Pathogenesis Of Circulatory Shock Research Articles

Inflammation, coagulation, and cellular injury in heat-induced shock.

The number of heatstroke victims hit record numbers in 2022 as global warming continues. In heat-induced injuries, circulatory shock is the most severe and deadly complication. This review aims to examine the mechanisms and potential approaches to heat-induced shock and the life-threatening complications of heatstroke. A computer-based online search was performed using the PubMed database and Web of Science database for published articles concerning heatstroke, shock, inflammation, coagulopathy, endothelial cell, cell death, and heat shock proteins. Dehydration and heat-induced cardiomyopathy were reported as the major causes of heat-induced shock, although other heat-induced injuries are also involved in the pathogenesis of circulatory shock. In addition to dehydration, the blood volume decreases considerably due to the increased vascular permeability as a consequence of endothelial damage. Systemic inflammation is induced by factors that include elevated cytokine and chemokine levels, dysregulated coagulation/fibrinolytic responses, and the release of damage-associated molecular patterns (DAMPs) from necrotic cell death that cause distributive shock. The cytoprotective heat shock proteins can also facilitate circulatory disturbance under excess heat stress. Multiple mechanisms are involved in the pathogenesis of heat-induced shock. In addition to dehydration, heat stress-induced cardiomyopathy due to the thermal damage of mitochondria, upregulated inflammation via damage-associated molecular patterns released from oncotic cells, unbalanced coagulation/fibrinolysis, and endothelial damage are the major factors that are related to circulatory shock.

Tumour necrosis factor-alpha as a target of melanocortins in haemorrhagic shock, in the anaesthetized rat.

The cytokine tumour necrosis factor-alpha (TNF-alpha) is involved (mostly through the activation of inducible nitric oxide synthase) in the pathogenesis of circulatory shock. On the other hand, melanocortin peptides are potent and effective in reversing haemorrhagic shock, both in animals (rat, dog) and in humans. This prompted us to study the influence of the melanocortin peptide ACTH-(1-24) on the blood levels of TNF-alpha in haemorrhage-shocked rats and on the in vitro production of TNF-alpha by lipopolysaccharide (LPS)-activated macrophages. Plasma levels of TNF-alpha were undetectable before starting bleeding and greatly increased 20 min after bleeding termination in saline-treated rats. In rats treated with ACTH-(1-24) the almost complete restoration of cardiovascular function was associated with markedly reduced levels of TNF-alpha 20 min after bleeding termination. On the other hand, ACTH-(1-24) did not influence TNF-alpha plasma levels in sham-operated, unbled rats. In vitro, ACTH-(1-24) (25-100 nM) dose-dependently reduced the LPS-stimulated production of TNF-alpha by peritoneal macrophages harvested from untreated, unbled rats. These results indicate that inhibition of TNF-alpha overproduction may be an important component of the mechanism of action of melanocortins in reversing haemorrhagic shock.

Leukocyte integrin very late antigen-4/vascular cell adhesion molecule-1 adhesion pathway in splanchnic artery occlusion shock.

We investigated the role played by the very late antigen-4 (VLA-4)/ vascular cell adhesion molecule-1 (VCAM-1) interaction in the pathogenesis of splanchnic artery occlusion shock. Splanchnic artery occlusion shock was induced in anaesthetized rats by clamping splanchnic arteries for 45 min. Sham operated animals were used as controls. Survival time, serum tumour necrosis factor (TNF-alpha), monocyte and lymphocyte cell count and the responsiveness to acetylcholine of aortic rings were studied. Furthermore we investigated the VCAM-1 expression on vessel endothelium and the percentage of VLA-4 positive leukocytes. Splanchnic artery occlusion shocked rats had a decreased survival time (76 +/- 10 min, while sham shocked rats survived more than 4 h), increased serum levels of TNF-alpha (328 +/- 11 U/ml), a decreased number of both monocytes and lymphocytes and reduced responsiveness to acetylcholine (10 nM-10 microM) of aortic rings. In addition we found an increased expression of endothelial VCAM-1 on aortic rings and a reduced percentage of VLA-4 positive lymphocytes and monocytes. Passive immunization with specific antibodies raised against either VCAM-1 or VLA-4 (2 mg/kg, i.v., 3 h before splanchnic artery occlusion shock) increased survival, improved monocyte and lymphocyte count and restored the responsiveness of aortic rings to acetylcholine (P < 0.01). Finally, inhibition of TNF-alpha biosynthesis reversed the increased endothelial expression of VCAM-1 and the reduced percentage of integrin VLA-4 positive leukocytes. Our findings suggest that (i) VLA-4/VCAM-1 interaction has a role in the pathogenesis of circulatory shock; (ii) this interaction might be a target for new therapeutic approaches to the therapy of low-flow states.

Prevention of the Expression of Inducible Nitric Oxide Synthase by Aminoguanidine or Aminoethyl-Isothiourea in Macrophages and in the Rat

An enhanced formation of nitric oxide (NO) following the induction of the inducible isoform of NOS (iNOS) has been implicated in the pathogenesis of circulatory shock and inflammation. This study elucidates the effects of the NOS inhibitors aminoethyl-isothiourea (AE-ITU), aminoguanidine (AG), NG-methyl-L-arginine (L-NMMA) or Nω-Nitro-L-arginine methyl ester (L-NAME) on the expression of iNOS protein lipopolysaccharide (LPS) in macrophages and the rat (lung homogenates). The expression of iNOS protein was detected by Western blot analysis using a specific iNOS antibody. In the absence of LPS, the iNOS protein was expressed neither in macrophages nor in the lung. LPS (1 μg·ml−1) resulted in the expression of iNOS protein in macrophages, which was significantly inhibited by pretreatment of cells with AE-ITU or AG, but not by L-NMMA or L-NAME. In addition, LPS (10 mg·kg−1, i.v.) also caused an increase in the expression of iNOS protein in lungs obtained from rats at 6 h after LPS, which was significantly reduced by treatment of LPS-rats with AE-ITU or AG, but not with L-NMMA or L-NAME. Thus, AE-ITU or AG inhibit not only iNOS activity, but also the induction of iNOS proteinin vitroandin vivocaused by endotoxin.

Free radicals and diseases

In recent years, it has been shown that reactive oxygen species or free radicals are closely involved in various biological reactions. At normal rate of generation, some free radicals are useful in the human body. However, when oxygen free radical generation exceeds the capacity of antioxidant defenses, the result is oxidative stress. Oxidative stress occurs in many human diseases and sometimes makes a significant contribution to their pathogenesis. Especially, oxygen free radicals such as Superoxide anion radical and hydroxyl radical, are thought to mediate a large portion of the tissue damage produced after inflammation, ischemia, and ischemia/reperfusion of the small intestine, stomach, heart, kidney, liver and skin, and may also be involved in the pathogenesis of circulatory shock and disseminated intravascular coagulation. In addition, reactive oxygen metabolites and free radicals are involved in many pathogenic conditions via DNA damage, inactivation of nitric oxide (NO)(1), oxidation of LDL, and activation of adhesion molecules(2–4) (Figure 1). Herein, we summarized recent data that supported free radical involvement in ischemia/reperfusion injury and digestive diseases, and reviewed the antioxidant therapy for these pathophysiological conditions.

Oxygen-derived free radicals in the pathogenesis of experimental shock

Oxygen-derived free radicals are naturally produced in biological systems mostly in ischemia and hypoxia related conditions. Imbalance of physiological defenses against oxygen-derived free radicals causes cellular damage. In our laboratory the role of oxygen radicals in the pathogenesis of circulatory shock was studied by exploiting the scavenging action of the spin-trapping compound phenyl-butyl-nitrone (PBN) in experiments concerning: (1) survival after shock, (2) microcirculatory derangements in endotoxin shock, (3) fluidity modifications of cell membranes during shock, (4) exhalation of ethane as non-invasive marker of shock. In some experiments the steroid methylprednisolone was used. Results showed that administration of PBN and of the steroid (1) ensures survival after otherwise lethal shock as confirmed by decreased ethane exhalation, (2) prevents microcirculatory troubles, (3) maintains stability of cell membranes. These findings strongly support the role of oxygen-derived free radicals in the pathogenesis and pathophysiology of circulatory shock.

Inhibition of lipoxygenase pathway improves survival in endotoxin shock

The data presented in this paper together with the findings of Hagmann et al. [4] suggest an important role of metabolites of the lipoxygenase pathway in the pathogenesis of endotoxin shock. Selective inhibition of lipoxygenase by FLM 5011 prevented the development of irreversible shock state nearly completely decreasing the mortality rate to 0.05. p ]Further investigations on the precise mechanism of the action of lipoxygenase metabolites are necessary to evaluate their actual significance in the complex pathogenesis of circulatory shock.

Pancreatic hypoperfusion and the production of a myocardial depressant factor in hemorrhagic shock.

Hemorrhagic shock was produced in dogs by bleeding to a systemic blood pressure of 45 mm Hg for 3 hours, followed by reinfusion of the shed blood. A rapid decrease in pancreatic blood flow occurred and pancreatic perfusion remained at 15-25% of control over the entire 3-hour oligemic period. As a consequence of this marked degree of pancreatic hypoperfusion, autolytic changes occurred in pancreatic acinar cell ultrastructure, particularly in the enlarging of lysosomes which developed many vacuoles. Plasma proteolytic indices (e.g., cathepsin D activity and amino nitrogen concentration) markedly increased during shock as well as the activity of a myocardial depressant factor (MDF). MDF was also produced in incubated pancreatic homogenates obtained from nonshocked dogs and in non-incubated homogenates from shocked dogs. MDF activity in the homogenates was closely correlated with amino nitrogen concentration. These data suggest that pancreatic hypoperfusion plays a key role in MDF formation and ultimately in the pathogenesis of circulatory shock. Moreover, MDF activity was found not to be associated either with pentobarbital concentration or the salt content of active fractions of plasma and pancreatic tissue. Ashing of active fractions was very effective in destroying MDF activity. These data are consistent with the earlier findings that indicate MDF to be a peptide having a molecular weight of 500-1,000.

The lysosomal protease--myocardial depressant factor system in circulatory shock.

Circulatory shock is characterized by severe perturbations in the homeostatic regulation of cardiovascular function leading to conditions which are incompatible with life. The nature of these perturbations is not clearly understood, nor are the origins of the positive feedback loops generated by these disturbances. Despite the obvious gaps in our knowledge, certain findings have been uncovered in recent years which, in the light of new information, point to a final common pathway in the pathogenesis of circulatory shock. These findings are: 1. a marked reduction in blood flow to the splanchnic viscera very early in circulatory shock of varying etiologies (1) 2. a marked alteration in lysosomal membranes with the attendant release of lysosomal hydrolases into the plasma during many forms of shock (2) 3. a profound impairment of myocardial performance late in circulatory shock (3,4) KeywordsPositive Feedback LoopLysosomal EnzymeLysosomal MembraneNegative Inotropic EffectToxic FactorThese keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Role of the pancreas in the pathogenesis of circulatory shock.

Several toxic factors have been proposed as mediators of irreversibility in circulatory shock (6, 17, 29, 48, 57). Most, however, have not been enthusiastically received because their participation in the pathophysiology of the shock state remains unsupported by convincing evidence and no factor has been isolated. Recently, a myocardial depressant factor (MDF) has been isolated from the plasma of both experimental animals (30) and man (42) in a variety of shock states, including hemorrhagic (9, 32, 54), endotoxic (55), cardiogenic (23), bowel ischemic (20, 37), burn (2), and pancreatitis (35) shock.KeywordsLysosomal EnzymeHemorrhagic ShockNegative Inotropic EffectZymogen GranuleCirculatory ShockThese keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Significance of splanchnic proteases in the production of a toxic factor in hemorrhagic shock.

The pathogenesis of circulatory shock has been previously associated with the plasma accumulation of a myocardial depressant factor (MDF). The plasma accumulation of MDF in cats subjected to hemorrhagic shock was associated with marked increases (P &lt;0.01) in activities of plasma cathepsins A-B. The pH optima for three of the five cathepsins were in the range of 4.8-5.2, a pH range close to that found intracellularly during shock. Moreover, pancreatic and hepatic tissue from these cats exhibited significant decreases in total specific activities for these enzymes, compared with minimal changes in heart, duodenum and spleen. Decreases in total pancreatic cathepsin activities were associated with marked ultrastructural changes in pancreatic acinar cells primarily characterized by vacuolization of the lysosomes. Incubation of homogenates of splanchnic viscera of unshocked dogs revealed that significant concentrations of MDF were produced only in incubated pancreatic homogenates. Infusion of MDF in amounts half that produced by a cat pancreas into intact anesthetized cats yielded a significant circulatory depression indicated by a progressive decline in cardiac output and mean arterial blood pressure and a 54% decrease in cardiac work performance within 60 minutes. These data indicate that substantial amounts of lysosomal proteases are released during shock and that they operate in a suitable pH range to account for the production of quantities of MDF that are sufficient to induce a marked degree of cardiac depression.