Neutralizing the complement component C5a protects against lung injury and extrapulmonary organ injury in pneumococcal pneumonia induced sepsis

Mesenteric ischemia and reperfusion (I/R) injury can ensue from a variety of vascular diseases and represents a major cause of morbidity and mortality in intensive care units. It causes an inflammatory response associated with local gut dysfunction and remote organ injury. Adenosine monophosphate-activated protein kinase (AMPK) is a crucial regulator of metabolic homeostasis. The catalytic α1 subunit is highly expressed in the intestine and vascular system. In loss-of-function studies, we investigated the biological role of AMPKα1 in affecting the gastrointestinal barrier function. Male knock-out (KO) mice with a systemic deficiency of AMPKα1 and wild-type (WT) mice were subjected to a 30 min occlusion of the superior mesenteric artery. Four hours after reperfusion, AMPKα1 KO mice exhibited exaggerated histological gut injury and impairment of intestinal permeability associated with marked tissue lipid peroxidation and a lower apical expression of the junction proteins occludin and E-cadherin when compared to WT mice. Lung injury with neutrophil sequestration was higher in AMPKα1 KO mice than WT mice and paralleled with higher plasma levels of syndecan-1, a biomarker of endothelial injury. Thus, the data demonstrate that AMPKα1 is an important requisite for epithelial and endothelial integrity and has a protective role in remote organ injury after acute ischemic events.

Download Full-text

Redox Balance and Cellular Inflammation in the Diaphragm, Limb Muscles, and Lungs of Mechanically Ventilated Rats

Anesthesiology ◽

10.1097/aln.0b013e3181c38bed ◽

2010 ◽

Vol 112 (2) ◽

pp. 384-394 ◽

Cited By ~ 12

Author(s):

Judith Marín-Corral ◽

Leticia Martínez-Caro ◽

José A. Lorente ◽

Marta de Paula ◽

Lara Pijuan ◽

...

Keyword(s):

Oxidative Stress ◽

Mechanical Ventilation ◽

Lung Injury ◽

Protein Adducts ◽

Organ Injury ◽

Mechanically Ventilated ◽

Ventilator Induced Lung Injury ◽

Cellular Inflammation ◽

Cell Counts ◽

Limb Muscles

Background High tidal volume (VT) mechanical ventilation was shown to induce organ injury other than lung injury and systemic inflammation in animal models of ventilator-induced lung injury. The authors aimed to explore whether high VT mechanical ventilation per se induces early oxidative stress and inflammation in the diaphragm, limb muscles, and lungs of healthy rats exposed to ventilator-induced lung injury. Methods Protein carbonylation and nitration, antioxidants (immunoblotting), and inflammation (immunohistochemistry) were evaluated in the diaphragm, gastrocnemius, soleus, tibialis anterior, and lungs of mechanically ventilated healthy rats and in nonventilated control animals (n = 8/group) for 1 h, using two different strategies (moderate VT [VT = 9 ml/kg] and high VT [VT = 35 ml/kg]). Results The main findings are summarized as follows: compared with controls, (1) the diaphragms and gastrocnemius of high-VT rats exhibited a decrease in reactive carbonyls, (2) the soleus and tibialis of high- and moderate-VT rodents showed a reduction in reactive carbonyls and malondialdehyde-protein adducts, (3) the lungs of high-VT rats exhibited a significant rise in malondialdehyde-protein adducts, (4) the soleus and tibialis of both high- and moderate-VT rats showed a reduction in protein nitration, (5) the lungs of high- and moderate-VT rats showed a reduction in antioxidant enzyme levels, but not in the muscles, and (6) the diaphragms and gastrocnemius of all groups exhibited very low inflammatory cell counts, whereas the lungs of high-VT rats exhibited a significant increase in inflammatory infiltrates. Conclusions Although oxidative stress and inflammation increased in the lungs of rats exposed to high VT, the diaphragm and limb muscles exhibited a decline in oxidative stress markers and very low levels of cellular inflammation.

Download Full-text

Heparin-based blood purification attenuates organ injury in baboons with S. pneumoniae pneumonia

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00337.2020 ◽

2021 ◽

Author(s):

Lingye Chen ◽

Bryan D Kraft ◽

Victor L Roggli ◽

Zachary R Healy ◽

Christopher W Woods ◽

...

Keyword(s):

Septic Shock ◽

Pneumococcal Pneumonia ◽

Kidney Injury ◽

Blood Purification ◽

Dose Finding ◽

Organ Injury ◽

Inflammasome Activation ◽

Post Inoculation ◽

Extracorporeal Blood ◽

Extracorporeal Blood Purification

Background: Bacterial pneumonia is a major cause of morbidity and mortality worldwide despite the use of antibiotics, and novel therapies are urgently needed. Building on previous work, we aimed to 1) develop a baboon model of severe pneumococcal pneumonia and sepsis with organ dysfunction; and 2) test the safety and efficacy of a novel extracorporeal blood filter to remove pro-inflammatory molecules and improve organ function. Methods: After a dose-finding pilot study, twelve animals were inoculated with S. pneumoniae (5x109 CFU), given ceftriaxone at 24 hours post-inoculation, and randomized to extracorporeal blood purification using a filter coated with surface-immobilized heparin sulfate (n=6) or sham treatment (n=6) for 4 hours at 30 hours post-inoculation. For safety analysis, four uninfected animals also underwent purification. At 48 hours, necropsy was performed. Results: Inoculated animals developed severe pneumonia and septic shock. Compared with sham animals, septic animals treated with purification displayed significantly less kidney injury, metabolic acidosis, hypoglycemia, and shock (P<0.05). Purification blocked the rise in peripheral blood S. pneumoniae DNA, attenuated BAL CCL4, CCL2, and IL-18 levels, and reduced renal oxidative injury and classical NLRP3-inflammasome activation. Purification was safe in both uninfected and infected animals and produced no adverse effects. Conclusions: We demonstrate that heparin-based blood purification significantly attenuates levels of circulating S. pneumoniae DNA and BAL cytokines, and is renal-protective in baboons with severe pneumococcal pneumonia and septic shock. Purification was associated with less severe acute kidney injury, metabolic derangements, and shock. These results support future clinical studies in critically ill septic patients.

Download Full-text