Lung injury following trauma is a major cause of morbidity and mortality. Severe trauma can often generate conditions of ischemia reperfusion (IR) and result in sterile inflammatory injury directly or indirectly affecting the lung. The situaion can then be worsened by the later onset of infection. We are currently unable to predict the strength of the inflammatory response within the lung to severe trauma and individual patients' likelihood of developing lung injury, pneumonia, and long-term multi-organ dysfunction. Moreover, we are unable to effectively influence these processes therapeutically. The overall research goal is to understand how the innate immune system recognizes and responds to sterile injury and tissue damage, and how this response overlaps with and differs from that to infection. The objective of this proposal is to define the molecular and cellular pathways that control ventilated lung IR injury in mice and determine how conserved these pathways are with the patient response to lung IR injury in trauma. My central hypothesis is that pure lung IR injury is an acute but self-resolving inflammatory process, the strength and nature of which is coordinated by resident lung cells (alveolar macrophages) and whose manipulation can affect IR and subsequent responses to infection. The rationale for the proposed research is that once targets for lung IR therapy have been identified, and the periods of infectious vulnerability defined, novel approaches to treating trauma patients can be developed. The proposed experiments seek to investigate the innate immune responses to sterile lung injury in trauma and subsequent infection and to devise ways to manipulate these responses. Specifically, Aim 1 will determine if inflammatory responses elicited by ventilated lung ischemia reperfusion in mice cause long-term dysfunction and also establish a correlation with human immune responses to trauma and lung IR. The goal of Aim 2 is to determine how toll-like receptor (TLR) signaling and inflammasome activity in alveolar macrophages are regulated in ventilated lung IR responses in mice. Lastly, Aim 3 will determine the effect of lung IR inflammation on the pathophysiology of subsequent local and systemic infections (i.e., a two-hit model) in mice. The proposed research is expected to uncover the molecular and cellular pathways in alveolar macrophages that are important for the immune response to lung IR injury. This contribution will be significant because the research is expected to lead to the identification of targets for therapies and medical management interventions that can prevent unnecessary lung damage early in trauma while preserving the immune system's ability to stave off infections later.

Public Health Relevance

This project will define the innate immune molecular and cellular pathways involved in sterile lung injury in trauma and subsequent infection and also investigate ways to manipulate these pathways. If successful, the proposed studies will benefit public health by identifying targets for therapies that can prevent unnecessary lung damage early in trauma while preserving the immune system's ability to fight off infections.

Agency
National Institute of Health (NIH)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08GM110497-03
Application #
9208789
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Dunsmore, Sarah
Project Start
Project End
Budget Start
Budget End
Support Year
3
Fiscal Year
2017
Total Cost
Indirect Cost
Name
University of California San Francisco
Department
Anesthesiology
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94118
Prakash, Arun; Sundar, Shirin V; Zhu, Ying-Gang et al. (2015) Lung Ischemia-Reperfusion is a Sterile Inflammatory Process Influenced by Commensal Microbiota in Mice. Shock 44:272-9
Kangelaris, Kirsten Neudoerffer; Prakash, Arun; Liu, Kathleen D et al. (2015) Increased expression of neutrophil-related genes in patients with early sepsis-induced ARDS. Am J Physiol Lung Cell Mol Physiol 308:L1102-13
Wilhelmsen, Kevin; Xu, Fengyun; Farrar, Katherine et al. (2015) Extracellular signal-regulated kinase 5 promotes acute cellular and systemic inflammation. Sci Signal 8:ra86