Hypercatabolism and Anti-catabolic Therapies in the Persistent Inflammation, Immunosuppression, and Catabolism Syndrome

Abstract

Owing to the development of intensive care units, many patients survive their initial insults but progress to chronic critical illness (CCI). Patients with CCI are characterized by prolonged hospitalization, poor outcomes, and significant long-term mortality. Some of these patients get into a state of persistent low-grade inflammation, suppressed immunity, and ongoing catabolism, which was defined as persistent inflammation, immunosuppression, and catabolism syndrome (PICS) in 2012. Over the past few years, some progress has been made in the treatment of PICS. However, most of the existing studies are about the role of persistent inflammation and suppressed immunity in PICS. As one of the hallmarks of PICS, hypercatabolism has received little research attention. In this review, we explore the potential pathophysiological changes and molecular mechanisms of hypercatabolism and its role in PICS. In addition, we summarize current therapies for improving the hypercatabolic status and recommendations for patients with PICS.

Keywords: and catabolism syndrome; anti-catabolic therapy; chronic critical illness; gut dysfunction; hypercatabolism; immunosuppression; mitochondrial dysfunction; persistent inflammation.

FIGURE 1

Mitochondrial dysfunction and its impact on catabolism. Mitochondrial dysfunction in PICS decreases the production of ATP by inhibiting the expression and activity of some key enzymes in the ETC (complexes I, III, and IV) (130). Consequently, pyruvate is unable to generate energy through the OXPHOS but does so through glycolysis, and the levels of lactate and pyruvate increase as a result. Mitochondrial dysfunction also contributes to the overproduction of ROS, which, in turn, will inhibit the expression and activity of ETC complexes. Excessive ROS induces oxidative stress, which is harmful to skeletal muscle proteins. To meet tremendous energy demands under the condition of mitochondrial dysfunction, the body has to alter metabolic pathways and intensify the catabolism of macronutrients. These pathophysiological changes will contribute to long-term skeletal muscle wasting in patients with PICS. ROS, reactive oxygen species; CoQ, coenzyme Q; Cyt c, cytochrome c; OXPHOS, oxidative phosphorylation; ATP, adenosine triphosphate; ADP, adenosine diphosphate; ETC, electron transport chain; PICS, persistent inflammation, immunosuppression, and catabolism syndrome.

FIGURE 2

Gut dysfunction and its impact on catabolism. Gut dysfunction contributes to a hypercatabolic state in many ways. Gut hypoperfusion and increased epithelial apoptosis contribute to the intestinal barrier impairment, which is common in critically ill patients, leading to the increase in gut permeability and further hindering nutrient absorption from the small intestine. Alterations in intestinal microbiota such as Escherichia coli decrease protein synthesis through the IGF-1/PI3K/Akt signaling pathway. Changes in microbiota-derived metabolites such as SCFAs also lead to the development of hypercatabolism by inducing insulin resistance and lipolysis. Together, these alterations contribute to the hypercatabolic status in patients with PICS. IGF-1, insulin-like growth factor-1; PI3K, phosphoinositide 3-kinase; SCFAs, short-chain fatty acids; PICS, persistent inflammation, immunosuppression, and catabolism syndrome.

FIGURE 3

The vicious cycle of PICS. There is a strong interaction between persistent inflammation, immunosuppression, and catabolism. In PICS, ongoing catabolism results in malnutrition and muscle wasting, and its decomposition products such as mitochondrial DNA and other DAMPs may drive persistent low-grade inflammation. Mitochondrial dysfunction and gut dysfunction impair ATP production and, consequently, suppress immunity. Persistent inflammation induces the release of inflammatory cytokines and hormonal changes in patients with PICS, contributing to hypercatabolism. Besides, persistent inflammation also induces inappropriate bone marrow hyperplasia, causing the dramatic expansion of MDSCs in patients with PICS, which will inhibit the proliferation of immune cells. Suppressed immunity causes recurrent infections and inflammatory responses, which consume energy and nutrients. PICS, persistent inflammation, immunosuppression, and catabolism syndrome; MDSCs, myeloid derived suppressor cells; DAMPs, damage-associated molecular patterns; PAMPs, pathogen-associated molecular patterns. SCFAs, short-chain fatty acids; ROS, reactive oxygen species.

FIGURE 4

Summary of pathophysiological mechanisms of skeletal muscle wasting in PICS and related therapies. Many pathophysiological changes in PICS affect the function of skeletal muscle cells and contribute to skeletal muscle wasting in patients with PICS. Inflammatory cytokines, such as IL-6 and TNF-α, induce protein degradation by activating the gp130/JAK/STAT3 and IKK/IKB/NF-κB signaling pathways, contributing to the production of ROS in muscle cells. Elevated inflammatory cytokines also inhibit the mTOR-mediated signaling pathway to decrease protein synthesis. Some hormones such as growth hormones are inhibited during PICS, which will cause decreased IGF-1 levels and suppress the IGF-1/PI3K/Akt/mTOR signaling pathway. Alterations in Escherichia coli, as a part of gut dysfunction, also lead to the suppression of the IGF-1/PI3K/Akt/mTOR signaling pathway by inhibiting IGF-1 production. Hence, exercise and IGF-1 supplementation are encouraged for patients with PICS to activate the mTOR signaling pathway and promote protein synthesis. In addition, the expression of FOXO is upregulated in skeletal muscle cells, which can increase the activity of MAFbx and MuRF1, activating the ubiquitin-proteasome system as a result. The autophagy-lysosome system is also activated and the levels of autophagy-related genes are upregulated. Mitochondrial dysfunction contributes to the increase in ROS, which induces skeletal muscle wasting and hypercatabolism in PICS. Therefore, anti-inflammatory agents, anabolic and anti-catabolic agents, microbiota modulators, and antioxidants are recommended for patients with PICS. IL-6, interleukin 6; IL-6R, interleukin 6 receptor; JAK, Janus kinase; STAT3, signal transducer and activator of transcription 3; ROS, reactive oxygen species; TNF-α, tumor necrosis factor α; TNFR, tumor necrosis factor receptor; IKK, IκB kinase complex; NF-κB, nuclear factor-kappa B; FOXO, forkhead box protein O; MuRF1, muscle ring finger 1; MAFbx, muscle atrophy F-box; ATGs, autophagy-related genes; IGF-1, insulin-like growth factor-1; IGF1R, insulin-like growth factor-1 receptor; PI3K, phosphoinositide 3-kinase; mTOR, mammalian target of rapamycin; gp130, glycoprotein 130; PICS, persistent inflammation, immunosuppression, and catabolism syndrome.