Therapeutic Efficacy of Excretory-Secretory Products of Trichinella spiralis Adult Worms on Sepsis-Induced Acute Lung Injury in a Mouse Model

Abstract

Acute lung injury (ALI) is a common complication of systemic inflammation or sepsis with high morbidity and mortality. Although many studies have confirmed that helminth-derived proteins had strong immunomodulatory functions and could be used to treat inflammatory diseases, there is no report on the therapeutic effect of excretory-secretory products of Trichinella spiralis adult worms (Ts-AES) on sepsis-induced ALI. In this study, the therapeutic efficacy of Ts-AES on sepsis-induced ALI and the underlying immunological mechanism and the signaling pathway were investigated. The results indicated that after being treated with Ts-AES, the survival rate of mice with CLP-induced sepsis was significantly increased to 50% for 72 hours after CLP surgery compared to PBS control group with all mice died. The sepsis-induced ALI was largely mitigated characterized by reduced inflammation cell infiltration and pathological changes in lung tissue, with decreased lung injury scores and lung wet/dry weight ratio. The therapeutic efficacy of Ts-AES is associated with stimulated Tregs response with increased regulatory cytokines IL-10 and TGF-β and downregulated pro-inflammatory cytokines (TNF-α, IL-6, IL-1β). The expression of HMGB1, TLR2 and MyD88 in lung tissue was inhibited after treatment of Ts-AES. Our results demonstrated that Ts-AES play an important role in immunomodulation and confer a therapeutic effect on sepsis-induced ALI through inhibiting pro-inflammatory cytokines. The activation of Tregs and increased level of regulatory cytokines IL-10 and TGF-β are possibly involved in the immunomodulatory functions of Ts-AES through HMGB1/TLR2/MyD88 signal pathway. The findings suggest Ts-AES is a potential therapeutic agent for prevention and treatment of sepsis-induced ALI and other inflammatory diseases.

Regulatory T Cells: Angels or Demons in the Pathophysiology of Sepsis?

“…Intervention strategies (Tables 3 and 4), such as human recombinant cytokines (IL-15 and IL-36) (59,101), blocking phenotypes or chemokines [neuropilin (Nrp)-1, CTLA-4, lymphocyte activation gene (LAG)-3, and chemokine (C-X-C motif) ligand (CXCL) 4)] (50,58,77,82), nutrients (glutamine) (107), inhibiting molecules [sema3A, tissuenonspecific alkaline phosphatase (TNAP), Sirtuin1, P2Y12, COX-2, and poly ADP-ribose polymerase (PARP)] (48,51,102,(111)(112)(113), as well as even clinical therapeutics (high-volume hemofiltration, immunoglobulin, fresh frozen plasma, stem cells, and ulinastatin) (41,114,115,117,118) and traditional Chinese medicine (TCM) (electroacupuncture and tanshinone IIA) (103,106), can increase the chance of survival by inhibiting the heterogeneous characteristics of Treg-induced immunosuppression. Alternatively, other studies have shown improved outcomes in sepsis by increasing the heterogeneous characteristics of Tregs to inhibit sepsis-induced SIRS through intervention strategies such as human recombinant cytokines (IL-38 and IL-7) (96,97), blocking phenotypes or cytokines (CD28 and IL-3) (81,95), nutrients (arginine and fiber cellulose) (108,109), and others (bilirubin, ITK inhibitor, miR-126, maresin1, excretory-secretory products of Trichinella spiralis adult worms, and adipose-derived mesenchymal stem cell-derived exosomes) (19,20,70,98,99,116), as well as even clinical therapeutics (enteral nutrition and pre-and post-dilution during continuous veno-venous hemofiltration) (22,…”

“…In addition to the role Tregs play in maintaining immune homeostasis in dedicated lymphoid tissues, these cells exist in other tissues such as the lung, liver, renal, muscle, brain and myocardium (73,87,98,99,102,148). Many tissue-specific Treg functions go beyond our initial understanding of Tregs as immune inflammation-specific inhibitors (70,99,133).…”

“…In addition to the role Tregs play in maintaining immune homeostasis in dedicated lymphoid tissues, these cells exist in other tissues such as the lung, liver, renal, muscle, brain and myocardium (73,87,98,99,102,148). Many tissue-specific Treg functions go beyond our initial understanding of Tregs as immune inflammation-specific inhibitors (70,99,133). However, most previous interventional and observational studies on sepsis have focused on the functions and characteristics of Tregs in the peripheral circulation and spleen (41,48,76,96,101).…”

“…In the CLP model, the cecum of immunocompetent mice is sutured and then punctured to cause spillage of cecal contents into the peritoneum, which creates a life-threatening infection characterized by physical disorders (such as septic shock and acute organ failure) and ultimately death (99,106,161). Unfortunately, the precise composition of cecal contents that participates in the infection process is variable and has not been adequately evaluated in the case of acute organ failure (175).…”

Insight Into Regulatory T Cells in Sepsis-Associated Encephalopathy

“…is to maintain homeostasis ( 12 , 35 , 115 ). Many of these tissue-specific T regs functions, go beyond our initial understanding of T regs as immuno-inflammation-specific inhibitors ( 84 , 86 ), whereas a large number of previous intervention and observational studies on sepsis have focused on the functions and characteristics of T regs in the peripheral circulation and spleen ( 51 – 53 , 75 , 77 ). The timing and location of tissue-specific T regs -mediated immune homeostasis and regulation, remain undefined.…”