Pharmacology of fibrosis and tissue injury

Our plain-English summary of Pharmacology of fibrosis and tissue injury, by M. Chvapil (Environmental Health Perspectives, 1974).

The study

• Author: M. Chvapil
• Journal: Environmental Health Perspectives
• Published: 1974;9:283-94
• Cited by: 15 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Methods controlling tissue fibrosis are classified into those specifically inhibiting various metabolic aspects of collagen selectively in the injured tissue (ascorbic acid deficiency, effect of agent chelating Fe(2+), proline analogs, lathyrogens). The most promising method seems to be the blocking of crosslinks formation among collagen molecules by beta-aminopropionitrile, a competitive inhibitor of a crosslinking enzyme, lysyl oxidase. The second group of methods is called nonspecific, as they affect any stage of inflammatory process preceding the activation of fibroblasts. The importance of activated macrophages in the stimulation of fibroblast is discussed. Finally, a new concept is proposed, indicating the function of zinc ions in the control of the integrity of biomembrances, tissue reactivity to noxious agents. It is suggested that zinc may control NADPH dependent lipid peroxidation at the membrane level by inhibiting NADPH oxidase activity. The implication of these ideas to lung fibrosis induced by silica or asbestos is discussed.

In plain English

This 1974 article was a review-style presentation. The author surveyed ways to control tissue fibrosis (abnormal scarring) and metals' role in tissue injury, adding the author's own laboratory results. The author reported no asbestos experiments; the author's own work included silica (quartz), ethionine-fed rats, hypoxia and zinc. In quartz-injected mice, liver collagen (measured as hydroxyproline) was 0.63 mg per liver, against 0.18 mg in controls. The author reported that the iron-binding drug 1,10-phenanthroline significantly reduced this fibrosis, but rats given the drug showed no inhibition of the collagen-making enzyme. Silica raised red blood cell rupture to 92.0% at 30 minutes, against 22.5% in buffer alone, and caused signs of membrane fat oxidation. After silica exposure, 56% of mouse macrophages remained viable, against 79% from zinc-treated mice. The author judged blocking collagen crosslinking with beta-aminopropionitrile most promising and suggested metals such as zinc help regulate membrane integrity. The author suggested these ideas might bear on asbestos, citing another researcher's report that EDTA-extracted asbestos fibers lost cytotoxicity. The author called some findings preliminary, including the silica and red blood cell work.

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: Narrative review / conference presentation that combines a survey of published work with the author's own animal and laboratory (in vitro) experiments
• Who was studied: Laboratory animals and cells, for example: mice (H strain) injected with quartz; CFN female rats fed ethionine; rats exposed to high-altitude hypoxia; washed dog erythrocytes; peritoneal macrophages from control and zinc-treated mice. No human subjects.
• Exposure: The author's own experiments included silica (quartz) particles, ethionine in rats, high-altitude hypoxia and zinc, among others. Treatments tested included 1,10-phenanthroline, alpha-tocopherol and zinc chloride. Asbestos was not tested in the author's own experiments. The author discussed possible implications for asbestos fibers, including metal ions on the fiber, and cited Harington's observation on EDTA-extracted asbestos fibers.
• Main results:
  • In mice given intravenous quartz, total liver hydroxyproline (a collagen measure) was 0.63 plus or minus 0.17 mg per liver, against 0.18 plus or minus 0.07 mg in controls (p less than 0.001). The author stated that 1,10-phenanthroline significantly reduced this silica-induced liver fibrosis.
  • In organs and granuloma tissue of rats treated in vivo with 1,10-phenanthroline, the author found no inhibition of prolyl hydroxylase and no underhydroxylated collagen. The author therefore questioned the assumed mechanism.
  • Dog red blood cells with 5 mg silica showed 92.0% hemolysis at 30 minutes and 95.0% at 60 minutes. Cells in buffer alone showed 22.5% and 42.6%. With silica plus alpha-tocopherol, hemolysis was 46.0% and 56.4%. Alpha-tocopherol alone was itself hemolytic (85.0% and 87.0%).
  • Red blood cells incubated with silica formed more fluorescent lipid-peroxidation product than controls and showed changes in polyunsaturated fatty acids, mainly arachidonic acid. The author interpreted this as silica-induced lipid peroxidation.
  • Freshly isolated mouse peritoneal macrophages were 85% viable. Silica exposure lowered viability to 56%. Macrophages from zinc-treated mice exposed to silica were 79% viable.
  • Zinc given to mice reduced the macrophages' phagocytosis of Staphylococcus albus. The phagocytosis index was 62.8 plus or minus 5.2% of control at the low zinc dose and 48.7 plus or minus 7.6% at the high dose. The author suggested silica is less toxic to zinc-treated macrophages because they take it up less actively.
• The authors' conclusion: The author concluded that inhibiting collagen hydroxylation in living animals did not seem promising and that blocking collagen crosslinking (for example with beta-aminopropionitrile) offered more encouragement. The author also concluded that metals are involved in regulating the integrity of cell membranes, some destabilizing and some stabilizing them.
• Limitations the authors state:
  • The author described the silica and red blood cell membrane data as preliminary.
  • The malondialdehyde table showed results from one characteristic experiment, from unpublished work.
  • The author cautioned that a statistically significant 15% to 20% reduction in collagen may not be clinically important.
  • The author stated that the locally injected, polymer-linked beta-aminopropionitrile method needed more experimentation and called its results preliminary.

Topics

Medical terms in this study, explained in our Lexicon: Fibrosis, Collagen, Fibroblast, Macrophage.

Related studies

• A novel method for accurate collagen and biochemical assessment of pulmonary tissue utilizing one animal — C.R. Kliment, J.M. Englert, et al. (2011)
• Fibrogenesis — J.S. Harington (1974)
• Collagen synthesis and degradation during the development of asbestos-induced pulmonary fibrosis — M.G. Arden, I.Y. Adamson (1992)
• Mitochondrial biogenesis in the pulmonary vasculature during inhalational lung injury and fibrosis — M.S. Carraway, H.B. Suliman, et al. (2008)
• Inhibition of lung injury, inflammation, and interstitial pulmonary fibrosis by polyethylene glycol-conjugated catalase in a rapid inhalation model of asbestosis — B.T. Mossman, J.P. Marsh, et al. (1990)
• Mesothelial cell proliferation: a nonspecific response to lung injury associated with fibrosis — I.Y. Adamson, J. Bakowska, et al. (1994)

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