New treatments for deadly lung disease could be revealed by 3D modeling


Date:
September 14, 2020
Source:
University of Michigan
Summary:
A 3D bioengineered model of lung tissue is poking holes in decades
worth of flat, Petri dish observations into how the deadly disease
pulmonary fibrosis progresses.



FULL STORY ==========================================================================
A 3D bioengineered model of lung tissue built by University of Michigan researchers is poking holes in decades worth of flat, Petri dish
observations into how the deadly disease pulmonary fibrosis progresses.


==========================================================================
The causes of pulmonary fibrosis are not fully understood, but the
condition is marked by scar tissue that forms inside the lungs. That
scar tissue stiffens the walls of the lungs' air sacs, called alveoli,
or, at advanced stages, can completely fill the alveolar spaces. Both
scenarios make breathing difficult and decrease the amount of oxygen
entering the bloodstream. Often the condition is irreversible, eventually causing lung failure and death.

Some clinicians are concerned that critically ill COVID-19 patients may
develop a form of pulmonary fibrosis after a long stay in the ICU.

Researchers are searching for better treatments. While they've managed
to find some drugs that relieve symptoms or slow the progression in
practice, they haven't been able to reliably replicate those results in
today's 2D lab models.

So they don't understand how or why those drugs are working, and they
can't always predict which compounds will make a difference. The new
research from U- M takes a step in that direction, and it starkly
demonstrates how prior approaches have been ineffective.

The team showed that in some 2D models, drugs that are already known
to be effective in treatment do not produce test results that show
efficacy. Their 3D tissue engineered model of fibrotic lung tissue,
however, shows that those drugs work.

Before their tests on drugs, they first performed studies to understand
how tissue stiffness drives the appearance of myofibroblasts -- cells
that correlate with the progression of scarring.



========================================================================== "Even in cells from the same patient, we saw different outcomes," said
Daniel Matera, a doctoral candidate and research team member. "When
we introduced stiffness into the 2D testing environment, it activated myofibroblasts, essentially creating scar tissue. When we introduced that
same kind of stiffness into our 3D testing environment, it prevented
or slowed the activation of myofibroblasts, stopping or slowing the
creation of scar tissue." With the majority of pulmonary fibrosis
research relying on 2D testing, he said, many have believed the high lung stiffness in patients is what should be targeted by treatments. U-M's
research indicates that targeting stiffness alone may not hinder disease progression in patients, even if it works in a Petri dish.

To find effective treatments, researchers first screen libraries of pharmaceutical compounds. Today, they typically do that on cells cultured
on flat plastic or hydrogel surfaces, but these settings often do a poor
job of recreating what happens in the human body.

Brendon Baker, assistant professor in the U-M Department of Biomedical Engineering, and his team took a tissue engineering approach. They reconstructed 3D lung interstitium, or connective tissue, the home
of fibroblasts and location where fibrosis begins. Their goal was
to understand how mechanical cues from lung tissue affect fibroblast
behavior and disease progression.

"Recreating the 3D fibrous structure of the lung interstitium allowed
us to confirm effective drugs that wouldn't be identified as hits in traditional screening settings," Baker said.

At the center of the pulmonary fibrosis mystery is the fibroblast,
a cell found in the lung interstitium that is crucial to healing
but, paradoxically, can also drive disease progression. When
activated, after an injury or when disease is present, they become myofibroblasts. Regulated properly, they play an important role in wound healing, but when misregulated, they can drive chronic disease. In the
case of pulmonary fibrosis, they cause the stiffening of lung tissue
that hampers breathing.

"Our lung tissue model looks and behaves similarly to what we have
observed when imaging real lung tissue," Baker said. "Patient cells
within our model can actively stiffen, degrade or remodel their own
environment just like they do in disease." The study, published in the
current issue of Science Advances, is funded, in part, by the National Institutes of Health.


========================================================================== Story Source: Materials provided by University_of_Michigan. Note:
Content may be edited for style and length.


========================================================================== Journal Reference:
1. Daniel L. Matera, Katarina M. DiLillo, Makenzee R. Smith,
Christopher D.

Davidson, Ritika Parikh, Mohammed Said, Carole A. Wilke, Isabelle M.

Lombaert, Kelly B. Arnold, Bethany B. Moore, Brendon M. Baker.

Microengineered 3D pulmonary interstitial mimetics highlight
a critical role for matrix degradation in myofibroblast
differentiation. Science Advances, 2020; 6 (37): eabb5069 DOI:
10.1126/sciadv.abb5069 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2020/09/200914112226.htm

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