Glucagon-like peptide-1 receptor mediates the beneficial effect of liraglutide in an acute lung injury mouse model involving the thioredoxin-interacting protein

Abstract

Repurposing clinically used drugs is among important strategies in drug discovery. Glucagon-like peptide-1 (GLP-1) and its based diabetes drugs such as Liraglutide possess a spectrum of extra-pancreatic functions, while GLP-1 receptor (GLP-1R) is most abundantly expressed in the lung. Recent studies have suggested that GLP-1-based drugs exert beneficial effects in chronic as well as acute lung injury rodent models. We show here that Liraglutide pretreatment reduced lipopolysaccharide (LPS) induced acute lung injury in mice. It significantly reduced lung injury score, wet/dry lung weight ratio, bronchoalveolar lavage fluid (BALF) immune cell count and protein concentration, and cell apoptosis in the lung, associated with reduced lung inflammatory cytokine and chemokine gene expression. Importantly, these effects were virtually absent in GLP-1R-/- mice. A well-known function of GLP-1 and its based drugs in pancreatic β-cells is the attenuation of high-glucose stimulated expression of thioredoxin interacting protein (TxNIP), a key component of inflammasome. LPS challenged lung showed elevated TxNIP mRNA and protein expression, which was attenuated by Liraglutide treatment in a GLP-1R-dependent manner. Our observations hence suggest that GLP-1R is essential in mediating beneficial effects of Liraglutide in acute lung injury, with the inflammasome component TxNIP as a potential target.

Titanium Dioxide Nanoparticles Exacerbate Allergic Airway Inflammation via TXNIP Upregulation in a Mouse Model of Asthma

“…Thioredoxin-interacting protein (TXNIP), a critical regulator of pathological responses, is induced by various of stressors including inflammation, metabolic dysfunction, apoptosis, and lung dysfunction [ 12 , 13 , 14 ]. TXNIP has been expressed in the lungs of experimental animals exposed to lipopolysaccharide and ovalbumin (OVA), which induce increased inflammatory responses via the activation of inflammasomes [ 15 , 16 , 17 ]. In contrast, TXNIP is involved in the apoptotic response of lung tissues.…”

Use of GLP1RAs and occurrence of respiratory disorders: A meta‐analysis of large randomized trials of GLP1RAs

“…Although better glucose control from GLP1RAs may lead to low incidence of pneumonia in T2D that cannot completely explain the benefits from GLP1RAs on all the nine kinds of respiratory conditions assessed in the study. In contrast, some possible mechanisms for the benefits from GLP1RAs on relevant respiratory diseases are revealed by several small sample human studies 12,13 and animal studies 14,15 in which GLP1RAs were observed to benefit for COPD, 12,13 airway hyperresponsiveness, 14 and acute lung injury 15 via immunomodulating and antiinflammatory effects.…”

The anti-inflammatory feature of glucagon-like peptide-1 and its based diabetes drugs -- Therapeutic potential exploration in lung injury

“…It remains to be determined whether those extra-pancreatic functions of GLP-1 and its based drugs are mediated by certain brain-peripheral tissue axis or by a small portion of GLP-1R-producing cells scattered within each of those organs. However, we have learned for more than 25 years that lung is an extra-pancreatic organ, which exhibits the highest GLP-1R expression (102,103). Hence, great efforts have been made in clinical trials and in various lung injury models, seeking for the possibility to repurpose GLP-1-based drugs in chronic and acute lung injury treatment.…”

“…In 2020, our team has directly assessed the involvement of GLP-1R in mediating effect of liraglutide treatment in LPS-induced ALI mouse model. In this study, conducted by Zhou and colleagues, liraglutide was not administrated simultaneously with LPS challenge, but as a "preventative agent" which was subcutaneously administrated 2 hours before intratracheal LPS delivery (103). In such experimental settings, we observed that liraglutide pre-treatment significantly reduced LPS-induced acute lung injury, including the reduction on lung injury score, wet/dry lung weight ratio, immune cell counts, protein concentration in bronchoalveolar lavage fluid (BALF), and cell apoptosis in the lung.…”

“…Those effects were highly associated with reduced pulmonary mRNA expression of genes that encode inflammatory chemokines and cytokines. Importantly, none of those "preventative" effects were observed in GLP-1R knockout (KO) mice, highlighting the essential role of lung GLP-1R in mediating the effect of liraglutide in preventing lung injury (103). Based on such "preventative" effect observed, we suggested that retrospective studies should be conducted in T2D subjects received with or without GLP-1 based drugs, asking whether T2D patients are less vulnerable to ALI as well as chronic lung inflammatory injury after receiving GLP-1 based drug treatment (103,132,133).…”