Primary Faculty Mentor Name

Benjamin T Suratt

Status

Graduate

Student College

Larner College of Medicine

Program/Major

Cellular, Molecular and Biomedical Sciences

Primary Research Category

Biological Sciences

Secondary Research Category

Health Sciences

Presentation Title

Muscle contributes to the inflammatory environment following lung injury

Time

10:20 am

Location

Williams Family Room

Abstract

Joseph J Bivona III1, Sebastian Ventrone1, Melissa Floersch1, Blas Guigni1, Renee D. Stapleton1, D. Clark Files2, Michael Toth1, Benjamin T Suratt1

1 Department of Medicine, University of Vermont College of Medicine, Burlington, VT, USA

2 Internal Medicine-Pulmonary, Critical Care, Allergy and Immunology, Wake Forest University School of Medicine,

Winston-Salem, North Carolina

Rationale: Intensive care unit acquired weakness (ICUAW) occurs in nearly 50% of patients admitted to the ICU. Patients exhibiting ICUAW have increased in-hospital and post-ICU mortality. ICUAW, and the resulting atrophy and weakness specifically, are viewed as secondary consequences of excessive systemic inflammation. Muscle, however, has been reported to secrete various cytokines under the influence of stimuli such as exercise, suggesting that it may be a secretory organ in its own right. The interleukin 17 (IL-17) axis consists of the cytokines IL-17, interleukin 23 (IL-23), and granulocyte-colony stimulating factor (G-CSF) and are pivotal in the development of acute respiratory distress syndrome (ARDS). The current studies examine whether muscle produces cytokines in the setting of critical illness that may modulate systemic inflammation and impact distal organs and disease processes.

Methods: C57Bl/6CRL mice were exposed to nebulized lipopolysaccharide (LPS) to induce lung injury and examined 24 hours later. Whole gastrocnemius muscle was collected, mRNA extracted, and RT-qPCR analysis performed. As a complementary model, C2C12 mouse myoblasts were differentiated into myotubes in vitro and exposed to pathogen associated molecular pattern molecules (PAMPs), LPS (1 μg/ml) and Pam3CSK4 (0.1 μg/ml), as well as mediators of the IL-17 inflammatory cytokine axis, IL-23 (1 μg/ml) and IL-17A (0.1 μg/ml) for 0, 4, 8, and 24h. Cell lysates were then analyzed by RT-qPCR

Results: Lung injury induces whole skeletal muscle transcription of multiple inflammatory cytokines, including those central to the IL-17 axis (IL-23, IL-17, and (G-CSF). In vitro, PAMPs and IL-17 axis cytokines induce cytokine transcription in isolated myotubes.

Conclusions: Our data demonstrate that remote lung injury causes muscle to increase expression of inflammatory genes vital for the mobilization and maturation of neutrophils. Moreover, data in myotubes suggest that this upregulation may derive at least in part from muscle specifically, with myotubes potently expressing inflammatory and neutrophil stimulating genes following sterile (IL-23, IL-17a) or sepsis-like (LPS, Pam3CSK4) injury. Collectively, our data suggest that muscle may function as an endocrine organ in critical illness, amplifying local and/or systemic inflammation and creating a positive feedback loop in the case of IL-23.

This document is currently not available here.

Share

COinS
 

Muscle contributes to the inflammatory environment following lung injury

Joseph J Bivona III1, Sebastian Ventrone1, Melissa Floersch1, Blas Guigni1, Renee D. Stapleton1, D. Clark Files2, Michael Toth1, Benjamin T Suratt1

1 Department of Medicine, University of Vermont College of Medicine, Burlington, VT, USA

2 Internal Medicine-Pulmonary, Critical Care, Allergy and Immunology, Wake Forest University School of Medicine,

Winston-Salem, North Carolina

Rationale: Intensive care unit acquired weakness (ICUAW) occurs in nearly 50% of patients admitted to the ICU. Patients exhibiting ICUAW have increased in-hospital and post-ICU mortality. ICUAW, and the resulting atrophy and weakness specifically, are viewed as secondary consequences of excessive systemic inflammation. Muscle, however, has been reported to secrete various cytokines under the influence of stimuli such as exercise, suggesting that it may be a secretory organ in its own right. The interleukin 17 (IL-17) axis consists of the cytokines IL-17, interleukin 23 (IL-23), and granulocyte-colony stimulating factor (G-CSF) and are pivotal in the development of acute respiratory distress syndrome (ARDS). The current studies examine whether muscle produces cytokines in the setting of critical illness that may modulate systemic inflammation and impact distal organs and disease processes.

Methods: C57Bl/6CRL mice were exposed to nebulized lipopolysaccharide (LPS) to induce lung injury and examined 24 hours later. Whole gastrocnemius muscle was collected, mRNA extracted, and RT-qPCR analysis performed. As a complementary model, C2C12 mouse myoblasts were differentiated into myotubes in vitro and exposed to pathogen associated molecular pattern molecules (PAMPs), LPS (1 μg/ml) and Pam3CSK4 (0.1 μg/ml), as well as mediators of the IL-17 inflammatory cytokine axis, IL-23 (1 μg/ml) and IL-17A (0.1 μg/ml) for 0, 4, 8, and 24h. Cell lysates were then analyzed by RT-qPCR

Results: Lung injury induces whole skeletal muscle transcription of multiple inflammatory cytokines, including those central to the IL-17 axis (IL-23, IL-17, and (G-CSF). In vitro, PAMPs and IL-17 axis cytokines induce cytokine transcription in isolated myotubes.

Conclusions: Our data demonstrate that remote lung injury causes muscle to increase expression of inflammatory genes vital for the mobilization and maturation of neutrophils. Moreover, data in myotubes suggest that this upregulation may derive at least in part from muscle specifically, with myotubes potently expressing inflammatory and neutrophil stimulating genes following sterile (IL-23, IL-17a) or sepsis-like (LPS, Pam3CSK4) injury. Collectively, our data suggest that muscle may function as an endocrine organ in critical illness, amplifying local and/or systemic inflammation and creating a positive feedback loop in the case of IL-23.