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Insulin-like Growth Factor-1 in post-pneumonectomy lung regeneration

Yasa, Joe (2019) Insulin-like Growth Factor-1 in post-pneumonectomy lung regeneration. PhD thesis, Murdoch University.

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Abstract

Insulin Growth Factor-1 (IGF-1), is a key and highly regulated molecule which stimulates somatic growth. The level of serum IGF-1 in humans peaks at adolescence and declines with age. IGF-1 expression is also critical for embryonic lung development and is expressed in the regenerating lung of young animals following pneumonectomy (PNX), the surgical removal of a lung. The murine left-lung PNX model was used to investigate the hypothesis that IGF-1 enhances the regenerative capacity of the lung. The potential interactions of IGF-1 and the transcription factors early growth response protein 1 (EGR-1) and hypoxia-inducible factor-1α (HIF-1α) in post-PNX lung growth was also investigated.

I demonstrated that following left-lung PNX in young mice (aged 2-3 months) pre-operative total lung volume and tissue volume is restored by day 21 post-surgery. IGF-1 mRNA and protein levels were significantly induced in the remaining lung, with a transient but significant increase in IGF-1+, pIGF-1R+ and pERK-1/2+ lung cells, at day three post-PNX compared to SHAM treated mice. I then showed that intraperitoneal administration of IGF-1 following PNX significantly increases the rate of lung volume and tissue volume recovery and the level of lung cell proliferation, when assessed at day seven post-surgery. In contrast, blocking IGF-1 activity by pharmacological inhibition of IGF-1R signalling, significantly attenuated post-PNX lung growth.

In young mice receiving continuous subcutaneous infusion of IGF-1 following PNX, the rate of lung volume recovery to pre-operative levels was similar to age-matched PBS-treated PNX mice. However, lung sections assessed at day 23 post-surgery revealed that IGF-1-treated mice lungs had significantly higher numbers of IGF-1+, pIGF-1R+, pERK-1/2+ lung cells, proliferating SpC+ type two alveolar epithelial cells and number of alveoli per unit area, suggesting that IGF-1 treatment was associated with additional regenerative activity.

In old PNX mice (aged 22-24 months), there was a significant increase in aerated lung volume following continuous subcutaneous administration of IGF-1, compared to age-matched PBS-treated controls. However, unlike young mice, there was no evidence of restoration of pre-operative total lung volume or tissue volume by day 21 post-surgery in either treatment groups. Additionally, lung sections assessed at day 23 post-surgery revealed no differences between IGF-1 and PBS treated lungs in the numbers of IGF-1+, pIGF-1R+ and pERK-1/2+ lung cells, or proliferating SpC+ alveolar type two epithelial cells or the number of alveoli per unit area.

Finally, I investigated the potential for interactions of IGF-1 and the transcription factors EGR-1 and HIF-1α in post-PNX lung growth. I demonstrated that IGF-1 treatment can induce EGR-1 and HIF-1α protein expression in cultured 3T3 fibroblasts. Furthermore, both EGR-1 and HIF-1α were transiently increased in the parenchyma of the lung at day three post-PNX, coinciding with the peak of IGF-1 expression. Pharmacological inhibition of either EGR-1 or HIF-1α activity significantly reduced the density of CD31+ cells and CD31 protein levels in the lung. Additionally, pharmacological inhibition of HIF-1α activity in the lung following PNX significantly reduced lung cell proliferation at day seven post-surgery. Intraperitoneal administration of IGF-1 was able to restore the level of lung cell proliferation in HIF-1α inhibited PNX lungs to the levels of untreated PNX lungs.

These results collectively point to a temporally coordinated involvement IGF-1, EGR-1 and HIF-1α during post-PNX regenerative lung growth, and that additional IGF-1 treatment can enhance such growth following PNX in young mice, but not in aged mice. Furthermore, these studies have identified a potential age-dependent defect in responsiveness to IGF-1 in the lung, which warrants further investigation.

Item Type: Thesis (PhD)
Murdoch Affiliation: School of Veterinary and Life Sciences
United Nations SDGs: Goal 3: Good Health and Well-Being
Supervisor(s): Mead, Robert
URI: http://researchrepository.murdoch.edu.au/id/eprint/50128
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