characterized by chronic neutrophilic inflammation, various sputum biomarkers have been investigated in the association with the severity and prognosis of bronchiectasis. However, there is lack of data on the association between sputum interleukin-1beta (IL-1β), interleukin-8 (IL-8) and tumor necrosis factor-alpha (TNF-α) levels at clinical stable state and the clinical, spirometric and blood inflammatory parameters, as well as prognostic scores. The purpose of the study is to assess the association between sputum IL-1β, IL-8 and TNF-α levels at clinical stable state and various clinical and laboratory parameters in bronchiectasis. A prospective study was conducted in a major regional hospital and tertiary respiratory referral centre in Hong Kong, including 44 Chinese patients with bronchiectasis. The correlation between stable state sputum IL-1β, IL-8 and TNF-α levels with various clinical, laboratory and spirometric parameters in bronchiectasis, as well as FACED [forced expiratory volume in one second (FEV1), age, chronic colonisation by Pseudomonas aeruginosa, radiological extension and dyspnoea]/E-FACED (FACED plus exacerbations) scores were assessed. Baseline sputum IL-1β level was found to have significant moderate positive correlation with baseline blood high sensitivity C-reactive protein (hs-CRP) level with Pearson correlation coefficient (r) of 0.529 (P=0.001). Baseline sputum IL-8 level was found to have significant moderate positive correlation with baseline FACED and E-FACED score with r of 0.574 (P<0.001) and 0.539 (P<0.001) respectively. Baseline sputum TNF-α level was found to have significant moderate positive correlation with baseline FACED score with r of 0.520 (P<0.001). Sputum IL-1β and, IL-8 and TNF-α levels were shown to have significant correlation with various clinical, laboratory and spirometry parameters in bronchiectasis, as well as more severe disease as measured by FACED and E-FACED scores.

Role of the pontine respiratory group in the suppression of cough by codeine in cats

Codeine was microinjected into the area of the Kölliker-Fuse nucleus and the adjacent lateral parabrachial nucleus, within the pontine respiratory group in 8 anesthetized cats. Electromyograms (EMGs) of the diaphragm (DIA) and abdominal muscles (ABD), esophageal pressures (EP), and blood pressure were recorded and analyzed during mechanically induced tracheobronchial cough. Unilateral microinjections of 3.3 mM codeine (3 injections, each 37 ± 1.2 nl) had no significant effect on the cough number. However, the amplitudes of the cough ABD EMG, expiratory EP and, to a lesser extent, DIA EMG were significantly reduced. There were no significant changes in the temporal parameters of the cough. Control microinjections of artificial cerebrospinal fluid in 6 cats did not show a significant effect on cough data compared to those after codeine microinjections. Codeine-sensitive neurons in the rostral dorsolateral pons contribute to controlling cough motor output, likely through the central pattern generator of cough.

Severe bronchiectasis is associated with increased carotid intima-media thickness

BackgroundAlthough bronchiectasis has been shown to be associated with cardiovascular disease, there is limited evidence of an association with subclinical atherosclerosis, especially carotid intima-media thickness (CIMT).MethodsThis prospective study compared CIMT among patients with and without bronchiectasis, and among bronchiectatic patients classified according to disease severity using the FACED score. The study was carried out at a major regional hospital and tertiary respiratory referral centre in Hong Kong.ResultsTotal 155 Chinese patients with non-cystic fibrosis (CF) bronchiectasis and 512 controls were recruited. The mean CIMT was 0.58 ± 0.10 mm, 0.63 ± 0.11 mm and 0.66 ± 0.08 mm respectively among controls, patients with mild-to-moderate bronchiectasis and patients with severe bronchiectasis. There was no statistically significant difference in CIMT between patients with mild-to-moderate bronchiectasis and controls. Multivariate linear regression revealed that CIMT was significantly increased in patients with severe bronchiectasis relative to controls. The same phenomenon was observed among patients without a history of cardiovascular disease or cardiovascular risk factors.ConclusionsCIMT was significantly increased in patients with severe bronchiectasis compared with controls without bronchiectasis, but not among patients with mild-to-moderate bronchiectasis, which suggested the subclinical atherosclerosis to be more prevalent among patients with severe bronchiectasis.

Amygdalar involvement in respiratory dysfunction.

The brainstem has long been recognized as the major respiratory control center, but it has become increasingly appreciated that areas upstream of the brainstem modulate respiration and airway defensive behaviors. This review aims to define the role of the amygdala, a key temporal brain region essential for limbic function, in respiration and airway defenses. We summarize literature describing roles for the amygdala in control of respiration, swallow, cough, airway smooth muscle contraction, and mucus secretion. We emphasize the need to understand how the amygdala regulates these functions both at a local scale and network scale and identify knowledge gaps for current and future investigations. Lastly, we highlight literature suggesting that amygdala dysfunction may contribute to respiratory dysfunction.

Respiratory pathology in the TDP-43 transgenic mouse model of amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease that results in death within 2-5years of diagnosis. Respiratory failure is the most common cause of death in ALS. Mutations in the transactive response DNA binding protein 43 (TDP-43) encoded by the TARDBP gene are associated with abnormal cellular aggregates in neurons of patients with both familial and sporadic ALS. The role of these abnormal aggregates on breathing is unclear. Since respiratory failure is a major cause of death in ALS, we sought to determine the role of TDP-43 mutations on the respiratory motor unit in the Prp-hTDP-43A315T mouse model - a model that expresses human TDP-43 containing the A315T mutation. We assessed breathing using whole-body plethysmography, and investigated neuropathology in hypoglossal and phrenic respiratory motor units. Postmortem studies included quantification of hypoglossal and putative phrenic motor neurons, activated microglia and astrocytes in respiratory control centers, and assessment of hypoglossal and phrenic nerves of TDP43A315T mice. The male TDP43A315T mice display an early onset of rapid progression of disease, and premature death (less than 15weeks) compared to control mice and compared to female TDP43A315T mice who die between 20 and 35weeks of age. The TDP43A315T mice have progressive and profound breathing deficits at baseline and during a respiratory challenge. Histologically, hypoglossal and putative phrenic motor neurons of TDP43A315T mice are decreased and have increased microglial and astrocyte activation, indicating pronounced neurodegeneration and neuroinflammation. Further, there is axonopathy and demyelination in the hypoglossal and phrenic nerve of TDP43A315T mice. Thus, the TDP-43A315T mice have significant respiratory pathology and neuropathology, which makes them a useful translatable model for the study of novel therapies on breathing in ALS.

Imitating the respiratory activity of the brain stem by using artificial neural networks: exploratory study on an animal model of lactic acidosis and proof of concept.

Artificial neural networks (ANNs) are versatile tools capable of learning without prior knowledge. This study aims to evaluate whether ANN can calculate minute volume during spontaneous breathing after being trained using data from an animal model of metabolic acidosis. Data was collected from ten anesthetized, spontaneously breathing pigs divided randomly into two groups, one without dead space and the other with dead space at the beginning of the experiment. Each group underwent two equal sequences of pH lowering with pre-defined targets by continuous infusion of lactic acid. The inputs to ANNs were pH, ΔPaCO2 (variation of the arterial partial pressure of CO2), PaO2, and blood temperature which were sampled from the animal model. The output was the delta minute volume (ΔVM), (the change of minute volume as compared to the minute volume the animal had at the beginning of the experiment). The ANN performance was analyzed using mean squared error (MSE), linear regression, and the Bland-Altman (B-A) method. The animal experiment provided the necessary data to train the ANN. The best architecture of ANN had 17 intermediate neurons; the best performance of the finally trained ANN had a linear regression with R2 of 0.99, an MSE of 0.001 [L/min], a B-A analysis with bias ± standard deviation of 0.006 ± 0.039 [L/min]. ANNs can accurately estimate ΔVM using the same information that arrives at the respiratory centers. This performance makes them a promising component for the future development of closed-loop artificial ventilators.

A Neural Basis for Mutant ATAXIN-1 Induced Respiratory Dysfunction in Mouse Models of Spinocerebellar Ataxia Type 1.

Spinocerebellar ataxia type 1 (SCA1), a dominantly inherited neurodegenerative disorder caused by an expanded trinucleotide repeat in the ATAXIN-1 (ATXN1) gene, is characterized by motor dysfunction, cognitive impairment, and death from compromised swallowing and respiration. To delineate specific cell types that contribute to respiratory dysfunction, we utilized the floxed conditional knock-in f-ATXN1 146Q/2Q mouse. Whole body plethysmography during spontaneous respiration and respiratory challenge showed that f-ATXN1 146Q/2Q mice exhibit a spontaneous respiratory phenotype characterized by elevated respiratory frequency, volumes, and respiratory output. Consequently, the ability of f-ATXN1 146Q/2Q mice to increase ventilation during the challenge is impaired. To investigate the role of mutant ATXN1 expression in neural and skeletal muscle lineages, f-ATXN1 146Q/2Q mice were bred to Nestin-Cre and Acta1-Cre mice respectively. These analyses revealed that the abnormal spontaneous respiration in f-ATXN1 146Q/2Q mice involved two aspects: a behavioral phenotype in which SCA1 mice exhibit increased motor activity during respiratory testing and functional dysregulation of central respiratory control centers. Both aspects of spontaneous respiration were partially ameliorated by removing mutant ATXN1 from neural, but not skeletal muscle, cell lineages.

Central and peripheral mechanisms underlying respiratory deficits in a mouse model of accelerated senescence.

Aging invariably decreases sensory and motor stimuli and affects several neuronal systems and their connectivity to key brain regions, including those involved in breathing. Nevertheless, further investigation is needed to fully comprehend the link between senescence and respiratory function. Here, we investigate whether a mouse model of accelerated senescence could develop central and peripheral respiratory abnormalities. Adult male Senescence Accelerated Mouse Prone 8 (SAMP8) and the control SAMR1 mice (10months old) were used. Ventilatory parameters were assessed by whole-body plethysmography, and measurements of respiratory input impedance were performed. SAMP8 mice exhibited a reduction in the density of neurokinin-1 receptor immunoreactivity in the entire ventral respiratory column. Physiological experiments showed that SAMP8 mice exhibited a decreased tachypneic response to hypoxia (FiO2 = 0.08; 10min) or hypercapnia (FiCO2 = 0.07; 10min). Additionally, the ventilatory response to hypercapnia increased further due to higher tidal volume. Measurements of respiratory mechanics in SAMP8 mice showed decreased static compliance (Cstat), inspiratory capacity (IC), resistance (Rn), and elastance (H) at different ages (3, 6, and 10months old). SAMP8 mice also have a decrease in contractile response to methacholine compared to SAMR1. In conclusion, our findings indicate that SAMP8 mice display a loss of the NK1-expressing neurons in the respiratory brainstem centers, along with impairments in both central and peripheral respiratory mechanisms. These observations suggest a potential impact on breathing in a senescence animal model.

Central Neurogenic Hyperventilation Following Ischemic Stroke in the Pons

Central neurogenic hyperventilation (CNH) is a rare condition that characterized by an increase in the rate and depth of respiration to an extent that produces advanced respiratory alkalosis due to various central nervous disorder. The mechanism of CNH remains unclear. We reported a case of CNH in patients with progressive ischemic stroke in pons, including parabrachial nucleus, which is thought to have disrupted inhibitory impulses to the medullary respiratory center.

Proportions of Hypertension in Stable COPD Patients at the National Respiratory Center Persahabatan Hospital

Background: Chronic obstructive pulmonary disease (COPD) is the third leading cause of death worldwide. Most of these deaths are related to cardiovascular disease. This is due to systemic inflammation that causes increased vascular stiffness and hypertension. These comorbidities lead to poor quality of life, low exercise tolerance, and an increased risk of hospitalization. This study aims to report the proportion of hypertension among stable COPD patients in the Indonesian population.Methods: This cross-sectional study was conducted at the National Respiratory Center Persahabatan Hospital between February and March 2023. Stable COPD patients admitted to the Asthma and COPD Polyclinic who met the criteria were enrolled. Clinical information, vital signs, spirometry results, and DLCO measurements were collected.Results: There were 84 subjects participating in this study. The result of this study shows a 60.7% proportion of hypertension in stable COPD patients. Hypertension has a significant correlation with pulmonary functional values (P=0.021), severity degree of clinical COPD (P=0.004), Brinkman index (P=0.008), and age (P=0.0001). However, hypertension association with COPD duration (P=0.505) and DLCO (P=0.122) were not significant.Conclusion: The hypertension proportion in stable COPD Indonesian patients is 60.7%. Hypertension shows a significant association with pulmonary function values, severity degree of clinical COPD, Brinkman index, and age.

The Impact of Stress and Burnout on the Quality of Life of Healthcare Workers within the Covid-19 Pandemic

Background: The quality of an individual's life consists of the harmony of physical and mental health, which is influenced by working and material conditions and the social environment. Healthcare professionals face a lot of pressure caused by workload. Psychological pressure, lack of health personnel, and shift and overtime work lead to stress and burnout syndrome. Aim: This paper examines the impact of stress and burnout on the quality of life of healthcare workers during the COVID-19 pandemic. Methods: This cross-sectional study was conducted with 105 subjects who worked at the COVID wards at the COVID-19 Respiratory Centre of the University Hospital Centre Rijeka. Results: This research shows that healthcare workers developed symptoms of stress and experienced a high degree of burnout during the COVID-19 pandemic. A small number of healthcare professionals also experienced a worse quality of life. Conclusion: The COVID-19 pandemic put health workers under tremendous psychological pressure. In addition to numerous challenges such as work overload, long working hours, and impacts to work organization; health professionals had to deal with fear, uncertainty, high mortality rates, and the increased use of protective equipment. This impacted the quality of life for at least a small number of health workers.

Outcomes of different pulmonary rehabilitation protocols in patients under mechanical ventilation with difficult weaning: a retrospective cohort study

BackgroundThe endeavor of liberating patients from ventilator dependence within respiratory care centers (RCCs) poses considerable challenges. Multiple factors contribute to this process, yet establishing an effective regimen for pulmonary rehabilitation (PR) remains uncertain. This retrospective study aimed to evaluate existing rehabilitation protocols, ascertain associations between clinical factors and patient outcomes, and explore the influence of these protocols on the outcomes of the patients to shape suitable rehabilitation programs.MethodsConducted at a medical center in northern Taiwan, the retrospective study examined 320 newly admitted RCC patients between January 1, 2015, and December 31, 2017. Each patient received a tailored PR protocol, following which researchers evaluated weaning rates, RCC survival, and 3-month survival as outcome variables. Analyses scrutinized differences in baseline characteristics and prognoses among three PR protocols: protocol 1 (routine care), protocol 2 (routine care plus breathing training), and protocol 3 (routine care plus breathing and limb muscle training).ResultsAmong the patients, 28.75% followed protocol 1, 59.37% protocol 2, and 11.88% protocol 3. Variances in age, body-mass index, pneumonia diagnosis, do-not-resuscitate orders, Glasgow Coma Scale scores (≤ 14), and Acute Physiology and Chronic Health Evaluation II (APACHE) scores were notable across these protocols. Age, APACHE scores, and abnormal blood urea nitrogen levels (> 20 mg/dL) significantly correlated with outcomes—such as weaning, RCC survival, and 3-month survival. Elevated mean hemoglobin levels linked to increased weaning rates (p = 0.0065) and 3-month survival (p = 0.0102). Four adjusted models clarified the impact of rehabilitation protocols. Notably, the PR protocol 3 group exhibited significantly higher 3-month survival rates compared to protocol 1, with odds ratios (ORs) ranging from 3.87 to 3.97 across models. This association persisted when comparing with protocol 2, with ORs between 3.92 and 4.22.ConclusionOur study showed that distinct PR protocols significantly affected the outcomes of ventilator-dependent patients within RCCs. The study underlines the importance of tailored rehabilitation programs and identifies key clinical factors influencing patient outcomes. Recommendations advocate prospective studies with larger cohorts to comprehensively assess PR effects on RCC patients.

Aggravating factors of asthma among patients visited respiratory center at Shar Hospital outpatient in Sulaymaniyah-Kurdistan-Iraq

Backgroundand objectives:Asthma is a prevalent chronic disease in Kurdistan region. Identification of asthma triggers is essential in preventing and managing the disease.Our aim was to determine the most common aggravating factor of asthma in Suleimani city and assessing the correlation of age groups and gender to specific aggravating factors.Methods:This data collection was an observational cross-sectional study implementedin the Outpatients clinics in Suleimani city-Kurdistan region/Iraq from 2018 to 2022. Study subjects included one hundred and fifty asthmatic patients (150). The diagnosis of asthma in selected patients was established prior to the study inclusions.Results:The common aggravating factors of asthma as perceived by patients were air pollution (80.7%), dusts storms (76.7%), infection (74%), smoking (69.3%), exercise (66.7%), detergents (64.7%) and cold weather (64%).The triggers of asthma in adolescent and adult patients are different regarding age and gender.Conclusions:The common triggers of asthma in asthmatic patients in Suleimani city are pollution, dusts, viral infection, and tobacco.

PTEN inhibition promotes robust growth of bulbospinal respiratory axons and partial recovery of diaphragm function in a chronic model of cervical contusion spinal cord injury

High spinal cord injury (SCI) leads to persistent and debilitating compromise in respiratory function. Cervical SCI not only causes the death of phrenic motor neurons (PhMNs) that innervate the diaphragm, but also damages descending respiratory pathways originating in the rostral ventral respiratory group (rVRG) located in the brainstem, resulting in denervation and consequent silencing of spared PhMNs located caudal to injury. It is imperative to determine whether interventions targeting rVRG axon growth and respiratory neural circuit reconnection are efficacious in chronic cervical contusion SCI, given that the vast majority of individuals are chronically-injured and most cases of SCI involve contusion-type damage to the cervical region. We therefore employed a rat model of chronic cervical hemicontusion to test therapeutic manipulations aimed at reconstructing damaged rVRG-PhMN-diaphragm circuitry to achieve recovery of respiratory function. At a chronic time point post-injury, we systemically administered: an antagonist peptide directed against phosphatase and tensin homolog (PTEN), a central inhibitor of neuron-intrinsic axon growth potential; an antagonist peptide directed against receptor-type protein tyrosine phosphatase sigma (PTPσ), another important negative regulator of axon growth capacity; or a combination of these two peptides. PTEN antagonist peptide (PAP4) promoted partial recovery of diaphragm motor activity out to nine months post-injury (though this effect depended on the anesthetic regimen used during recording), while PTPσ peptide did not impact diaphragm function after cervical SCI. Furthermore, PAP4 promoted robust growth of descending bulbospinal rVRG axons caudal to the injury within the denervated portion of the PhMN pool, while PTPσ peptide did not affect rVRG axon growth at this location that is critical to control of diaphragmatic respiratory function. In conclusion, we find that, when PTEN inhibition is targeted at a chronic time point following cervical contusion, our non-invasive PAP4 strategy can successfully promote significant regrowth of damaged respiratory neural circuitry and also partial recovery of diaphragm motor function.