Mitochondrial biogenesis in the pulmonary vasculature during inhalational lung injury and fibrosis

Our plain-English summary of Mitochondrial biogenesis in the pulmonary vasculature during inhalational lung injury and fibrosis, by M.S. Carraway, H.B. Suliman, C. Kliment, et al (Antioxidants & Redox Signaling, 2008).

The study

• Authors: M.S. Carraway, H.B. Suliman, C. Kliment, K.E. Welty-Wolf, T.D. Oury, C.A. Piantadosi
• Journal: Antioxidants & Redox Signaling
• Published: 2008;10(2):269-75
• Cited by: 29 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Cell survival and injury repair is facilitated by mitochondrial biogenesis; however, the role of this process in lung repair is unknown. We evaluated mitochondrial biogenesis in the mouse lung in two injuries that cause acute inflammation and in two that cause chronic inflammation and pulmonary fibrosis. By using reporter mice that express green fluorescent protein (GFP) exclusively in mitochondria, we tracked mitochondrial biogenesis and correlated it with histologic lung injury, proliferation, and fibrosis. At 72 hours after acute LPS or continuous exposure to hyperoxia (Fio2, 1.0), the lungs showed diffuse infiltration by inflammatory cells in the alveolar region. In reporter mice, patchy new mitochondrial fluorescence was found in the alveolar region but was most prominent and unexpected in perivascular regions. At 14 days after instillation of asbestos or bleomycin, diffuse chronic inflammation had developed, and green fluorescence appeared in inflammatory cells in the expanded interstitium and was most intense in smooth muscle cells of pulmonary vessels. In all four lung injuries, mitochondrial fluorescence colocalized with mitochondrial superoxide dismutase, but not with proliferating cell nuclear antigen. These data indicate that vascular mitochondrial biogenesis is activated in diverse inhalational lung injuries along with oxidative stress. This finding indicates a unique and unexpected mechanism of metabolic adaptation to pulmonary fibrotic injuries.

In plain English

This was an animal experiment in mice at Duke University. The authors compared four lung injuries. Two were acute: breathing pure oxygen for 72 hours, or bacterial endotoxin (LPS) placed in the windpipe. Two were chronic: crocidolite asbestos (0.1 mg) or the drug bleomycin placed in the windpipe, with lungs examined 14 days later. Specially bred mice whose mitochondria (the cell's energy-producing parts) glow green were used to look for new mitochondria forming. The article does not say how many mice were used. Fourteen days after asbestos, the lungs showed inflammation, thickening of the lung tissue and substantial fibrosis (scarring). Green fluorescence rose most in the smooth muscle of small lung blood vessels. It also appeared in inflammatory cells. In all four injuries, the new mitochondria were found in the same places as an antioxidant enzyme linked to oxidative stress. In the vessels they did not match a marker of cell division. The authors concluded that lung vessel muscle cells may form new mitochondria in response to injury. They noted they did not measure molecular markers of this process, and that mouse models are not established to match human disease.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Animal experiment (laboratory study in mice using microscopy and fluorescent staining of lung tissue)
• Who was studied: Male mice: wild-type C57BL/6 mice aged 8 to 10 weeks, or transgenic mice whose mitochondria contain green fluorescent protein (mtGFP-tg mice), bred at Duke University. The number of mice is not stated.
• Exposure: Crocidolite asbestos fibers (0.1 mg) placed directly into the windpipe (intratracheal instillation), with lungs examined after 14 days. For comparison: bleomycin (2 mg/kg) by the same route for 14 days; LPS by the same route for 3 days; or breathing 100% oxygen (FiO2 1.0) for 72 hours. The fiber length unit is garbled in the text.
• Main results:
  • In asbestos-treated mice at 14 days, the lungs showed mixed inflammatory cells in the alveolar region and areas of marked thickening of the interstitium (the tissue between air sacs), with substantial fibrosis and collagen deposits on special staining.
  • In asbestos-treated reporter mice, small muscular lung blood vessels showed large increases in green (mitochondrial) fluorescence, mainly in the smooth muscle layer.
  • In asbestos-treated reporter mice, prominent mitochondria were also seen in chronic inflammatory cells of the thickened interstitium.
  • In the acute injuries (oxygen and LPS), increased mitochondrial fluorescence was seen around blood vessels and in inflammatory cells.
  • In both the acute and the fibrotic (asbestos and bleomycin) injuries, the new mitochondria appeared in the same locations as the mitochondrial antioxidant enzyme SOD2. The authors read this as a link with mitochondrial oxidative stress.
  • After asbestos and bleomycin, the cell-division marker PCNA was intense in the interstitium and inflammatory cells.
  • In the small blood vessels, cell division (PCNA) was located separately from the new mitochondria.
  • In both asbestos- and bleomycin-injured lungs, mitochondrial fluorescence overlapped with PCNA in some lung tissue (parenchymal) or inflammatory cells.
• The authors' conclusion: The authors concluded that vascular smooth muscle cells in the lung appear to increase formation of new mitochondria in response to both acute and chronic lung injuries, possibly as a compensating response. They suggested it may relate to vascular remodeling.
• Limitations the authors state:
  • The authors did not measure the molecular (transcriptional) markers of mitochondrial formation in these experiments.
  • The authors could not tell whether increased fluorescence in inflammatory cells reflected new mitochondria or simply more inflammatory cells arriving.
  • The authors could not exclude that some SOD2 staining merely marked new mitochondria rather than oxidative stress.
  • The authors stated that correspondence between mouse fibrosis models, including asbestos, and the human diseases is not established.

Topics

Medical terms in this study, explained in our Lexicon: Fibrosis, Inflammation, Chronic Inflammation, Pulmonary Fibrosis, Superoxide, Oxidative Stress.

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