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Hypercapnic acidosis induces mitochondrial dysfunction and impairs the ability of mesenchymal stem cells to promote distal lung epithelial repair.

ABSTRACT: Acute respiratory distress syndrome (ARDS) is a devastating disorder characterized by diffuse inflammation and edema formation. The main management strategy, low tidal volume ventilation, can be associated with the development of hypercapnic acidosis (HCA). Mesenchymal stem cells (MSCs) are a promising therapeutic candidate currently in early-phase clinical trials. The effects of HCA on the alveolar epithelium and capillary endothelium are not well established. The therapeutic efficacy of MSCs has never been reported in HCA. In the present study, we evaluated the effects of HCA on inflammatory response and reparative potential of the primary human small airway epithelial and lung microvasculature endothelial cells as well as on the capacity of bone marrow-derived MSCs to promote wound healing in vitro. We demonstrate that HCA attenuates the inflammatory response and reparative potential of primary human small airway epithelium and capillary endothelium and induces mitochondrial dysfunction. It was found that MSCs promote lung epithelial wound repair via the transfer of functional mitochondria; however, this proreparative effect of MSCs was lost in the setting of HCA. Therefore, HCA may adversely impact recovery from ARDS at the cellular level, whereas MSCs may not be therapeutically beneficial in patients with ARDS who develop HCA.-Fergie, N., Todd, N., McClements, L., McAuley, D., O'Kane, C., Krasnodembskaya, A. Hypercapnic acidosis induces mitochondrial dysfunction and impairs the ability of mesenchymal stem cells to promote distal lung epithelial repair.

SUBMITTER: Fergie N

PROVIDER: S-EPMC6436662 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Importance:Clinical studies investigating the effects of hypercapnia and hypercapnic acidosis in acute cerebral injury are limited. The studies performed so far have mainly focused on the outcomes in relation to the changes in partial pressure of carbon dioxide and pH in isolation and have not evaluated the effects of partial pressure of carbon dioxide and pH in conjunction. Objective:To review the association of compensated hypercapnia and hypercapnic acidosis during the first 24 hours of intensive care unit admission on hospital mortality in adult mechanically ventilated patients with cerebral injury. Design, Setting, and Participants:Multicenter, binational retrospective review of patients with cerebral injury (traumatic brain injury, cardiac arrest, and stroke) admitted to 167 intensive care units in Australia and New Zealand between January 2000 and December 2015. Patients were classified into 3 groups based on combination of arterial pH and arterial carbon dioxide (normocapnia and normal pH, compensated hypercapnia, and hypercapnic acidosis) during the first 24 hours of intensive care unit stay. Main Outcomes and Measures:Hospital mortality. Results:A total of 30 742 patients (mean age, 55 years; 21 827 men [71%]) were included. Unadjusted hospital mortality rates were highest in patients with hypercapnic acidosis. Multivariable logistic regression analysis and Cox proportional hazards analysis in 3 diagnostic categories showed increased odds of hospital mortality (cardiac arrest odds ratio [OR], 1.51; 95% CI, 1.34-1.71; stroke OR, 1.43; 95% CI, 1.27-1.6; and traumatic brain injury OR, 1.22; 95% CI, 1.06-1.42; P <.001) and hazard ratios (HR) (cardiac arrest HR, 1.23; 95% CI, 1.14-1.34; stroke HR, 1.3; 95% CI, 1.21-1.4; traumatic brain injury HR, 1.13; 95% CI, 1-1.27), in patients with hypercapnic acidosis compared with normocapnia and normal pH. There was no difference in mortality between patients who had compensated hypercapnia compared with patients who had normocapnia and normal pH. In patients with hypercapnic acidosis, the adjusted OR of hospital mortality increased with increasing partial pressure of carbon dioxide, while no such increase was noted in patients with compensated hypercapnia. Conclusions and Relevance:Hypercapnic acidosis was associated with increased risk of hospital mortality in patients with cerebral injury. Hypercapnia, when compensated to normal pH during the first 24 hours of intensive care unit admission, may not be harmful in mechanically ventilated patients with cerebral injury.

Project description:Our objective was to characterize the mechanisms by which local burn injury compromises epithelial barrier function in burn margin, containing the elements necessary for healing of the burn site, and in distal unburned skin, which serves as potential donor tissue.Experimental mouse scald burn injury.University Research Laboratory.C57/Bl6 Male mice, 8-12 weeks old.To confirm that dehydration was not contributing to our observed barrier defects, in some experiments mice received 1 mL of saline fluid immediately after burn, while a subgroup received an additional 0.5 mL at 4 hours and 1 mL at 24 hours following burn. We then assessed skin pH and transepidermal water loss every 12 hours on the burn wounds for 72 hours postburn.Burn margin exhibited increased epidermal barrier permeability indicated by higher pH, greater transepidermal water loss, and reduced lipid synthesis enzyme expression and structural protein production up to 96 hours postburn. By contrast, antimicrobial peptide production and protease activity were elevated in burn margin. Skin extracts from burn margin did not exhibit changes in the ability to inhibit bacterial growth. However, distal unburned skin from burned mice also demonstrated an impaired response to barrier disruption, indicated by elevated transepidermal water loss and reduced lipid synthesis enzyme and structural protein expression up to 96 hours postburn. Furthermore, skin extracts from distal unburned skin exhibited greater protease activity and a reduced capacity to inhibit bacterial growth of several skin pathogens. Finally, we established that antimicrobial peptide levels were also altered in the lung and bladder, which are common sites of secondary infection in burn-injured patients.These findings reveal several undefined deficiencies in epithelial barrier function at the burn margin, potential donor skin sites, and organs susceptible to secondary infection. These functional and biochemical data provide novel insights into the mechanisms for graft failure and secondary infection after burn injury.

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Hypercapnic acidosis induces mitochondrial dysfunction and impairs the ability of mesenchymal stem cells to promote distal lung epithelial repair.

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