A cervical spinal cord injury induces permanent paralysis, and often leads to respiratory distres... more A cervical spinal cord injury induces permanent paralysis, and often leads to respiratory distress. To date, no efficient therapeutics have been developed to improve/ameliorate the respiratory failure following high cervical spinal cord injury (SCI). Here we propose a murine pre-clinical model of high SCI at the cervical 2 (C2) metameric level to study diverse post-lesional respiratory neuroplasticity. The technique consists of a surgical partial injury at the C2 level, which will induce a hemiparalysis of the diaphragm due to a deafferentation of the phrenic motoneurons from the respiratory centers located in the brainstem. The contralateral side of the injury remains intact and allows the animal recovery. Unlike other SCIs which affect the locomotor function (at the thoracic and lumbar level), the respiratory function does not require animal motivation and the quantification of the deficit/recovery can be easily performed (diaphragm and phrenic nerve recordings, whole body ventilation). This pre-clinical C2 SCI model is a powerful, useful, and reliable pre-clinical model to study various respiratory and non-respiratory neuroplasticity events at different levels (molecular to physiology) and to test diverse putative therapeutic strategies which might improve the respiration in SCI patients.
Obstructive sleep apnea (OSA) is associated with impaired airway reflexes. Cough is the main airw... more Obstructive sleep apnea (OSA) is associated with impaired airway reflexes. Cough is the main airway defense mechanism but the effect of OSA on cough is unknown. Thirty-two female obese patients scheduled to undergo bariatric surgery were studied. They were classified as presenting OSA (20 patients) when the apnea-hypopnea index (AHI) was greater than 5 h. Cough sensitivity was measured with citric acid. Increasing concentrations of nebulized citric acid were delivered until cough was elicited. The concentrations eliciting one (C1) and two coughs (C2) were recorded and log transformed (log C1 and log C2). log C1 and log C2 (median (interquartile)) were 1.90 mg/mL (0.90) and 2.2 mg/mL (0.30) in OSA patients and 1.60 mg/mL (0.45) and 1.60 mg/mL (0.45) in non-OSA patients, respectively (comparison between groups: p = 0.0372 for log C1 and p = 0.0227 for log C2). A significant relationship was observed between AHI and log C1 and log C2. Cough sensitivity is therefore, decreased in female obese OSA patients and this decreased sensitivity is positively correlated with disease severity.
Nasal continuous positive airway pressure (nCPAP) has been widely established in the treatment of... more Nasal continuous positive airway pressure (nCPAP) has been widely established in the treatment of obstructive sleep apnea syndrome (OSAS). However, only few studies have evaluated long-term effects of this treatment on lung function. This study assesses the effect of nCPAP on lung function parameters and response to bronchodilators in 50 OSAS patients. Spirometry and arterial blood gas measurements were performed before starting nCPAP and after 16.878 months of treatment. Of the 50 study patients (55712 years, with an apnea/hypopnea index of 47734 h À1 ), 15 had asthma, 13 had chronic obstructive pulmonary disease (COPD) and 22 had no obstructive airway disease (NOAD). In the entire population, significant decreases in FEF 50 (from 69738% to 61730%, Po0:005), FEF 25 (from 53734% to 46728%, Po0:05) and FEF 25À75 (from 65733% to 57727%, Po0:005) were observed after treatment. No impairment of lung function was found in COPD and asthmatic patients. In contrast, lung function was changed in the NOAD group where FEF 50 , FEF 25 and FEF 25À75 as well as FEV 1 and FEV 1 /VC ratio were significantly reduced. Moreover, bronchial hyperresponsiveness occurred in five of 22 patients of this group. These results suggest that tolerance of nCPAP should be handled by long-term follow-up of flowvolume loops. r
Changes that may modify the capacity of macrophages to control mycobacterial growth could favour ... more Changes that may modify the capacity of macrophages to control mycobacterial growth could favour the reactivation of bacillary proliferation within protective granulomas developed in response to mycobacterial infection. There is increasing evidence that diesel exhaust particles (DEPs) could suppress some macrophage functions, but it is not known whether DEPs may alter macrophage mycobactericidal activity. The aim of this study was to assess the effect of DEPs on the mycobactericidal activity of human mononuclear phagocytes in vitro. Human monocytes from healthy donors were cultured for 3 days in the presence or absence of DEPs or carbon black particles (CBPs), and then infected with a Mycobacterium bovis bacillus Calmette-Guérin reporter strain expressing luciferase activity. DEPs were rapidly internalized by monocyte-derived macrophages without cytotoxic effect. Mycobactericidal activity of cells exposed to DEPs was not different from that of cells cultured in their absence or in the presence of CBPs. Although our study was restricted to the mycobactericidal activity of human macrophages in vitro, the results indicate that DEPs do not directly influence the first line of defence against microorganisms. Whether exposure to DEPs influences the adaptive immune response against mycobacterial infections remains to be determined.
The mechanisms through which immune and inflammatory responses stimulate the expression of an- ti... more The mechanisms through which immune and inflammatory responses stimulate the expression of an- timycobacterial activity by human macrophages remain poorly defined. To study this question, we developed a method permitting the rapid quantification of viable mycobacteria, based on the detec- tion of luciferase activity expressed by a Mycobacterium bovis Bacillus Calmette-Guerin (BCG) re- porter strain, and used this approach to
Background: Hepatocyte and keratinocyte growth factors are key growth factors in the process of a... more Background: Hepatocyte and keratinocyte growth factors are key growth factors in the process of alveolar repair. We hypothesized that excessive alveolar destruction observed in lung emphysema involves impaired expression of hepatocyte and keratinocyte growth factors or their respective receptors, c-met and keratinocyte growth factor receptor. The aim of our study was to compare the expression of hepatocyte and keratinocyte growth factors and their receptors in lung samples from 3 groups of patients: emphysema; smokers without emphysema and non-smokers without emphysema.
The prevalence of patent foramen ovale (PFO) is high. As identified at autopsy it is found in app... more The prevalence of patent foramen ovale (PFO) is high. As identified at autopsy it is found in approximately 25% of the general population. Anatomically a PFO represents a channel through which unidirectional blood flow from the right to the left atrium may occur. This potential interatrial shunt of unoxygenated venous blood into the oxygenated arterial system may lead to hypoxaemia. Usually right to left shunting across a PFO is transient and without clinical significance. Increased pulmonary arterial pressure may give rise to left-right pressure gradient reversal and right to left shunting across a PFO. High pressure in the right heart chambers, even without pulmonary arterial hypertension, can potentially lead to the reopening of a foramen ovale. In other cases inferior vena cava flow deviation might lead to right to left shunting across a PFO. Right to left shunting without pressure increase inside the right heart chambers is usually transient and even positional and its diagnosis is more difficult.
The innate immune system, including phagocytic cells, is the first line of defense against pathog... more The innate immune system, including phagocytic cells, is the first line of defense against pathogens. During infection by microorganisms such as viruses, bacteria, or parasites, phagocytic cells produce an excess of oxidants, a crucial process for the clearance of pathogens. This increase in oxidants creates an imbalance between oxidants and endogenous antioxidants. Left unchecked, this acute or chronic oxidative stress can lead to apoptotic cell-death and oxidative stress-induced diseases including neurodegenerative and cardiovascular disorders, premature aging, secondary infections, and cancer. The activation of nuclear factor E2-related factor 2 (Nrf2) is an efficient antioxidant defensive mechanism used by host cells to counteract oxidative stress. The transcription factor Nrf2 has been identified as the master regulator of several hundred of genes involved in the antioxidant defense response. The review objectives were to collect recent findings on the contribution of oxidative stress to complications of infection, and to highlight the beneficial impact of antioxidants in reducing inflammation and oxidant-related tissue damage. Furthermore, a direct relationship between infection and decline in Nrf2 activity has been demonstrated. Thus, an interesting therapeutic approach in disease prevention and treatment of stress-related diseases may consist in optimizing antibiotic or antiviral therapy with a combination of Nrf2 inducer treatment.
A cervical spinal cord injury induces permanent paralysis, and often leads to respiratory distres... more A cervical spinal cord injury induces permanent paralysis, and often leads to respiratory distress. To date, no efficient therapeutics have been developed to improve/ameliorate the respiratory failure following high cervical spinal cord injury (SCI). Here we propose a murine pre-clinical model of high SCI at the cervical 2 (C2) metameric level to study diverse post-lesional respiratory neuroplasticity. The technique consists of a surgical partial injury at the C2 level, which will induce a hemiparalysis of the diaphragm due to a deafferentation of the phrenic motoneurons from the respiratory centers located in the brainstem. The contralateral side of the injury remains intact and allows the animal recovery. Unlike other SCIs which affect the locomotor function (at the thoracic and lumbar level), the respiratory function does not require animal motivation and the quantification of the deficit/recovery can be easily performed (diaphragm and phrenic nerve recordings, whole body ventilation). This pre-clinical C2 SCI model is a powerful, useful, and reliable pre-clinical model to study various respiratory and non-respiratory neuroplasticity events at different levels (molecular to physiology) and to test diverse putative therapeutic strategies which might improve the respiration in SCI patients.
Airways are continually exposed to multiple inhaled oxidants and protect themselves with cellular... more Airways are continually exposed to multiple inhaled oxidants and protect themselves with cellular and extracellular antioxidants throughout the epithelial lining fluid and tissues. Oxidative stress, resulting from the increased oxidative burden and decreased level of antioxidant proteins, is involved in cellular and tissue damage related to the pathogenesis of many acute and chronic respiratory diseases. Evidence suggested that nuclear factor erythroid-2-related factor 2 (Nrf2), a transcription factor that controls antioxidant response element (ARE)-regulated antioxidant and cytoprotective genes has an essential protective role in the lungs against oxidative airway diseases. Therefore, Nrf2 promises to be an attractive therapeutic target for intervention and prevention strategies in respiratory diseases. We have reviewed major findings on the mechanisms of lung protection against oxidative stress by Nrf2 and the current literature suggesting that Nrf2 is a valuable therapeutic target.
A cervical spinal cord injury induces permanent paralysis, and often leads to respiratory distres... more A cervical spinal cord injury induces permanent paralysis, and often leads to respiratory distress. To date, no efficient therapeutics have been developed to improve/ameliorate the respiratory failure following high cervical spinal cord injury (SCI). Here we propose a murine pre-clinical model of high SCI at the cervical 2 (C2) metameric level to study diverse post-lesional respiratory neuroplasticity. The technique consists of a surgical partial injury at the C2 level, which will induce a hemiparalysis of the diaphragm due to a deafferentation of the phrenic motoneurons from the respiratory centers located in the brainstem. The contralateral side of the injury remains intact and allows the animal recovery. Unlike other SCIs which affect the locomotor function (at the thoracic and lumbar level), the respiratory function does not require animal motivation and the quantification of the deficit/recovery can be easily performed (diaphragm and phrenic nerve recordings, whole body ventilation). This pre-clinical C2 SCI model is a powerful, useful, and reliable pre-clinical model to study various respiratory and non-respiratory neuroplasticity events at different levels (molecular to physiology) and to test diverse putative therapeutic strategies which might improve the respiration in SCI patients.
Obstructive sleep apnea (OSA) is associated with impaired airway reflexes. Cough is the main airw... more Obstructive sleep apnea (OSA) is associated with impaired airway reflexes. Cough is the main airway defense mechanism but the effect of OSA on cough is unknown. Thirty-two female obese patients scheduled to undergo bariatric surgery were studied. They were classified as presenting OSA (20 patients) when the apnea-hypopnea index (AHI) was greater than 5 h. Cough sensitivity was measured with citric acid. Increasing concentrations of nebulized citric acid were delivered until cough was elicited. The concentrations eliciting one (C1) and two coughs (C2) were recorded and log transformed (log C1 and log C2). log C1 and log C2 (median (interquartile)) were 1.90 mg/mL (0.90) and 2.2 mg/mL (0.30) in OSA patients and 1.60 mg/mL (0.45) and 1.60 mg/mL (0.45) in non-OSA patients, respectively (comparison between groups: p = 0.0372 for log C1 and p = 0.0227 for log C2). A significant relationship was observed between AHI and log C1 and log C2. Cough sensitivity is therefore, decreased in female obese OSA patients and this decreased sensitivity is positively correlated with disease severity.
Nasal continuous positive airway pressure (nCPAP) has been widely established in the treatment of... more Nasal continuous positive airway pressure (nCPAP) has been widely established in the treatment of obstructive sleep apnea syndrome (OSAS). However, only few studies have evaluated long-term effects of this treatment on lung function. This study assesses the effect of nCPAP on lung function parameters and response to bronchodilators in 50 OSAS patients. Spirometry and arterial blood gas measurements were performed before starting nCPAP and after 16.878 months of treatment. Of the 50 study patients (55712 years, with an apnea/hypopnea index of 47734 h À1 ), 15 had asthma, 13 had chronic obstructive pulmonary disease (COPD) and 22 had no obstructive airway disease (NOAD). In the entire population, significant decreases in FEF 50 (from 69738% to 61730%, Po0:005), FEF 25 (from 53734% to 46728%, Po0:05) and FEF 25À75 (from 65733% to 57727%, Po0:005) were observed after treatment. No impairment of lung function was found in COPD and asthmatic patients. In contrast, lung function was changed in the NOAD group where FEF 50 , FEF 25 and FEF 25À75 as well as FEV 1 and FEV 1 /VC ratio were significantly reduced. Moreover, bronchial hyperresponsiveness occurred in five of 22 patients of this group. These results suggest that tolerance of nCPAP should be handled by long-term follow-up of flowvolume loops. r
Changes that may modify the capacity of macrophages to control mycobacterial growth could favour ... more Changes that may modify the capacity of macrophages to control mycobacterial growth could favour the reactivation of bacillary proliferation within protective granulomas developed in response to mycobacterial infection. There is increasing evidence that diesel exhaust particles (DEPs) could suppress some macrophage functions, but it is not known whether DEPs may alter macrophage mycobactericidal activity. The aim of this study was to assess the effect of DEPs on the mycobactericidal activity of human mononuclear phagocytes in vitro. Human monocytes from healthy donors were cultured for 3 days in the presence or absence of DEPs or carbon black particles (CBPs), and then infected with a Mycobacterium bovis bacillus Calmette-Guérin reporter strain expressing luciferase activity. DEPs were rapidly internalized by monocyte-derived macrophages without cytotoxic effect. Mycobactericidal activity of cells exposed to DEPs was not different from that of cells cultured in their absence or in the presence of CBPs. Although our study was restricted to the mycobactericidal activity of human macrophages in vitro, the results indicate that DEPs do not directly influence the first line of defence against microorganisms. Whether exposure to DEPs influences the adaptive immune response against mycobacterial infections remains to be determined.
The mechanisms through which immune and inflammatory responses stimulate the expression of an- ti... more The mechanisms through which immune and inflammatory responses stimulate the expression of an- timycobacterial activity by human macrophages remain poorly defined. To study this question, we developed a method permitting the rapid quantification of viable mycobacteria, based on the detec- tion of luciferase activity expressed by a Mycobacterium bovis Bacillus Calmette-Guerin (BCG) re- porter strain, and used this approach to
Background: Hepatocyte and keratinocyte growth factors are key growth factors in the process of a... more Background: Hepatocyte and keratinocyte growth factors are key growth factors in the process of alveolar repair. We hypothesized that excessive alveolar destruction observed in lung emphysema involves impaired expression of hepatocyte and keratinocyte growth factors or their respective receptors, c-met and keratinocyte growth factor receptor. The aim of our study was to compare the expression of hepatocyte and keratinocyte growth factors and their receptors in lung samples from 3 groups of patients: emphysema; smokers without emphysema and non-smokers without emphysema.
The prevalence of patent foramen ovale (PFO) is high. As identified at autopsy it is found in app... more The prevalence of patent foramen ovale (PFO) is high. As identified at autopsy it is found in approximately 25% of the general population. Anatomically a PFO represents a channel through which unidirectional blood flow from the right to the left atrium may occur. This potential interatrial shunt of unoxygenated venous blood into the oxygenated arterial system may lead to hypoxaemia. Usually right to left shunting across a PFO is transient and without clinical significance. Increased pulmonary arterial pressure may give rise to left-right pressure gradient reversal and right to left shunting across a PFO. High pressure in the right heart chambers, even without pulmonary arterial hypertension, can potentially lead to the reopening of a foramen ovale. In other cases inferior vena cava flow deviation might lead to right to left shunting across a PFO. Right to left shunting without pressure increase inside the right heart chambers is usually transient and even positional and its diagnosis is more difficult.
The innate immune system, including phagocytic cells, is the first line of defense against pathog... more The innate immune system, including phagocytic cells, is the first line of defense against pathogens. During infection by microorganisms such as viruses, bacteria, or parasites, phagocytic cells produce an excess of oxidants, a crucial process for the clearance of pathogens. This increase in oxidants creates an imbalance between oxidants and endogenous antioxidants. Left unchecked, this acute or chronic oxidative stress can lead to apoptotic cell-death and oxidative stress-induced diseases including neurodegenerative and cardiovascular disorders, premature aging, secondary infections, and cancer. The activation of nuclear factor E2-related factor 2 (Nrf2) is an efficient antioxidant defensive mechanism used by host cells to counteract oxidative stress. The transcription factor Nrf2 has been identified as the master regulator of several hundred of genes involved in the antioxidant defense response. The review objectives were to collect recent findings on the contribution of oxidative stress to complications of infection, and to highlight the beneficial impact of antioxidants in reducing inflammation and oxidant-related tissue damage. Furthermore, a direct relationship between infection and decline in Nrf2 activity has been demonstrated. Thus, an interesting therapeutic approach in disease prevention and treatment of stress-related diseases may consist in optimizing antibiotic or antiviral therapy with a combination of Nrf2 inducer treatment.
A cervical spinal cord injury induces permanent paralysis, and often leads to respiratory distres... more A cervical spinal cord injury induces permanent paralysis, and often leads to respiratory distress. To date, no efficient therapeutics have been developed to improve/ameliorate the respiratory failure following high cervical spinal cord injury (SCI). Here we propose a murine pre-clinical model of high SCI at the cervical 2 (C2) metameric level to study diverse post-lesional respiratory neuroplasticity. The technique consists of a surgical partial injury at the C2 level, which will induce a hemiparalysis of the diaphragm due to a deafferentation of the phrenic motoneurons from the respiratory centers located in the brainstem. The contralateral side of the injury remains intact and allows the animal recovery. Unlike other SCIs which affect the locomotor function (at the thoracic and lumbar level), the respiratory function does not require animal motivation and the quantification of the deficit/recovery can be easily performed (diaphragm and phrenic nerve recordings, whole body ventilation). This pre-clinical C2 SCI model is a powerful, useful, and reliable pre-clinical model to study various respiratory and non-respiratory neuroplasticity events at different levels (molecular to physiology) and to test diverse putative therapeutic strategies which might improve the respiration in SCI patients.
Airways are continually exposed to multiple inhaled oxidants and protect themselves with cellular... more Airways are continually exposed to multiple inhaled oxidants and protect themselves with cellular and extracellular antioxidants throughout the epithelial lining fluid and tissues. Oxidative stress, resulting from the increased oxidative burden and decreased level of antioxidant proteins, is involved in cellular and tissue damage related to the pathogenesis of many acute and chronic respiratory diseases. Evidence suggested that nuclear factor erythroid-2-related factor 2 (Nrf2), a transcription factor that controls antioxidant response element (ARE)-regulated antioxidant and cytoprotective genes has an essential protective role in the lungs against oxidative airway diseases. Therefore, Nrf2 promises to be an attractive therapeutic target for intervention and prevention strategies in respiratory diseases. We have reviewed major findings on the mechanisms of lung protection against oxidative stress by Nrf2 and the current literature suggesting that Nrf2 is a valuable therapeutic target.
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Papers by Marcel Bonay