Original Research: ACE2 activator associated with physical exercise potentiates the reduction of pulmonary fibrosis

Exp Biol Med (Maywood). 2017 Jan;242(1):8-21. doi: 10.1177/1535370216665174. Epub 2016 Aug 21.


The interstitial lung diseases are poorly understood and there are currently no studies evaluating the association of physical exercise with an ACE2 activator (DIZE) as a possible treatment for this group of diseases. We evaluate the effects of pharmacological treatment with an angiotensin-converting enzyme 2 activator drug, associated with exercise, on the pulmonary lesions induced by bleomycin. From the 96 male Balb/c mice used in the experiment, only 49 received 8 U/kg of bleomycin (BLM, intratracheally). The mice were divided into control (C) and bleomycin (BLM) groups, sedentary and trained (C-SED, C-EXE, BLM-SED, BLM-EXE), control and bleomycin and also sedentary and trained treated with diminazene (C-SED/E, C-EXE/E, BLM-SED/E, BLM-EXE/E). The animals were trained five days/week, 1 h/day with 60% of the maximum load obtained in a functional capacity test, for four weeks. Diminazene groups were treated (1 mg/kg, by gavage) daily until the end of the experiment. The lungs were collected 48 h after the training program, set in buffered formalin and investigated by Gomori's trichrome, immunohistochemistry of collagen type I, TGF-β1, beta-prolyl-4-hydroxylase, MMP-1 and -2. The BLM-EXE/E group obtained a significant increase in functional capacity, reduced amount of fibrosis and type I collagen, decreased expression of TGF-β1 and beta-prolyl-4-hydroxylase and an increase of metalloproteinase -1, -2 when compared with the other groups. The present research shows, for the first time, that exercise training associated with the activation of ACE2 potentially reduces pulmonary fibrosis.

Keywords: ACE2 activation; MMPs; TGF-β; beta-prolyl-4-hydroxylase; physical exercise; type I collagen.

MeSH terms

  • Angiotensin-Converting Enzyme 2
  • Animals
  • Collagen Type I / metabolism
  • Diminazene / pharmacology*
  • Disease Models, Animal
  • Lung / drug effects
  • Lung / metabolism
  • Lung / pathology
  • Male
  • Matrix Metalloproteinase 1 / metabolism
  • Matrix Metalloproteinase 2 / metabolism
  • Mice, Inbred BALB C
  • Peptidyl-Dipeptidase A / metabolism*
  • Physical Conditioning, Animal / physiology*
  • Physical Endurance / drug effects
  • Pulmonary Fibrosis / drug therapy
  • Pulmonary Fibrosis / physiopathology
  • Pulmonary Fibrosis / therapy*


  • Collagen Type I
  • Peptidyl-Dipeptidase A
  • Ace2 protein, mouse
  • Angiotensin-Converting Enzyme 2
  • Matrix Metalloproteinase 2
  • Matrix Metalloproteinase 1
  • Diminazene