Acute Lung Injury
Acute lung injury (ALI) and the adult respiratory distress syndrome (ARDS) are states of acute inflammation in the lung that leads to disruption of the alveolar-capillary barrier and leakage of fluid, protein, and cells into the lung’s interior resulting in compromised lung function. We focus on the innate immune response in ALI, specifically the role of activated platelets (see below) in accelerating lung inflammation, and a consequence of platelet-neutrophil interactions—the elaboration of neutrophil extracellular traps, or NETs. Models of transfusion-related acute lung injury (TRALI), bacterial pneumonia, cystic fibrosis, and ischemia-reperfusion injury are used. Clinical samples from ARDS patients are used to test “hits” in the mouse studies.
Lung Transplantation
Lung transplantation is an increasingly utilized approach to treat a variety of patients with end-stage lung disease; however, it is limited by poor long-term outcomes. We model two major complications of lung transplantation: primary graft dysfunction (PGD) and obliterative bronchiolitis (OB). A major tool is the single-lung orthotopic lung transplant model in mice (combined with cold ischemia to produce PGD). Investigations include the role of activated platelets, NETs (see below), and DAMPs in promoting ischemia-reperfusion injury. Studies also include biological samples in the early post-operative period from patients undergoing lung transplantation. OB is being modeled with a genetic approach to selectively express allo-antigens in the lung epithelium to study early and late events in OB pathogenesis.
Platelet Biogenesis in the Lung
We have recently discovered that the lung circulation is an important participant in the production of platelets from megakaryocytes, and that the lung is a site of megakaryocyte residence. These studies are aided by the application of live, two-photon microscopy in the mouse lung (and other organs), and by using the lung transplant approach to determine the hematopoietic potential of the mouse lung. Ongoing studies include determining the niche-promoting factors for hematopoietic progenitors and mature megakaryocytes in the lung, the molecular contributions of the lung endothelium to platelet production, and the innate immune function of lung megakaryocytes.
Two-photon Lung Intravital Microscopy
We have developed a novel approach to image the live mouse lung using two-photon microscopy, and we are applying this technique to all projects in the lab, using it as tool for novel discovery, and collaborating with colleagues on a variety of projects related to pulmonary biology.
