Research Overview
Severe trauma and hemorrhage render the patient more susceptible to a second, seemingly trivial inflammatory stimulus, the so-called “two-hit” hypothesis. Post-trauma sepsis, which involves activation of innate immunity, can lead to severe multi-organ failure, systemic inflammatory response syndrome (SIRS), and death. Studies have suggested that cell priming caused by a first hit is the mechanism for enhanced response of the cell to a second hit.
Polymorphonuclear neutrophils (PMNs) are essential effector cells of the innate immune system. The accumulation of PMNs in tissue is considered a critical event in organ inflammation and injury and has been the target of preventative strategies. PMN migration is a result of a cascade of cellular events, in which PMNs, endothelial cells (ECs), epithelia, and macrophages (MΦ) act in concert. Studies from Dr. Fan’s lab explored interrelated novel findings indicating that receptor cross-talk mechanisms occurring in PMNs, ECs, and MΦ are important determinants for augmenting PMN migration in the setting of SIRS. In PMNs, LPS through toll-like receptor (TLR) 4 and phosphoinositide 3-kinase Υ signaling down-regulates the expression of G protein-coupled receptor kinases (GRK)2 and GRK5 in response to chemokine, and the reduced expression of GRKs decreases chemokine receptor desensitization and markedly augments the PMN migration response. However, in ECs and MΦ, LPS/TLR4 signaling upregulates TLR2, and oxidant signaling derived from PMN NADPH oxidase enhances the TLR2 upregulation through PMN-EC or PMN-MΦ interaction and results in an amplified expression of adhesion molecules in the ECs and release of cytokines and chemokines from the MΦ in response to TLR2 ligands, thereby promoting PMN migration. Furthermore, Dr. Fan’s lab demonstrated that hemorrhagic shock is potent to activate PMN NADPH oxidase through high-mobility group box 1 (HMGB1) -TLR4 - p38 MAPK signaling, and therefore initiates the mechanisms of cell priming. Taken together, receptor cross-talk mechanisms are critical determinants for cell priming and subsequent augmented PMN migration in sepsis.
The ongoing research projects in Dr. Fan’s lab include several lines that aim to elucidate the mechanisms of hemorrhagic shock-induced activation of inflammasome, pyroptosome, and autophagy in innate immune cells, as well as the significance of the resultant alterations in the development of post-hemorrhage SIRS.
Lab Members
- Principal Investigator: Jie Fan, MD, PhD
- YueHua Li
Location
W901 Biomedical Science Tower and VA Pittsburgh Healthcare System 1W139, 1W140, and 1W143
Publications
Publications from the Fan Lab can be viewed through PubMed.