Mesenchymal inflammatory signaling in regulation of the immune response and tissue dysfunction during lipopolysaccharide-induced acute lung injury

PROJECT SUMMARY/ABSTRACT Acute respiratory distress syndrome (ARDS) is a type of respiratory failure characterized by severe pulmonary inflammation leading to alveolar injury, non-cardiogenic pulmonary edema, and impaired gas exchange often necessitating mechanical ventilation. ARDS can be caused by direct or indirect injury to the lungs, with the

most common etiologies of injury being pneumonia, aspiration of gastric contents and sepsis. Despite significant interest in finding new therapies for ARDS, treatment has remained predominately supportive, highlighting the need for improved mechanistic understanding. The pulmonary mesenchyme resides in close

proximity to the alveolar epithelium, vascular endothelium, and resident and recruited immune cells, placing the mesenchyme in an optimal position to synthesize and respond to signals from the microenvironment. In this proposal we aim to elucidate how the pulmonary mesenchyme incorporates inflammatory signals to modify the

immune response and tissue injury in ARDS. The nuclear factor -B (NF-B) family of transcription factors are activated downstream of several pattern-recognition and cytokine receptors, and play an important role in mediating inflammatory responses. A20, encoded by Tnfaip3, is a negative regulator of NF-B, and has been

found in both immune and epithelial cells to play a crucial role in limiting excessive inflammation and tissue injury. The intranasal delivery of bacterial lipopolysaccharide (LPS) is a well-accepted murine model for ARDS, and LPS is known to activate NF-B through the pattern-recognition receptor Toll-like receptor 4 (TLR4).

Preliminary data from our lab shows that in response to LPS, lung fibroblasts in which Tnfaip3 has been deleted have increased expression of both chemokines and cytokines known to recruit immune cells and alter vascular permeability, both physiologically important aspects of ARDS pathogenesis. We hypothesize that

impaired negative regulation of mesenchymal NF-B signaling in ARDS leads to increased pulmonary recruitment of immune cells and physiologic injury, and propose experiments to test this hypothesis. Answering these questions will lead to important insight into the role of the lung mesenchyme in mediating the

pathophysiology of ARDS. We hope that the fundamental knowledge gained with these studies will eventually contribute to the development of more targeted therapeutics for this devastating disease. The above experimental proposal is part of a comprehensive training plan that I have built with my mentors to develop the

skills and knowledge needed to become a successful independent investigator in the field of lung biology, with an emphasis on acute lung injury/ARDS. As a unique part of this plan I have assembled a Career Development Committee composed of physician-scientists from the fields of pulmonology and immunology who will serve as

both scientific and career advisors. Upon completion of the proposed training plan with the support of my mentors, advisors, and within the strong research environment that UCSF provides, I will be well-positioned to make both a meaningful contribution to the understanding of ARDS and meet my training goals.