Tissue scarring (also known as fibrosis) has a multi-factorial origin of occurrence, such as chronic inflammatory processes, involvement of heavy metals, metabolic derangements, and other causes that lead to tissue damage or injury. Moderate to severe scarring interferes with normal functioning of tissues and organs, ultimately leading to death due to vital organ failure. According to the latest estimates, the cause of death in more than 50% cases is scarring or fibrosis of vital organs like the kidney, liver, heart and lungs.
Dr. Dean Sheppard, a Professor of Medicine at UC San Francisco, explained that despite an important cause of organ dysfunction, there is no FDA treatment currently that can manage the scarring of tissues. However, the research team of UCSF has been able to arrest and reverse the tissue changes in fibroses lungs, kidneys, and other scarred tissues of laboratory mice by controlling integrins.
Background of the Research:
Integrins are specialized proteins that are present on the surface of cell membranes, and are required to connect multiple cells to form solid tissues and organs, such as the heart, liver, and lungs via an extracellular matrix. In addition, integrins also act as receptors to transmit information about the events that take place inside the cells to ECM components and vice versa.
For example, in case of any tissue injury, intracellular signals generated within the cells are transmitted to ECM in order to stimulate the synthesis of collagen by specialized proteins like TGF-beta. This is the primary patho-physiological event that leads to scar formation and tissue fibrosis.
Scarring of tissues is the result of over-activation of this primary repair process, which leads to excessive formation and deposition of collagen, stiffening of tissues, resulting impairment in tissue function, and even more signaling of TGF-beta to produce collagen; thereby starting a vicious cycle of events.
Details of the Research:
The preliminary work is performed by Neil C. Henderson in collaboration with international team of researchers from Sweden and Germany and nationwide network of brilliant scientists like Joseph H. McCarty from the University of Texas MD Anderson Cancer Center, Adam Lacy-Hulbert from Harvard Medical School and Massachusetts General Hospital and others by targeting cell-surface proteins or receptors.
Henderson is also the first author of the study and a former post-doctoral associate in Sheppard’s laboratory (who is currently working at University of Edinburgh). The research team employed highly organized genetic techniques to selectively knock out the genes for cell-surface proteins (also referred to as alpha V integrins. These proteins are present on the fibroblasts that are responsible for the synthesis of collagen (that in excess secretion leads to scarring and fibrosis).
As expected, the research team identified that the propensity to develop liver scarring when exposed to toxic insults (that otherwise cause scarring in normal mice) produced little effect in mice with genetic deletion of alpha V integrins — the 5-member family of protein receptors. The team also observed the protective potential against fibrosis of the kidney and lung.
However, no change in the protective response was observed when individual members of the family were targeted, suggesting a complete genetic knock-out of the family is needed in order to prevent fibrosis.
The results of this discovery appeared online in the scientific journal Nature Medicine on Nov, 10th 2013.
Development of drugs to block the activity of Integrins:
As a result of this discovery, the scientists at St. Louis University in Missouri developed a special pharmacological preparation that can block the action of all 5 members of the integrin family. The preparation prevented fibrosis in the tissues in the similar manner as genetic deletion of the integrin family. The drug CWHM 12 not only prevented the onset of new fibrosis, but also arrested and even reversed the scarring in lung and liver tissue.
Although, the research suggested that in order to stop fibrosis, inactivation of all 5- member5 memberss of integrin family is needed; Sheppard still believes that there is still a chance to prepare a more targeted pharmacological preparation that can specifically target only one integrin member (instead of all). He added: “We’re working really hard now to narrow this down to which specific integrin might be critically important.”
Until Sheppard’s research brings more fruitful results, the new drug CWHM 12 can be used as an inhalant to control lung fibrosis by delivering a small dose directly to the target tissue.
Researchers who also contributed to this study include:
– University of Texas M.D. Anderson Cancer Center scientist, Joseph H. McCarty
– UCSF researchers Marilyn M. Giacomini, Tom Arnold, Yoshio Katamura, Juan D. Rodriguez, and Jacquelyn J. Maher
– University of Edinburgh scientists, Antonella Pelicorro, Alison Mackinnon and John P. Iredale
– Saint Louis University’s Center for World Health and Medicine scientists, David W. Griggs. Peter G. Ruminksi and Michael J. Prinsen
– Adam Lacy-Hulbert from Massachusetts General Hospital and Harvard Medical School
The research also involved researchers from institutes outside of America:
– Max Planck Institute for Molecular Biomedicine at the University of Münster, Germany investigator, Ralf H. Adams
– The research team from Uppsala University and Karolinska Institute in Sweden included Elisabeth Raschperger and Christer Betsholtz