Lung Injury and Repair: Early Therapeutic Considerations

• Author / Creator

  Rey Parra, Gloria Juliana

• Acute Lung Injury/Acute Respiratory Distress Syndrome (ALI/ARDS) remain a major health issue because of a high mortality and morbidity rate. Despite progress in understanding the pathogenesis of ALI, there is currently no drug-based therapy promoting lung repair. A predominant pathological finding in ALI is diffuse alveolar epithelial damage. Rapid recovery of the alveolar epithelium is crucial for lung repair and prevention of the development of lung fibrosis post-ALI/ARDS. In order to identify new therapeutic strategies aimed at improving epithelial function to accelerate repair and decrease the mortality/morbidity of patients with ARDS, we investigated two innovative concepts: (1) the lung healing capacity of the MRL (Murphy-Roth Large) mouse strain know for its unique capacity for both accelerated and regenerative wound healing, and (2) stem cell-based treatments. We used two well-established ALI/ARDS models: lipopolysaccharide, LPS-induced ALI/ARDS and bleomycin, BLM-induced ALI/ARDS complicated by fibrosis. We found that MRL/MPJ mice have attenuated lung inflammation and injury in the LPS-induced model of ARDS compared to C57BL/6 control mice. The healing potential of MRL/MPJ mice is in part attributable to alveolar epithelial type 2 cells (AT2, putative distal lung progenitor cells) since they displayed an accelerated wound closure in vitro and their conditioned media attenuated LPS-induced ALI/ARDS in C57BL/6 mice. Conversely, in BLM-induced lung injury, MRL/MPJ healer mice showed no differences in their repair capacity compared to C57BL6 controls. This could be attributable to the marked toxicity of BLM on AT2 cells. We also tested the therapeutic potential of human umbilical cord blood cells (HUCBC) in BLM-induced lung injury. HUCB decreased collagen deposition, as well as improved lung function and exercise capacity. Moreover, HUCBC secreted relaxin and angiotensin converting enzyme 2 (ACE2), 2 molecules known for their antifibrotic effects. We further explored the antifibrotic effects of ACE2 by showing worsened lung fibrosis in ACE2 knock out, whereas exogenous administration of human recombinant ACE2 significantly attenuated fibrosis and improved lung function in BLM induced lung injury. In summary, our studies provide new therapeutic options for lung repair after injury.

• Subjects / Keywords

  • Lung injury
  • MRL mice
  • Pulmonary fibrosis

• Graduation date

  Spring 2012

• Type of Item

  Thesis

• Degree

  Doctor of Philosophy

• DOI

  https://doi.org/10.7939/R3ZG6GG4N

• License

  This thesis is made available by the University of Alberta Libraries with permission of the copyright owner solely for non-commercial purposes. This thesis, or any portion thereof, may not otherwise be copied or reproduced without the written consent of the copyright owner, except to the extent permitted by Canadian copyright law.