title: Impact of chemically-modified tetracycline 3 on intertwined physiological, biochemical, and inflammatory networks in porcine sepsis/ARDS.
abstract: Sepsis can lead to multiple organ dysfunction, including the Acute Respiratory Distress Syndrome (ARDS), due to intertwined, dynamic changes in inflammation and organ physiology. We have demonstrated the efficacy of Chemically-Modified Tetracycline 3 (CMT-3) at reducing inflammation and ameliorating pathophysiology in the setting of a clinically realistic porcine model of ARDS. Here, we sought to gain insights into the derangements that characterize sepsis/ARDS and the possible impact of CMT-3 thereon, by combined experimental and computational studies. Two groups of anesthetized, ventilated pigs were subjected to experimental sepsis via placement of a peritoneal fecal clot and intestinal ischemia/reperfusion by clamping the superior mesenteric artery for 30 min. The treatment group (n = 3) received CMT-3 at 1 hour after injury (T1), while the control group (n = 3) received a placebo. Multiple inflammatory mediators, along with clinically relevant physiologic and blood chemistry variables, were measured serially until death of the animal or T48. Principal Component Analysis (PCA) and Dynamic Bayesian Network (DBN) inference were used to relate these variables. PCA revealed a separation of cardiac and pulmonary physiologic variables by principal component, and a decreased rank of oxygen index and arterial PO2/FiO2 ratio in the treatment group compared to control. DBN suggested a conserved network structure in both control and CMT-3 animals: a response driven by positive feedback between interleukin-6 and lung dysfunction. Resulting networks further suggested that in control animals, acute kidney injury, acidosis, and respiratory failure play an increased role in the response to insult compared to CMT-3 animals. These combined in vivo and in silico studies in a high fidelity, clinically applicable animal model suggest a dynamic interplay between inflammatory, physiologic, and blood chemistry variables in the setting of sepsis and ARDS that may be dramatically altered by pleiotropic interruption of inflammation by CMT-3.
authors.affiliation: Department of Surgery, University of Pittsburgh Pittsburgh, PA, USA.
authors.forename: David
authors.initials: D
authors.lastname: Sadowsky
authors.affiliation: Department of Surgery, Upstate Medical University Syracuse, NY, USA.
authors.forename: Gary
authors.initials: G
authors.lastname: Nieman
authors.affiliation: Department of Surgery, University of Pittsburgh Pittsburgh, PA, USA.
authors.forename: Derek
authors.initials: D
authors.lastname: Barclay
authors.affiliation: Department of Sports Medicine and Nutrition, University of Pittsburgh Pittsburgh, PA, USA ; Center for Inflammation and Regenerative Modeling, McGowan Institute for Regenerative Medicine, University of Pittsburgh Pittsburgh, PA, USA.
authors.forename: Qi
authors.initials: Q
authors.lastname: Mi
authors.affiliation: Department of Surgery, University of Pittsburgh Pittsburgh, PA, USA ; Center for Inflammation and Regenerative Modeling, McGowan Institute for Regenerative Medicine, University of Pittsburgh Pittsburgh, PA, USA.
authors.forename: Ruben
authors.initials: R
authors.lastname: Zamora
authors.affiliation: Center for Inflammation and Regenerative Modeling, McGowan Institute for Regenerative Medicine, University of Pittsburgh Pittsburgh, PA, USA ; Department of Mathematics, University of Pittsburgh Pittsburgh, PA, USA.
authors.forename: Gregory
authors.initials: G
authors.lastname: Constantine
authors.affiliation: Department of Oral Biology and Pathology, School of Dental Medicine, SUNY Stony Brook Stony Brook, NY, USA.
authors.forename: Lorne
authors.initials: L
authors.lastname: Golub
authors.affiliation: Department of Oral Biology and Pathology, School of Dental Medicine, SUNY Stony Brook Stony Brook, NY, USA.
authors.forename: Hsi-Ming
authors.initials: HM
authors.lastname: Lee
authors.affiliation: Department of Surgery, Upstate Medical University Syracuse, NY, USA.
authors.forename: Shreyas
authors.initials: S
authors.lastname: Roy
authors.affiliation: Department of Biological Sciences, SUNY Cortland Cortland, NY, USA.
authors.forename: Louis A
authors.initials: LA
authors.lastname: Gatto
authors.affiliation: Department of Surgery, University of Pittsburgh Pittsburgh, PA, USA ; Center for Inflammation and Regenerative Modeling, McGowan Institute for Regenerative Medicine, University of Pittsburgh Pittsburgh, PA, USA.
authors.forename: Yoram
authors.initials: Y
authors.lastname: Vodovotz
keywords: ARDS; CMT-3; MODS; Sepsis; data-driven; model; networks; porcine; shock