Dipeptidyl peptidase-4 inhibitor linagliptin reduces inflammatory response, ameliorates tissue edema formation, and improves survival in severe sepsis

Denis Delic; Thomas Klein; Christian T Wohnhaas; Huiying Feng; Xinchun Lin; Jin-Rui Zhang; Dongmei Wu

doi:10.1016/j.biopha.2024.117778

Dipeptidyl peptidase-4 inhibitor linagliptin reduces inflammatory response, ameliorates tissue edema formation, and improves survival in severe sepsis

Biomed Pharmacother. 2024 Dec 25:182:117778. doi: 10.1016/j.biopha.2024.117778. Online ahead of print.

Authors

Denis Delic¹, Thomas Klein², Christian T Wohnhaas², Huiying Feng³, Xinchun Lin³, Jin-Rui Zhang⁴, Dongmei Wu⁵

Affiliations

¹ Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riss, Germany. Electronic address: denis.delic@boehringer-ingelheim.com.
² Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riss, Germany.
³ Department of Research, Mount Sinai Medical Center, Miami Beach, FL, USA.
⁴ First Clinical Medical College, Guangdong Pharmaceutical University, Guangzhou, Guangdong, PR China.
⁵ Department of Research, Mount Sinai Medical Center, Miami Beach, FL, USA. Electronic address: dwu@msmc.com.

PMID: 39724680
DOI: 10.1016/j.biopha.2024.117778

Abstract

Background: Excessive inflammation in sepsis causes microvascular dysfunction associated with organ dysfunction and high mortality. The present studies aimed to examine the therapeutic potential of linagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor in a clinically relevant polymicrobial sepsis model in mice.

Methods: Sepsis was induced by cecal ligation and puncture (CLP). Mice were grouped into: Sham control+vehicle; Group 2: CLP+vehicle; Group 3: CLP+dexamethasone (10 mg/kg, s.c.) given 6 h after CLP; Group 4: CLP+linagliptin (1 mg/kg, s.c.) given 6 h after CLP. The experiment was terminated 24 hours after CLP in two experimental sets. Seven-day survival following CLP was determined in a third experimental set.

Results: Treatment with linagliptin inhibited DPP-4 activity, increased the levels of active forms of endogenous gastric inhibitory polypeptide and glucagon-like peptide-1, without affecting the blood glucose levels in CLP mice. Compared to vehicle treatment, administration of linagliptin reduced sepsis-induced tissue hyper permeability as evidenced by a reduction in vascular Evans blue leakage, prevented edema formation in the lung, heart, liver and kidney. Furthermore, linagliptin or dexamethasone reduced sepsis-induced proinflammatory cytokine and chemokine production, such as IL-1β, IL-2, IL-10, IL-23, IL-27, VCAM-1, eotaxin, MDC, MCSF1, GCP-2, and NGAL. Importantly, administration of linagliptin improved the 7-day survival rate following CLP in mice. RNA sequencing in lung and heart revealed that linagliptin attenuated key inflammatory pathways including TNF alpha (via NFκB) and IL6/JAK/STAT3 signaling and activated interferon signaling in the heart.

Conclusions: Linagliptin treatment can attenuate the inflammatory response, protect against severe sepsis-induced vascular hyperpermeability, reduce multiorgan injury, and most importantly, improve the survival.

Keywords: DPP-4; Inflammation; Linagliptin; Sepsis; Vascular permeability.