scholarly journals Selective V1aagonism attenuates vascular dysfunction and fluid accumulation in ovine severe sepsis

2012 ◽  
Vol 303 (10) ◽  
pp. H1245-H1254 ◽  
Author(s):  
Sebastian Rehberg ◽  
Yusuke Yamamoto ◽  
Linda Sousse ◽  
Eva Bartha ◽  
Collette Jonkam ◽  
...  
Keyword(s):  
Vascular Dysfunction ◽  
Neutrophil Migration ◽  
Weight Ratio ◽  
Dry Weight ◽  
Hemodynamic Instability ◽  
Left Ventricular ◽  
Myeloperoxidase Activity ◽  
Stroke Work ◽  
Fluid Accumulation ◽  
Pulmonary Tissue

Vasopressin analogs are used as a supplement to norepinephrine in septic shock. The isolated effects of vasopressin agonists on sepsis-induced vascular dysfunction, however, remain controversial. Because V2-receptor stimulation induces vasodilation and procoagulant effects, a higher V1a- versus V2-receptor selectivity might be advantageous. We therefore hypothesized that a sole, titrated infusion of the selective V1a-agonist Phe2-Orn8-Vasotocin (POV) is more effective than the mixed V1a-/V2-agonist AVP for the treatment of vascular and cardiopulmonary dysfunction in methicillin resistant staphylococcus aureus pneumonia-induced, ovine sepsis. After the onset of hemodynamic instability, awake, chronically instrumented, mechanically ventilated, and fluid resuscitated sheep were randomly assigned to receive continuous infusions of either POV, AVP, or saline solution (control; each n = 6). AVP and POV were titrated to maintain mean arterial pressure above baseline − 10 mmHg. When compared with that of control animals, AVP and POV reduced neutrophil migration (myeloperoxidase activity, alveolar neutrophils) and plasma levels of nitric oxide, resulting in higher mean arterial pressures and a reduced vascular leakage (net fluid balance, chest and abdominal fluid, pulmonary bloodless wet-to-dry-weight ratio, alveolar and septal edema). Notably, POV stabilized hemodynamics at lower doses than AVP. In addition, POV, but not AVP, reduced myocardial and pulmonary tissue concentrations of 3-nitrotyrosine, VEGF, and angiopoietin-2, thereby leading to an abolishment of cumulative fluid accumulation (POV, 9 ± 15 ml/kg vs. AVP, 110 ± 13 ml/kg vs. control, 213 ± 16 ml/kg; P < 0.001 each) and an attenuated cardiopulmonary dysfunction (left ventricular stroke work index, PaO2-to-FiO2ratio) versus control animals. Highly selective V1a-agonism appears to be superior to unselective vasopressin analogs for the treatment of sepsis-induced vascular dysfunction.

scholarly journals Transmural distribution of metabolic abnormalities and glycolytic activity during dobutamine-induced demand ischemia

2008 ◽  
Vol 294 (6) ◽  
pp. H2680-H2686 ◽  
Author(s):  
Mohammad N. Jameel ◽  
Xiaohong Wang ◽  
Marcel H. J. Eijgelshoven ◽  
Abdul Mansoor ◽  
Jianyi Zhang
Keyword(s):  
Blood Flow ◽  
Coronary Stenosis ◽  
Energy Demand ◽  
Weight Ratio ◽  
Dry Weight ◽  
High Energy ◽  
Left Ventricular ◽  
Cardiac Work ◽  
Induced Demand ◽  
Systolic Thickening

The heterogeneity across the left ventricular wall is characterized by higher rates of oxygen consumption, systolic thickening fraction, myocardial perfusion, and lower energetic state in the subendocardial layers (ENDO). During dobutamine stimulation-induced demand ischemia, the transmural distribution of energy demand and metabolic markers of ischemia are not known. In this study, hemodynamics, transmural high-energy phosphate (HEP), 2-deoxyglucose-6-phosphate (2-DGP) levels, and myocardial blood flow (MBF) were determined under basal conditions, during dobutamine infusion (DOB: 20 μg·kg−1·min−1 iv), and during coronary stenosis + DOB + 2-deoxyglucose (2-DG) infusion. DOB increased rate pressure products (RPP) and MBF significantly without affecting the subendocardial-to-subepicardial blood flow ratio (ENDO/EPI) or HEP levels. During coronary stenosis + DOB + 2-DG infusion, RPP, ischemic zone (IZ) MBF, and ENDO/EPI decreased significantly. The IZ ratio of creatine phosphate-to-ATP decreased significantly [2.30 ± 0.14, 2.06 ± 0.13, and 2.04 ± 0.11 to 1.77 ± 0.12, 1.70 ± 0.11, and 1.72 ± 0.12 for EPI, midmyocardial (MID), and ENDO, respectively], and 2-DGP accumulated in all layers, as evidenced by the 2-DGP/PCr (0.55 ± 0.12, 0.52 ± 0.10, and 0.37 ± 0.08 for EPI, MID, and ENDO, respectively; P < 0.05, EPI > ENDO). In the IZ the wet weight-to-dry weight ratio was significantly increased compared with the normal zone (5.9 ± 0.5 vs. 4.4 ± 0.4; P < 0.05). Thus, in the stenotic perfused bed, during dobutamine-induced high cardiac work state, despite higher blood flow, the subepicardial layers showed the greater metabolic changes characterized by a shift toward higher carbohydrate metabolism, suggesting that a homeostatic response to high-cardiac work state is characterized by more glucose utilization in energy metabolism.

Mechanisms of increased pulmonary microvascular permeability induced by FMLP in isolated rabbit lungs

1992 ◽  
Vol 73 (5) ◽  
pp. 2074-2082 ◽  
Author(s):  
H. Tanaka ◽  
J. D. Bradley ◽  
L. J. Baudendistel ◽  
T. E. Dahms
Keyword(s):  
Polymorphonuclear Leukocytes ◽  
Weight Ratio ◽  
Dry Weight ◽  
Microvascular Permeability ◽  
Cyclooxygenase Inhibitors ◽  
Myeloperoxidase Activity ◽  
Oxygen Species ◽  
Chemotactic Peptide ◽  
Isolated Lung ◽  
Baseline Values

We observed that the chemotactic peptide N-formyl-L-methionyl-L-leucyl-L- phenylalanine (FMLP) induced pulmonary edema when polymorphonuclear leukocytes (PMNs) were added to isolated constant-flow buffer-perfused rabbit lungs. This study was designed to test the hypothesis that PMNs activated by FMLP induced lung injury by the modulation of reactive oxygen species (ROS), cyclooxygenase products, or cysteinyl leukotrienes (LTs). Addition of FMLP alone did not increase microvascular permeability (Kf). When PMNs were added to the isolated lung, FMLP caused an 80% increase in Kf. Wet-to-dry weight ratio was also significantly increased with PMNs + FMLP compared with FMLP only. There was a significant positive correlation between total myeloperoxidase activity in lung tissue and Kf values after FMLP (30 min). Pretreatment with two dissimilar cyclooxygenase inhibitors, meclofenamate or ibuprofen, had no effect on the PMN + FMLP-induced increase in Kf. However, the ROS inhibitor catalase and the nonantioxidant LT synthesis blocker MK 886 inhibited the PMN + FMLP increase in Kf. Perfusate levels of LTs (LTC4, -D4, and -E4) were significantly increased from baseline values 30 min after FMLP. Both MK 886 and catalase suppressed the elevation of LTs after PMN + FMLP. These results indicate that FMLP increased a pulmonary microvascular permeability in isolated buffer-perfused rabbit lungs that is PMN dependent and mediated by LT produced possibly by a result of ROS production.

scholarly journals Ganoderic acid A attenuates lipopolysaccharide-induced lung injury in mice

2019 ◽  
Vol 39 (5) ◽  
Author(s):  
Bing Wan ◽  
Yan Li ◽  
Shuangshuang Sun ◽  
Yang Yang ◽  
Yanling LV ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Mouse Model ◽  
Weight Ratio ◽  
Dry Weight ◽  
Lavage Fluid ◽  
Myeloperoxidase Activity ◽  
Protective Effects ◽  
Ganoderic Acid ◽  
Lower Lung

Abstract The present study aimed to investigate the protective effects of ganoderic acid A (GAA) on lipopolysaccharide (LPS)-induced acute lung injury. In mouse model of LPS-induced acute lung injury, we found that GAA led to significantly lower lung wet-to-dry weight ratio and lung myeloperoxidase activity, and attenuated pathological damages. In addition, GAA increased superoxide dismutase activity, but decreased malondialdehyde content and proinflammatory cytokines levels in the bronchoalveolar lavage fluid. Mechanistically, GAA reduced the activation of Rho/ROCK/NF-κB pathway to inhibit LPS-induced inflammation. In conclusion, our study suggests that GAA attenuates acute lung injury in mouse model via the inhibition of Rho/ROCK/NF-κB pathway.

Vascular permeability and epithelial transport effects on lung edema formation in ischemia and reperfusion

1994 ◽  
Vol 77 (3) ◽  
pp. 1116-1121 ◽  
Author(s):  
P. L. Khimenko ◽  
J. W. Barnard ◽  
T. M. Moore ◽  
P. S. Wilson ◽  
S. T. Ballard ◽  
...  
Keyword(s):  
Weight Ratio ◽  
Dry Weight ◽  
Transport Processes ◽  
Transport Systems ◽  
Lung Edema ◽  
Ischemia And Reperfusion ◽  
Fluid Accumulation ◽  
Edema Formation ◽  
Rat Lungs ◽  
Edema Fluid

To determine the role of various Na+ transport systems in the edema fluid accumulation after ischemia and reperfusion in the lung, we evaluated the effect of amiloride (a Na+ channel blocker), ouabain (a Na(+)-K(+)-adenosinetriphosphatase blocker), and phloridzin (a Na(+)-glucose cotransport blocker) in isolated rat lungs. Ischemia and reperfusion (I/R) significantly increased the edema accumulation, with the wet-to-dry weight ratios increasing to 10.14 +/- 0.58 from 6.03 +/- 0.05 in control lungs (P < 0.04). Amiloride significantly augmented the amount of edema fluid (wet-to-dry weight ratio 12.26 +/- 0.77), and ouabain further increased the amount of edema (wet-to-dry weight ratio 18.58 +/- 1.00). Phloridzin did not significantly affect edema formation associated with I/R. Isoproterenol decreased the amount of edema formation in the presence and absence of amiloride. This occurred because the endothelial permeability as assessed by filtration coefficient was restored to normal values and less edema formed. The present study indicates that Na+ channels and Na(+)-K(+)-adenosinetriphosphatase, components of the active Na+ absorption transport system, are very important in opposing edema fluid accumulation in rat lungs subjected to I/R injury and operate as an edema safety factor. However, if the endothelial damage associated with I/R is allowed to persist, then the transport processes, even if operative, are insufficient to prevent continuous edema accumulation.

scholarly journals ADAM15 deficiency attenuates pulmonary hyperpermeability and acute lung injury in lipopolysaccharide-treated mice

2013 ◽  
Vol 304 (3) ◽  
pp. L135-L142 ◽  
Author(s):  
Chongxiu Sun ◽  
Richard S. Beard ◽  
Danielle L. McLean ◽  
Robert R. Rigor ◽  
Thomas Konia ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Weight Ratio ◽  
Dry Weight ◽  
Immunofluorescent Staining ◽  
Mouse Lung ◽  
Myeloperoxidase Activity ◽  
Barrier Dysfunction ◽  
Obvious Effect ◽  
Inflammatory Injury

ADAM15 is a disintegrin and metalloprotease recently implicated in cancer and chronic immune disorders. We have recently characterized ADAM15 as a mediator of endothelial barrier dysfunction. Whether this molecule contributes to acute inflammation has not been evaluated. The purpose of this study was to investigate the role of ADAM15 in mediating pulmonary microvascular leakage during acute inflammatory injury. Immunofluorescent staining and Western blotting revealed that the endothelium was the main source of ADAM15 in lung tissue. In a mouse model of acute lung injury induced by lipopolysaccharide (LPS), upregulation of ADAM15 was observed in association with pulmonary edema and neutrophil infiltration. The LPS-induced inflammatory injury, as demonstrated by bronchoalveolar lavage neutrophil count, lung wet-to-dry weight ratio, and myeloperoxidase activity, was significantly attenuated in Adam15 −/− mice. Studies with primary cell culture demonstrated abundant ADAM15 expression in endothelial cells (ECs) of mouse lung but not in neutrophils. Deficiency of ADAM15 in ECs had no obvious effect on basal permeability but significantly attenuated hyperpermeability response to LPS as evidenced by albumin flux assay and measurements of transendothelial electrical resistance, respectively. ADAM15 deficiency also reduced neutrophil chemotactic transmigration across endothelial barriers in the presence or absence of formyl-methionyl-leucyl-phenylalanine (fMLP). Rescue expression of ADAM15 in Adam15 −/− ECs restored neutrophil transendothelial migration. These data indicate that ADAM15 upregulation contributes to inflammatory lung injury by promoting endothelial hyperpermeability and neutrophil transmigration.

scholarly journals Standardization of a method of prolonged thoracic surgery and mechanical ventilation in rats to evaluate local and systemic inflammation

2011 ◽  
Vol 26 (1) ◽  
pp. 38-43 ◽  
Author(s):  
Camila Ferreira Leite ◽  
Ivan Felizardo Contrera Toro ◽  
Edson Antunes ◽  
Ricardo Kalaf Mussi
Keyword(s):  
Mechanical Ventilation ◽  
Thoracic Surgery ◽  
Serum Protein ◽  
Weight Ratio ◽  
Dry Weight ◽  
Myeloperoxidase Activity ◽  
Protein Extravasation ◽  
Inflammatory Changes ◽  
Experimental Group

Purpose: To evaluate the immediate pulmonary and systemic inflammatory response after a long-term operative period. Methods: Wistar rats in the experimental group were anaesthetized and submitted to tracheostomy, thoracotomy and remained on mechanical ventilation during three hours. Control animals were not submitted to the operative protocol. The following parameters have been evaluated: pulmonary myeloperoxidase activity, pulmonary serum protein extravasation, lung wet/dry weight ratio and measurement of levels of cytokines in serum. Results: Operated animals exhibited significantly lower serum protein extravasation in lungs compared with control animals. The lung wet/dry weight ratio and myeloperoxidase activity did not differ between groups. Serum cytokines IL-1ß, TNF-, and IL-10 levels were not detected in groups, whereas IL-6 was detected only in operated animals. Conclusion: The experimental mechanical ventilation in rats with a prolonged surgical time did not produce significant local and systemic inflammatory changes and permit to evaluate others procedures in thoracic surgery.

Abstract 176: Saxagliptin and Tadalafil Differentially Alter Global and Cellular Cardiac Function in a Translational Miniature Swine Model of Left Ventricle Hypertrophy

2014 ◽  
Vol 115 (suppl_1) ◽  
Author(s):  
Jessica A Hiemstra ◽  
Anne K Gibson ◽  
Jan R Ivey ◽  
Melissa S Cobb ◽  
Christopher P Baines ◽  
...  
Keyword(s):  
Cardiac Function ◽  
Pde5 Inhibitor ◽  
Weight Ratio ◽  
Left Ventricular ◽  
Lv Function ◽  
Swine Model ◽  
Stroke Work ◽  
Wall Stiffness ◽  
Cgmp Signaling ◽  
Whole Heart

Left ventricular (LV) hypertrophy is a common characteristic of heart failure with preserved ejection fraction (HFpEF). Our lab recently characterized a mini-swine model of LV hypertrophy induced by aortic banding (AB) that displays clinical features associated with HFpEF including LV hypertrophy, diastolic dysfunction, and depressed contractile reserve. Disrupted cGMP signaling, a result of impaired production or enhanced catabolism, may play a role in development of HFpEF. We hypothesized preservation of cGMP signaling would attenuate pathological remodeling and improve cardiac function. The purpose of this study was to promote cGMP signaling via two mechanisms: 1) the DPP4 inhibitor saxagliptin; and 2) the PDE5 inhibitor tadalafil. We assessed whole heart and individual cardiomyocyte function 6 months post-AB in: control non-banded (CON; n=6), AB-control (AB; n=7), AB saxagliptin-treated (AB-SAX; n=7), and AB tadalafil-treated (AB-TAD; n=8) swine. Heart weight:body weight ratio increased to a similar extent in all AB groups. However, changes in cardiomyocyte morphology were variable. Cardiomyocyte length was increased only in the AB-TAD group, while cell width increased in both AB and AB-TAD animals. Cardiomyocyte length:width ratio decreased in the AB and AB-TAD groups, commensurate with decreased LV end diastolic (ED) and end systolic (ES) volumes. These changes were prevented in AB-SAX animals, as LV volumes and cell morphology were similar to CON. Pressure-volume analysis showed resting LV wall stiffness (ED pressure volume relationship [EDPVR] slope) was increased similarly in all AB groups. Increased resting LV contractility (ESPVR and preload recruitable stroke work) was observed in AB and AB-TAD animals. Interestingly, cardiomyocyte shortening was reduced in the AB-TAD group contrasting findings observed at the whole heart level. Saxaglitpin attenuated hypercontractile LV function at rest and preserved normal cardiomyocyte shortening. In conclusion, LV and cardiomyocyte function was distinctly altered in response to separate methods of pharmacological cGMP regulation. Our data suggest different pharmacological approaches to augment cGMP signaling promote distinct LV functional adaptations to developing HF.

scholarly journals Agmatine Protects against Zymosan-Induced Acute Lung Injury in Mice by Inhibiting NF-κB-Mediated Inflammatory Response

2014 ◽  
Vol 2014 ◽  
pp. 1-10 ◽  
Author(s):  
Xuanfei Li ◽  
Zheng Liu ◽  
He Jin ◽  
Xia Fan ◽  
Xue Yang ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Lung Inflammation ◽  
Weight Ratio ◽  
Dry Weight ◽  
Lavage Fluid ◽  
Myeloperoxidase Activity ◽  
Beneficial Effects ◽  
Hypoxic Ischemia ◽  
Tnf Α

Acute lung injury (ALI) is characterized by overwhelming lung inflammation and anti-inflammation treatment is proposed to be a therapeutic strategy for ALI. Agmatine, a cationic polyamine formed by decarboxylation of L-arginine, is an endogenous neuromodulator that plays protective roles in diverse central nervous system (CNS) disorders. Consistent with its neuromodulatory and neuroprotective properties, agmatine has been reported to have beneficial effects on depression, anxiety, hypoxic ischemia, Parkinson’s disease, and gastric disorder. In this study, we tested the effect of agmatine on the lung inflammation induced by Zymosan (ZYM) challenge in mice. We found that agmatine treatment relieved ZYM-induced acute lung injury, as evidenced by the reduced histological scores, wet/dry weight ratio, and myeloperoxidase activity in the lung tissue. This was accompanied by reduced levels of TNF-α, IL-1β, and IL-6 in lung and bronchoalveolar lavage fluid and decreased iNOS expression in lung. Furthermore, agmatine inhibited the phosphorylation and degradation of IκB and subsequently blocked the activation of nuclear factor (NF)-κB induced by Zymosan. Taken together, our results showed that agmatine treatment inhibited NF-κB signaling in lungs and protected mice against ALI induced by Zymosan, suggesting agmatine may be a potential safe and effective approach for the treatment of ALI.

scholarly journals Hyperbaric Oxygen Combined With Hydrogen-rich Saline Protect Against Acute Lung Injury Induced by Lipopolysaccharide in Rat Model

2021 ◽  
Author(s):  
Yintao Chang ◽  
Zhenzhen Zhang ◽  
Xiaochen Bao ◽  
Mingdong Wang ◽  
Yuxiang Jin ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Hyperbaric Oxygen ◽  
Cell Apoptosis ◽  
Combined Treatment ◽  
Weight Ratio ◽  
Dry Weight ◽  
Inflammatory Factors ◽  
Therapeutic Effects ◽  
Pulmonary Tissue

Abstract Background: To investigate the effects of hydrogen-rich saline (HRS) combined with hyperbaric oxygen (HBO) on acute lung injury (ALI) and its clinical significance.Methods: 40 adult male Sprague-Dawlay rats were randomly divided into 5 groups: the sham, LPS, LPS + HBO, LPS + HRS and LPS + HBO + HRS. LPS at a rate of 3mg/kg was injected into the trachea of the experimental animals to develop ALI model, then the animals were respectively given simple HBO or HRS treatment or combined treatment. 3 days later, we study lung pathological, the levels of inflammatory factors , and cell apoptosis in the pulmonary tissue was detected by Tunel and cell apoptosis rate was calculated accordingly. Results: In the groups treated with HRS and HBO, pulmonary pathological data, wet-dry weight ratio and immflammatory factors in the pulmonary tissues and avelar lavage fluid were signficantly superiror to those of the sham group（P<0.05）. Cell apoptosis detection revealed that the simple treatment with HRS or HBO, or combined treatment with both, can all alleviate cell apoptosis, and the combined treatment with HRS and HBO was obviously superior to single treatment（P<0.05）.Conclusions: HRS and HBO could all decrease the release of immflammatory cytokines in lung tissue, reduce accumulation of oxidative products and alleviate apoptosis of pulmoanry cells, and could produce good therapeutic effects on ALI induced by LPS. HBO combined with HRS seems to have a synergistic effect on the decrease of cell apoptosis, and in the expression of immflammatory cytokines and the generation of related immflammatory products, the combined use of HBO and HRS showed a decreasing trend as compared with simple application.

Neutrophil elastase and oxygen radicals: synergism in lung injury after hindlimb ischemia

1991 ◽  
Vol 260 (6) ◽  
pp. H1852-H1856 ◽  
Author(s):  
C. R. Welbourn ◽  
G. Goldman ◽  
I. S. Paterson ◽  
C. R. Valeri ◽  
D. Shepro ◽  
...  
Keyword(s):  
Lung Injury ◽  
Oxygen Radicals ◽  
Weight Ratio ◽  
Dry Weight ◽  
Polymorphonuclear Neutrophils ◽  
Myeloperoxidase Activity ◽  
Hindlimb Ischemia ◽  
Elastase Inhibitor ◽  
Neutrophil Sequestration ◽  
Tourniquet Ischemia

Hindlimb ischemia and reperfusion lead to lung injury dependent on activated polymorphonuclear neutrophils (PMN) adherence. This study tests whether elastase and oxygen radicals participate in PMN-induced injury once they have become sequestered in lungs. Anesthetized rats treated with saline (n = 9) or the specific elastase inhibitor methoxysuccinyl-L-Ala-L-Ala-L-Pro-L-Val-chloromethylketone (MAAPV, n = 6) underwent 4 h of bilateral hindlimb tourniquet ischemia followed by 4 h of reperfusion. At this time, in saline-treated rats, PMN were sequestered in lungs as assayed by myeloperoxidase activity [(MPO) 51 +/- 5 U/g tissue], higher than MPO in saline-treated sham rats (n = 9; 18 +/- 3 U/g MPO; P less than 0.01); bronchoalveolar lavage (BAL) fluid leukotriene (LT) B4 levels increased to 594 +/- 46 relative to 200 +/- 38 pg/ml in shams (P less than 0.01); increased permeability was documented by BAL fluid protein content of 599 +/- 91 compared with 214 +/- 35 micrograms/ml in sham animals (P less than 0.01); and edema was shown by increase in lung wet-to-dry weight ratio of 4.77 +/- 0.14 relative to 4.00 +/- 0.09 in sham rats (P less than 0.01). In MAAPV-treated animals, lung neutrophil sequestration (62 +/- 9 U/g MPO) and rise of LTB4 in BAL fluid (780 +/- 244 pg/ml) were not affected, but both BAL fluid protein (335 +/- 32 micrograms/ml) and lung wet-to-dry weight ratio (4.21 +/- 0.17) were reduced (both P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

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