Skeletal Muscle and Lymphocyte Mitochondrial Dysfunctions in Septic Shock Trigger ICU-Acquired Weakness and Sepsis-Induced Immunoparalysis

Abstract

Fundamental events driving the pathological processes of septic shock-induced multiorgan failure (MOF) at the cellular and subcellular levels remain debated. Emerging data implicate mitochondrial dysfunction as a critical factor in the pathogenesis of sepsis-associated MOF. If macrocirculatory and microcirculatory dysfunctions undoubtedly participate in organ dysfunction at the early stage of septic shock, an intrinsic bioenergetic failure, sometimes called “cytopathic hypoxia,” perpetuates cellular dysfunction. Short-term failure of vital organs immediately threatens patient survival but long-term recovery is also severely hindered by persistent dysfunction of organs traditionally described as nonvital, such as skeletal muscle and peripheral blood mononuclear cells (PBMCs). In this review, we will stress how and why a persistent mitochondrial dysfunction in skeletal muscles and PBMC could impair survival in patients who overcome the first acute phase of their septic episode. First, muscle wasting protracts weaning from mechanical ventilation, increases the risk of mechanical ventilator-associated pneumonia, and creates a state of ICU-acquired muscle weakness, compelling the patient to bed. Second, failure of the immune system (“immunoparalysis”) translates into its inability to clear infectious foci and predisposes the patient to recurrent nosocomial infections. We will finally emphasize how mitochondrial-targeted therapies could represent a realistic strategy to promote long-term recovery after sepsis.

Peripheral Blood Mononuclear Cells and Platelets Mitochondrial Dysfunction, Oxidative Stress, and Circulating mtDNA in Cardiovascular Diseases

“…In this view, since CVDs are generally systemic diseases, an attempt based on circulating cells might be proposed to better understand CVD pathophysiology and to discover new biomarkers. Indeed, growing evidence suggests that the assessment of mitochondrial respiratory function of circulating peripheral blood mononuclear cells (PBMCs) and platelets might be viewed as a marker to detect the mitochondrial dysfunction in different tissues, including the heart [10][11][12][13][14].…”

“…Mitochondrial dysfunction might be inferred from tissues' or cells' oxygen consumption (reflecting mitochondrial oxidative capacity) and the mitochondrial membrane potential (reflecting the ability of the electron transport system to maintain the gradient of proton driving ATP production). Thus, the failure of mitochondria to produce ATP results in an energy deficit, impairing cells, and finally, organ function [14][15][16][17][18][19].…”

“…Alternatively, peripheral blood mononuclear cells (PBMCs) and/or platelets represent an easily available population of cells allowing mitochondrial function studies. Analysis of the energetic profile (mitochondrial function) of circulating blood cells in experimental animals and humans appears as a new research field with potential applications in the development of disease biomarkers in several settings, including respiratory and CVDs [10][11][12][13][14]19,23,24].…”

Septic shock: perspective methods of diagnostics and therapy based on immunopathogenesis

“…Этот «компенсаторный» противовоспалительный ответ приводит к глубокой иммуносупрессии. Лимфопения является частью CARS и является результатом апоптоза почти всех классов лимфоцитов, особенно B-клеток и CD4 + T-клеток [29]. Исследователи Monserrat J. и соавт.…”

Comparison of the clinical application values of PCT, hs-CRP and SAA detection in the early diagnosis of sepsis

“…Sepsis is associated with a very high mortality and is the main cause of death of non-heart disease patients in the ICU. 1 Therefore, timely diagnosis of sepsis to guide treatment has become an important task for clinicians. Laboratory tests on sepsis provided strong evidence for the diagnosis of sepsis, mainly including hematological indicators and pathogen culture.…”