Since the original descriptions of "putrefaction" by Hippocrates, sepsis has been recognized as a major cause of human suffering and mortality. Despite major advances made in understanding the systemic inflammatory response to infection, clinical trials of sepsis therapeutics have been repeatedly disappointing. These failure highlight the need for new, multidisciplinary perspectives into the onset, progression, and resolution of septic organ injury. The endothelial glycocalyx is a layer of glycosaminoglycans and associated proteoglycans lining the vascular surface. In vivo, the glycocalyx forms a substantial endothelial surface layer (ESL) that influences inflammation, endothelial permeability, and vascular tone-biologic processes highly relevant to sepsis pathophysiology. We have recently identified that the pulmonary ESL, by regulating exposure of endothelial surface adhesion molecules, serves a gatekeeping function controlling neutrophil transit into the lung. In response to an infectious stimulus, activated endothelial cells cleave the pulmonary ESL, allowing neutrophil adhesion and subsequent extravasation. Teleologically, this gatekeeping function would additionally require precise cellular control of ESL reconstitution, thereby limiting the magnitude of pulmonary inflammation. These processes of ESL repair, despite therapeutic relevance to patients with sepsis, have been unexplored. We hypothesize that a degraded pulmonary ESL is rapidly reconstituted in otherwise-healthy mice, allowing for maintenance of pulmonary vascular homeostasis. During sepsis, ESL reconstitution is delayed, contributing to the excessive pulmonary inflammation and edema characteristic of septic lung injury. Using state-of-the-art pulmonary intravital microscopy (E. Schmidt, Pulmonary/Critical Care, University of Colorado) and glycomic (R. Linhardt, Chemistry, Rensselaer Polytechnic Institute) approaches, we propose to (1) determine the mechanisms underlying pulmonary ESL reconstitution, (2) identify how these mechanisms are suppressed during sepsis, and (3) therapeutically manipulate these mechanisms to accelerate ESL reconstitution and attenuate septic lung injury. These multidisciplinary investigations, representing a highly novel collaboration within the field of sepsis, will be complemented by animal models of septic lung injury as well as analyses of biologic samples obtained from humans with severe sepsis. In summary, this proposal offers a new, multidisciplinary perspective on sepsis: that ESL integrity is a critical determinant of the onset and progression of septic organ injury. Investigating processes of ESL reconstitution may therefore identify novel therapeutic targets in a critical illness that, despite millennia of study, still lacks a clinically-efficacious, pathophysiology-targeted treatment.

Public Health Relevance

Sepsis is a common, severe condition caused by the body's response to an overwhelming infection. Sepsis can cause harm to people by damaging an important layer of sugars that lines blood vessels in the lungs. We are studying how this damaged layer of sugars can be repaired, so that we can find a new, effective treatment for sepsis.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL125371-01
Application #
8803172
Study Section
Special Emphasis Panel (ZHL1-CSR-O (S1))
Program Officer
Sarkar, Rita
Project Start
2014-09-15
Project End
2019-05-31
Budget Start
2014-09-15
Budget End
2015-05-31
Support Year
1
Fiscal Year
2014
Total Cost
$697,032
Indirect Cost
$149,891
Name
University of Colorado Denver
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
041096314
City
Aurora
State
CO
Country
United States
Zip Code
80045