A two-hit model of sepsis plus hyperoxia causes lung permeability and inflammation

2021 ◽  
Author(s):  
Julie A. Bastarache ◽  
Kyle Smith ◽  
Jordan J Jesse ◽  
Nathan D Putz ◽  
Jamie E Meegan ◽  
...  
Keyword(s):  
Lung Injury ◽  
Cell Count ◽  
Weight Ratio ◽  
Abdominal Sepsis ◽  
Lung Injury Score ◽  
Lung Edema ◽  
Injury Score ◽  
Final Model ◽  
Cell Counts ◽  
Lung Epithelial

Mouse models of acute lung injury (ALI) have been instrumental for studies of the biologic underpinnings of lung inflammation and permeability, but murine models of sepsis generate minimal lung injury. Our goal was to create a murine sepsis model of ALI that reflects the inflammation, lung edema, histologic abnormalities and physiologic dysfunction that characterize ALI. Using a cecal slurry (CS) model of polymicrobial abdominal sepsis and exposure to hyperoxia (95%), we systematically varied timing and dose of the CS injection, fluids and antibiotics and dose of hyperoxia. We found that CS alone had a high mortality rate that was improved with the addition of antibiotics and fluids. Despite this, we did not see evidence of ALI as measured by bronchoalveolar lavage (BAL) cell count, total protein, CXCL-1 or by lung wet:dry weight ratio. Addition of hyperoxia (95% FiO2) to CS immediately after CS injection increased BAL cell counts and CXCL-1 and lung wet:dry weight ratio but was associated with 40% mortality. Splitting the hyperoxia treatment into two 12 hour exposures (0-12 hours24-36 hours) after CS injection increased survival to 75% and caused significant lung injury compared to CS alone as measured by increased BAL total cell count (92500 vs 240000, p=0.0004), BAL protein (71 vs 103 ug/ml, p=0.0030, and lung wet:dry weight ratio (4.5 vs 5.5 p=0.0005), and compared to sham as measured by increased BAL CXCL-1 (20 vs 2372 pg/ml, p<0.0001), and histologic lung injury score (1.9 vs 4.2, p=0.0077). Additionally, our final model showed evidence of lung epithelial (increased BAL and plasma RAGE) and endothelial (increased Syndecan-1 and sulfated glycosaminoglycans) injury. In conclusion, we have developed a clinically relevant mouse model of sepsis-induced ALI using IP injection of CS, antibiotics and fluids, and hyperoxia. This clinically relevant model can be used for future studies of sepsis-induced ALI.

Does Early Posttreatment with Lidocaine Attenuate Endotoxin-induced Acute Lung Injury in Rabbits?

1995 ◽  
Vol 83 (1) ◽  
pp. 169-177. ◽  
Author(s):  
Kahoru Nishina ◽  
Katsuya Mikawa ◽  
Nobuhiro Maekawa ◽  
Yumiko Takao ◽  
Hidefumi Obara
Keyword(s):  
Acute Lung Injury ◽  
Treatment Group ◽  
Lung Injury ◽  
Weight Ratio ◽  
Lung Damage ◽  
Lung Mechanics ◽  
Lung Edema ◽  
Platelet Counts ◽  
Peripheral Leukocyte ◽  
Cell Counts

Background It is well known that endotoxin causes acute lung injury, resulting in adult respiratory distress syndrome. Lidocaine pretreatment has recently been shown to attenuate endotoxin-induced lung injury in rabbits. The aim of the current study was to determine whether early postinjury treatment with intravenous lidocaine could attenuate acute lung injury induced by endotoxin in rabbits. Methods Thirty-two male anesthetized rabbits were randomly assigned to receive one of four treatments (n = 8 for each group): infusion of saline (group S-S), infusion of saline with lidocaine treatment (group S-L), infusion of Escherichia coli endotoxin (100 micrograms.kg-1 over a 60-min period) without lidocaine treatment (group E-S), or infusion of endotoxin with lidocaine treatment (group E-L). Ten minutes after the end of infusion of endotoxin (groups E-L and E-S) or saline (groups S-S and S-L), the animals received a bolus injection followed by continuous infusion of lidocaine (2 mg.kg-1 + 2 mg.kg-1.h-1 in groups S-L and E-L) or saline (groups S-S and E-S). The rabbits' lungs were ventilated with 40% O2. Hemodynamics, peripheral leukocyte and platelet counts, and arterial O2 tension (PaO2) were recorded during the ventilation period (6 h). After the observation, lung mechanics; the cell fraction of bronchoalveolar lavage fluid (BALF); and concentrations of activated complement components C3a and C5a, cytokines, and arachidonic acid metabolites in BALF were measured and analyzed. The ratio of lung wet weight to dry weight (W/D weight ratio) and albumin concentrations in BALF were analyzed as indexes of pulmonary edema. The Cypridina luciferin analogue-dependent chemiluminescence (representing O2 production) by neutrophils isolated from the pulmonary artery and light-microscopic findings of the lung were compared among the four groups. Results Endotoxin caused decreases in peripheral leukocyte and platelet counts, lung compliance, and PaO2. It caused increases in lung W/D weight ratio; polymorphonuclear cell counts in BALF; and albumin, C3a, C5a, tumor necrosis factor-alpha, interleukin (IL)-1 beta, IL-6, IL-8, and thromboxane B2 concentrations in BALF. Lidocaine attenuated the changes in W/D weight ratio and morphologic lung damage. The change in compliance, decrease in PaO2, and albumin concentrations in BALF were slightly but significantly less in rabbits receiving lidocaine after injury. The Cypridina luciferin analogue-dependent chemiluminescence by neutrophils was greater in rabbits receiving endotoxin without lidocaine than in those receiving endotoxin with lidocaine. Conclusions These results indicate that early treatment with lidocaine attenuates endotoxin-induced lung edema in rabbits without affecting chemical mediators in BALF. However, the improvement is slight and likely to be of little clinical significance.

scholarly journals Thaliporphine Derivative Improves Acute Lung Injury after Traumatic Brain Injury

2015 ◽  
Vol 2015 ◽  
pp. 1-10
Author(s):  
Gunng-Shinng Chen ◽  
Kuo-Feng Huang ◽  
Chien-Chu Huang ◽  
Jia-Yi Wang
Keyword(s):  
Traumatic Brain Injury ◽  
Acute Lung Injury ◽  
Brain Injury ◽  
Lung Injury ◽  
Weight Ratio ◽  
Dry Weight ◽  
Lung Injury Score ◽  
Injury Score ◽  
Aqp4 Expression ◽  
Protein Levels

Acute lung injury (ALI) occurs frequently in patients with severe traumatic brain injury (TBI) and is associated with a poor clinical outcome. Aquaporins (AQPs), particularly AQP1 and AQP4, maintain water balances between the epithelial and microvascular domains of the lung. Since pulmonary edema (PE) usually occurs in the TBI-induced ALI patients, we investigated the effects of a thaliporphine derivative, TM-1, on the expression of AQPs and histological outcomes in the lung following TBI in rats. TM-1 administered (10 mg/kg, intraperitoneal injection) at 3 or 4 h after TBI significantly reduced the elevated mRNA expression and protein levels of AQP1 and AQP4 and diminished the wet/dry weight ratio, which reflects PE, in the lung at 8 and 24 h after TBI. Postinjury TM-1 administration also improved histopathological changes at 8 and 24 h after TBI. PE was accompanied with tissue pathological changes because a positive correlation between the lung injury score and the wet/dry weight ratio in the same animal was observed. Postinjury administration of TM-1 improved ALI and reduced PE at 8 and 24 h following TBI. The pulmonary-protective effect of TM-1 may be attributed to, at least in part, downregulation of AQP1 and AQP4 expression after TBI.

scholarly journals The assessment of severity of lung injury in sepsis

2004 ◽  
Vol 132 (11-12) ◽  
pp. 404-408
Author(s):  
Ljubica Arsenijevic ◽  
Nada Popovic ◽  
Zvezdana Kojic
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Respiratory Distress Syndrome ◽  
Respiratory Distress ◽  
Distress Syndrome ◽  
Lung Injury Score ◽  
Pulmonary Dysfunction ◽  
Lethal Outcome ◽  
Injury Score ◽  
Respiratory Dysfunction

Adult respiratory distress syndrome (ARDS) is an acute and severe pulmonary dysfunction. It is clinically characterized by dyspnea and tachypnea, progressive hypoxemia (within 12-48 hours), reduction of pulmonary compliance and diffuse bilateral infiltrates seen on pulmonary radiogram. Etiological factors giving rise to development of the syndrome are numerous. The acute lung injury (AU) is defined as the inflammation syndrome and increased permeability, which is associated with radiological and physiological disorders. Lung injury score (LIS), which is composed of four components, is used for making a distinction between two separate but rather similar syndromes. The study was aimed at the assessment of the severity of the lung injury in patients who had suffered from sepsis of the gynecological origin and its influence on the outcome of the disease. The total of 43 female patients was analyzed. Twenty patients (46.51%) were diagnosed as having ARDS based on the lung injury score, while 23 patients (53.48%) were diagnosed with acute lung injury. In our series, lung injury score ranged from 0.7 to 3.3 in ARDS patients, and lethal outcome ensued in 11 (55%) cases in this group. As for the patients with the acute lung injury, the score values ranged from 0.3 to 1.3 and only one patient from this group died (4.34%). The obtained results indicate that high values of the lung injury score are suggestive of the severe respiratory dysfunction as well as that lethal outcome is dependent on LIS value.

scholarly journals Mesenchymal Stromal Cells Attenuate Infection-Induced Acute Respiratory Distress Syndrome in Animal Experiments: A Meta-Analysis

2020 ◽  
Vol 29 ◽  
pp. 096368972096918
Author(s):  
Wang Fengyun ◽  
Zhou LiXin ◽  
Qiang Xinhua ◽  
Fang Bin
Keyword(s):  
Acute Respiratory Distress Syndrome ◽  
Lung Injury ◽  
Respiratory Distress Syndrome ◽  
Respiratory Distress ◽  
Distress Syndrome ◽  
Meta Analysis ◽  
Weight Ratio ◽  
Lung Injury Score ◽  
Control Group ◽  
Inflammatory Factor

Mesenchymal stromal cell (MSC) therapy is a potential therapy for treating acute lung injury (ALI) or acute respiratory distress syndrome (ARDS), which was widely studied in the last decade. The purpose of our meta-analysis was to investigate the efficacy of MSCs for simulated infection-induced ALI/ARDS in animal trials. PubMed and EMBASE were searched to screen relevant preclinical trials with a prespecified search strategy. 57 studies met the inclusion criteria and were included in our study. Our meta-analysis showed that MSCs can reduce the lung injury score of ALI caused by lipopolysaccharide or bacteria (standardized mean difference (SMD) = −2.97, 95% CI [−3.64 to −2.30], P < 0.00001) and improve the animals’ survival (odds ratio = 3.64, 95% CI [2.55 to 5.19], P < 0.00001). Our study discovered that MSCs can reduce the wet weight to dry weight ratio of the lung (SMD = −2.58, 95% CI [−3.24 to −1.91], P < 0.00001). The proportion of the alveolar sac in the MSC group was higher than that in the control group (SMD = 1.68, 95% CI [1.22 to 2.13], P < 0.00001). Moreover, our study detected that MSCs can downregulate the levels of proinflammatory factors such as interleukin (IL)-1β, IL-6, and tumor necrosis factor-α in the lung and it can upregulate the level of anti-inflammatory factor IL-10. MSCs were also found to reduce the level of neutrophils and total protein in bronchoalveolar lavage fluid, decrease myeloperoxidase (MPO) activity in the lung, and improve lung compliance. MSC therapy may be a promising treatment for ALI/ARDS since it may mitigate the severity of lung injury, modulate the immune balance, and ameliorate the permeability of lung vessels in ALI/ARDS, thus facilitating lung regeneration and repair.

Leukotriene B4 induces lung injury in the rabbit: role of neutrophils and effect of indomethacin

1993 ◽  
Vol 74 (5) ◽  
pp. 2174-2179 ◽  
Author(s):  
K. Yoshimura ◽  
S. Nakagawa ◽  
S. Koyama ◽  
T. Kobayashi ◽  
T. Homma
Keyword(s):  
Arachidonic Acid ◽  
Lung Injury ◽  
Weight Ratio ◽  
Leukotriene B4 ◽  
Arachidonic Acid Metabolism ◽  
Microvascular Permeability ◽  
Lung Edema ◽  
Lung Weight ◽  
Fluid Filtration ◽  
Pmn Leukocytes

The effects of exogenous leukotriene B4 (LTB4) on the pulmonary microvascular permeability and the roles of polymorphonuclear (PMN) leukocytes and the cyclooxygenase products of arachidonic acid in the microvascular response to LTB4 in the isolated non-blood-perfused rabbit lungs were studied. Microvascular permeability and lung edema were evaluated by use of the fluid filtration coefficient (Kf) and the wet-to-dry lung weight ratio (W/D ratio), respectively. Pulmonary capillary pressure was estimated by the double occlusion technique. We studied five groups of lungs: lungs were given 1) both PMN leukocytes and a bolus injection of LTB4 (5 micrograms, n = 6), 2) LTB4 alone (n = 5), 3) PMN leukocytes alone (n = 5), 4) control vehicles (n = 5), or 5) indomethacin (40 micrograms/ml) before PMN leukocytes and LTB4 (n = 6). We observed that LTB4 increased Kf and W/D ratio in the presence of PMN leukocytes in the perfusate without affecting the pulmonary arterial and capillary pressures. Neither LTB4 alone nor PMN leukocytes alone produced changes in Kf and W/D ratio. Indomethacin failed to inhibit the LTB4-induced increases in Kf and W/D ratio. These results suggest that LTB4 produces lung injury that is dependent on PMN leukocytes but not on the cyclooxygenase pathway of arachidonic acid metabolism.

scholarly journals Alda-1 Prevents Pulmonary Epithelial Barrier Dysfunction following Severe Hemorrhagic Shock through Clearance of Reactive Aldehydes

2019 ◽  
Vol 2019 ◽  
pp. 1-9 ◽  
Author(s):  
Tianfeng Hua ◽  
Min Yang ◽  
Yangyang Zhou ◽  
Limin Chen ◽  
Huimei Wu ◽  
...  
Keyword(s):  
Lung Injury ◽  
Hemorrhagic Shock ◽  
Rat Model ◽  
Weight Ratio ◽  
Dry Weight ◽  
Epithelial Barrier ◽  
Lung Edema ◽  
Epithelial Tissue ◽  
Diffuse Infiltration ◽  
Reactive Aldehydes

Severe hemorrhagic shock and resuscitation (HS/R) can lead to lung injury, resulting in respiratory insufficiency. We investigated whether treatment with Alda-1, an ALDH2 activator, decreased lung injury induced by severe HS/R in a rat model. Male Sprague-Dawley rats were randomized into three groups, hemorrhagic shock + placebo, hemorrhagic shock + Alda-1, and sham. All animals were heparinized, and then 50% of the total calculated blood volume was collected over 60 minutes. After 40 minutes of hemorrhagic shock, animals were reinfused with the shed blood over 40 minutes and then observed for an additional 2 hours. Concentrations of 4-HNE, TNF-α, IL-6, and ALDH2 activity were detected; lung injury and lung wet-to-dry weight ratios were assessed. Expression of occludin and ZO-1 proteins in lung tissues was also determined. At 2 hours after resuscitation, lung injury was significantly reduced and the wet-to-dry weight ratio was notably decreased in the Alda-1 group compared with placebo (P<0.05). Alda-1 treatment also significantly increased the activity of ALDH2 and decreased the levels of toxic 4-HNE (P<0.05). In the Alda-1 group, IL-6 and TNF-α were dramatically decreased compared with placebo-treated animals (P<0.05). Expression of occludin and ZO-1 proteins was significantly decreased in the placebo group compared with the Alda-1 group (P<0.05). Thus, in a rat model of severe HS/R, treatment with Alda-1 increased the activity of ALDH2, significantly accelerated the clearance of reactive aldehydes, and concomitantly alleviated lung injury through improvement of pulmonary epithelial barrier integrity resulting in decreased alveolar epithelial tissue permeability, lung edema, and diffuse infiltration of inflammatory cells.

scholarly journals Lung Inflammatory and Oxidative Alterations After Exogenous Surfactant Therapy Fortified With Budesonide in Rabbit Model of Meconium Aspiration Syndrome

2016 ◽  
pp. S653-S662 ◽  
Author(s):  
P. MIKOLKA ◽  
J. KOPINCOVÁ ◽  
P. KOŠÚTOVÁ ◽  
D. ČIERNY ◽  
A. ČALKOVSKÁ ◽  
...  
Keyword(s):  
Oxidative Damage ◽  
Expression Profiles ◽  
Rabbit Model ◽  
Weight Ratio ◽  
Meconium Aspiration Syndrome ◽  
Exogenous Surfactant ◽  
Lung Edema ◽  
Edema Formation ◽  
Meconium Aspiration ◽  
Cell Counts

Meconium aspiration syndrome (MAS) triggers inflammatory and oxidative pathways which can inactivate both pulmonary surfactant and therapeutically given exogenous surfactant. Glucocorticoid budesonide added to exogenous surfactant can inhibit inflammation and thereby enhance treatment efficacy. Neonatal meconium (25 mg/ml, 4 ml/kg) was administered intratracheally (i.t.) to rabbits. When the MAS model was prepared, animals were treated with budesonide i.t. (Pulmicort, 0.25 mg/kg, M+B); with surfactant lung lavage (Curosurf®, 10 ml/kg, 5 mg phospholipids/ml, M+S) followed by undiluted Curosurf® i.t. (100 mg phospholipids/kg); with combination of budesonide and surfactant (M+S+B); or were untreated (M); or served as controls with saline i.t. instead of meconium (C). Animals were oxygen-ventilated for additional 5 h. Cell counts in the blood and bronchoalveolar lavage fluid (BAL), lung edema formation (wet/dry weight ratio), oxidative damage of lipids/ proteins and inflammatory expression profiles (IL-2, IL-6, IL-13, TNF-α) in the lung homogenate and plasma were determined. Combined surfactant+budesonide therapy was the most effective in reduction of neutrophil counts in BAL, oxidative damage, levels and mRNA expression of cytokines in the lung, and lung edema formation compared to untreated animals. Curosurf fortified with budesonide mitigated lung inflammation and oxidative modifications what indicate the perspectives of this treatment combination for MAS therapy.

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