Pathophysiology, staging and therapy of severe sepsis in baboon models

Abstract

We review our baboon models of Escherichia coli sepsis that mimic, respectively, the shock/disseminated intravascular coagulation (DIC) and organ failure variants of severe sepsis, and analyse the pathophysiologic processes that are unique to each. The multi-stage, multi-factorial characteristics of severe sepsis develop as a result of the initial insult, which - depending on its intensity - activates components of the intravascular compartment leading to overwhelming shock/DIC; or initiates a sequence of events involving both the intra- and extravascular (tissues) compartments that lead to organ failure. In the latter case, the disorder passes through two stages: an initial inflammatory/coagulopathic intravascular first stage triggered by E. coli, followed by an extravascular second stage, involving components unique to each organ and triggered by ischemia/reperfusion (oxidative stress and histone release). Although a myriad of overlapping cellular and molecular components are involved, it is the context in which these components are brought into play that determine whether shock/DIC or organ failure predominate. For example, inflammatory and thrombotic responses amplified by thrombin in the first case whereas similar responses are amplified by complement activation products in the second. Rather than blocking specific mediators, we found that attenuation of the thrombin and complement amplification pathways can effectively reverse the shock/DIC and organ failure exhibited by the LD(100) and LD(50) E. coli models of severe sepsis, respectively. Translation of these concepts to successful intervention in the respective baboon models of E. coli sepsis and the application to their clinical counterparts is described.

Fig 1

Summary diagram of the three models of E. coli sepsis and their clinical counterparts.

Fig 2

Time-course changes of plasma biomarkers during E. coli sepsis in baboons challenged with LD₅₀ and stratified into potential survivors (LD₅₀-S) and non-survivors (LD₅₀-NS), as compared to the LD₁₀₀ and LD₁₀ groups.

Fig 3

Histopathological features of the lung samples from potential survivors (LD₅₀-S) and non-survivors (LD₅₀-NS), as compared to LD₁₀₀E. coli challenged baboons. Hematoxylin-eosin staining of the lung samples from the LD₅₀-NS (A), LD₅₀-S (B) and LD₁₀₀ (F) experimental groups; sirius red staining and epipolarized light imaging of collagen deposition in the samples from LD₅₀-S (D) versus LD₅₀-NS (E); (C) electron micrograph demonstrating the presence of fibroblasts (fb) and collagen (coll) in the interalveolar space, in the lung of animals from the LD50-NS group. Scale bars: (A): 150 μm; (A and F insets): 25 μm; (B, D and E): 250 μm; (C): 5 μm.

Fig 4

Gene expression analysis of the lung from LD₅₀-S versus LD₅₀-NS baboons using Ingenuity Pathway analysis. (A) Canonical pathways that are differentially induced in non-survivors based on the – log (p) and ratio values (LD₅₀-S:LD₅₀-NS); (B) canonical death receptor signaling pathway demonstrates the inhibition of anti-apoptotic and cell survival genes (BID, BCL2 and cIAP) in non-survivors (LD₅₀-NS), as compared to survivors (LD₅₀-S) challenged with LD₅₀E. coli. Gene expression changes over 2-fold threshold are indicated by colour code: green: downregulation; red: up-regulation.

Fig 5

Diagram illustrating the mechanisms controlling the stage-specific pathophysiologic responses in the baboon models of severe sepsis. The first stage (top) inflammatory and coagulopathic responses are induced by E. coli and involves cytokine and TF expression by leukocytes. These responses are further amplified by thrombin that overrides the PC and TFPI regulatory networks. During the second stage (bottom), organ-specific injury responses to oxidative stress and histones are further amplified by complement activation products that act on cellular components (platelets, PMNs) recruited from the intravascular compartment.