EPIDERMAL GROWTH FACTOR SIGNALING IN THE REGENERATING AXOLOTL LUNG

Background: Lung injury, through both disease and trauma, affects many people worldwide. Efforts to elucidate novel mechanisms of lung regeneration have the potential to change lives and transform health care. While there are many who would benefit from a breakthrough in lung regeneration research, there are few models of lung regeneration that may be studied. The axolotl salamander, Ambystoma mexicanum, has long been held as a model organism of vertebrate regeneration, particularly in limbs. It is thought that they regenerate all of their tissues, but exploration of lung regeneration has not been performed until now. Methods: During this study, we used immunohistochemistry, qPCR and surgical techniques to interrogate the molecular basis of lung regeneration in the axolotl. Results: Proliferation was observed to be a global response throughout the lung tissue of the axolotl after lung injury. This would suggest the regeneration utilizes a compensatory mechanism. ErbB4 mRNA was found to be upregulated at one week post-amputation in the axolotl lung. Injected neuregulin-1 was mitogenic to lung tissue and upregulated ErbB4 as seen in lung injury. When we inhibited ErbB2, we found that lung regeneration was halted. Conclusions: In this experiment we have found that axolotl lung tissue regenerates using a compensatory mechanism, contrary to limb regeneration. Additionally, epidermal growth factor signaling is crucial for regeneration to take place, specifically through the ErbB2:ErbB4 receptor heterodimer. Neuregulin-1 can induce proliferation in the lung, and is a likely candidate to exert molecular control over lung regeneration.