Multi-scale models of lung fibrosis

Julie Leonard-Duke a, Stephanie Evans b, Riley T. Hannan c, Thomas H. Barker a,

Jason H.T. Bates d, Catherine A. Bonham e, Bethany B. Moore f,
Denise E. Kirschner b and Shayn M. Peirce a,g
a - Department of Biomedical Engineering, University of Virginia, PO Box 800759, Charlottesville, VA 22908, USA
b - Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, MI 48109, USA
c - Department of Pathology, University of Virginia, Charlottesville, VA 22908, USA
d - Department of Medicine, Vermont Lung Center, University of Vermont College of Medicine, Burlington, VT 05405, USA
e - Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA 22908, USA
f - Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, and Department of Microbiology and
Immunology, University of Michigan Medical Center, Ann Arbor, MI 48109, USA
g - Robert M. Berne Cardiovascular Research Center, University of Virginia, Charlottesville, VA 22908, USA

Corresponding to Shayn M. Peirce: Department of Biomedical Engineering, University of Virginia, Health System, PO
Box 800759, Charlottesville, VA 22908, USA. shayn@virginia.edu.
https://doi.org/10.1016/j.matbio.2020.04.003

Abstract
The architectural complexity of the lung is crucial to its ability to function as an organ of gas exchange; the
branching tree structure of the airways transforms the tracheal cross-section of only a few square centimeters
to a blood-gas barrier with a surface area of tens of square meters and a thickness on the order of a micron or
less. Connective tissue comprised largely of collagen and elastic fibers provides structural integrity for this
intricate and delicate system. Homeostatic maintenance of this connective tissue, via a balance between cat-
abolic and anabolic enzyme-driven processes, is crucial to life. Accordingly, when homeostasis is disrupted
by the excessive production of connective tissue, lung function deteriorates rapidly with grave consequences
leading to chronic lung conditions such as pulmonary fibrosis. Understanding how pulmonary fibrosis devel-
ops and alters the link between lung structure and function is crucial for diagnosis, prognosis, and therapy.
Further information gained could help elaborate how the healing process breaks down leading to chronic dis-
ease. Our understanding of fibrotic disease is greatly aided by the intersection of wet lab studies and mathe-
matical and computational modeling. In the present review we will discuss how multi-scale modeling has
facilitated our understanding of pulmonary fibrotic disease as well as identified opportunities that remain open
and have produced techniques that can be incorporated into this field by borrowing approaches from multi-
scale models of fibrosis beyond the lung.
© 2020 Elsevier B.V. All rights reserved.

Introduction process is hijacked by heightened and/or prolonged

Fibrosis is a condition where excess fibrous con-
nective tissue forms in an organ during a reparative
(or reactive) process. Fibrosis occurs often in the
lung, and is associated with a myriad of diseases,
from lung cancer to certain infections to idiopathic
pulmonary fibrosis (IPF). Lung fibrosis ensues when
the remodeling phase of the natural wound healing
inflammation, leading to differentiation of fibroblasts
into myofibroblasts that deposit extracellular matrix
(ECM) in non-homeostatic ways [1
3]. Whether
manifested locally by an identifiable trigger (e.g.,
tumors or tuberculosis granulomas) or in a more
spatially distributed fashion throughout the lung by
an unknown trigger (e.g., IPF), the main “output” of
lung fibrosis
stiffening of lung tissue
is thought

0945-053X/© 2020 Elsevier B.V. All rights reserved. Matrix Biology. (2020) 00, 1
16
2 Multi-scale models of lung fibrosis
to be the same, although the mechanisms driving
this behavior may differ between conditions. Conse-
quently, lung fibrosis is a complex process that has
multiple inputs that may vary across diseases and
include biomolecular signals, mechanical signals,
and different interacting cell types that operate and
intersect with one another over a broad range of
length and time scales.
Since the lungs are difficult tissues to study, par-
ticularly during fibrotic processes, alternative
approaches have become increasingly useful to
tease out the intricacies of lung disease. We will
summarize in this review how pairing computational
modeling with wet lab studies has proven to be a
powerful tool for studying lung fibrosis by elucidating
new mechanisms of disease that span spatial and
temporal scales and by providing quantitative and
predictive frameworks for identifying and evaluating
potential new treatments [4-6]. Computer models
integrate what is known and/or hypothesized about
a system to predict something not yet known. Spe-
cifically, they are able to combine different types of
experimental data (e.g., collected from in vitro mod-
els, in vivo models, or clinical specimens) using
physical laws and theories (e.g., momentum or diffu-
sion) that have mathematical implementations to
calculate the outcomes for simulated biologically rel-
evant scenarios. In making predictions that are
rooted in both data and theory, computer models
extend scientific discovery beyond the set of experi-
mentally testable questions thereby accelerating
and enriching the discovery process.
The present review summarizes how computa-
tional modeling has been applied to the study of
fibrosis and different fibrotic lung conditions and the
insights that have been garnered from them. We
specifically highlight an emerging and powerful cate-
gory of computational models, multi-scale computa-
tional models, which integrate mechanisms of
disease across the molecular (e.g., microscopic),
cellular (e.g., mesoscopic), and tissue and organ (e.
g., macroscopic) levels [7]. Our review also dis-
cusses the challenges that lung fibrosis research
faces, particularly regarding current experimental
limitations, and how computational modeling could
be deployed in conjunction with experiments to over-
come these challenges and yield breakthroughs in
understanding that may have substantial clinical
benefits.
The biology of lung fibrosis
Fibrosis has been regarded as the prolonging, or
dysfunction, of the final phases of the body’s normal
wound healing cascade, which progresses along
four well-characterized stages: hemostasis, inflam-
mation, proliferation and remodeling [8]. Fibrosis
can occur when the inflammation stage fails to
terminate, leading to the extended presence of
proinflammatory factors, such as interleukin-1 (IL-1)
and tumor necrosis factor-alpha (TNF-a), and ele-
vated levels of matrix-modifying enzymes, such as
matrix metalloproteases (MMPs) [9]. The inflamma-
tion stage typically overlaps temporally with the pro-
liferation stage, meaning while inflammation is
upregulated, fibroblasts in the affected area may be
stimulated to produce excess collagen, which stif-
fens the ECM. Notably, inflammatory processes are
complex and can lead to other outcomes that do not
involve fibroblasts, such as abcess formation [10],
but when fibroblasts are activated, alteration of the
chemo-mechanical characteristics of the ECM can
affect many other cells in the tissue niche, including
cells of the microvasculature (e.g. endothelial cells)
that are critically responsible for ensuring adequate
tissue perfusion [2]. Several computational models
have been created in attempts to understand the
dynamics of the wound healing cascade and the
manifestation of fibrosis in tissues outside the lung,
such as skin [11
13] or liver [14,15].
Fibrosis can occur in the lung as an end result of
many different diseases (e.g. cancer, infection, bron-
chiolitis obliterans, COPD, scleroderma, rheumatoid
arthritis, hypersensitivity pneumonitis and IPF).
Interestingly, some of these diseases (e.g. sclero-
derma and rheumatoid arthritis-associated interstitial
lung disease) have systemic manifestations causing
fibrosis in multiple organs but other diseases, such
as IPF seem to be uniquely localized to the lung
[16]. The reasons for such differences in disease
manifestations are not clear.
Fibrosis in the lung tends to follow this general
wound healing paradigm, but there are some mech-
anisms of fibrosis that are unique to the lung. The
architecture of the normal lung allows for efficient
gas exchange, while also providing barrier function
against inhaled particles and pathogens [17]. The
lung contains of a variety of cell types including type
I and II alveolar epithelial cells (AECs), endothelial
cells and fibroblasts. The alveoli of the lung are lined
with thin type I AECs that are in close proximity to
endothelial cells which allow for efficient gas
exchange. Type I AECs are thin and cover over
90% of the surface area of the lung [18], while type II
AECs generate surfactant which has lipid compo-
nents that reduce surface tension during breathing
and protein components that provide host defense
functions [18-20]. Fibroblasts provide flexible struc-
ture supporting the epithelial and endothelial cells.
Fibrosis is believed to develop in response to a lung
injury. In the lung, this generally refers to an injury to
the type I and/or type II AECs. Limited damage to
type I AECs is repaired by proliferation and differen-
tiation of the type II AECs to reestablish the epithelial
barrier [21]. If damage is minimal, this heals without
scarring; however, if damage is more severe, then
other types of progenitor cells (e.g. Keratin 5þ basal
Multi-scale models of lung fibrosis
cells [22]) can be mobilized to effect repair which is
often disordered. Significant damage to either type I
or type II AECs disrupts the homeostatic signaling
between AECs and fibroblasts allowing for the mes-
enchymal cells (fibroblasts) to expand, become acti-
vated and begin synthesis of extracellular matrix.
The initial injury leads to the release of damage
associated molecular pattern molecules or DAMPs
which trigger innate immune receptors to initiate
inflammatory responses resulting in release of che-
mokines and recruitment of inflammatory cells [23,
24]. The repair and fibrosis process are influenced
by the phenotypes of the monocyte-macrophages
that are recruited and also by the release of pro-
fibrotic growth factors such as transforming growth
factor (TGF)b and cytokines such as IL-13, IL-4, IL-
17 and tumor necrosis factor (TNF)a [25].
For many fibrosing interstitial lung diseases
(ILDs), what is not known is the inciting injury. Viral
infections [26], genetic mutations [27], acid aspira-
tion [28] and inhaled particulate matter [29] are
hypothesized as causes of initial injury and possible
exacerbating factors in IPF, which is one canonical
form of idiopathic progressive ILD. These factors
exacerbate both the intracellular, through endoplas-
mic reticulum stress and mitochondrial dysfunction,
and extracellular, through recruitment of inflamma-
tory cells and activation of fibroblasts, environment
[24,30
32]. In other cases of lung fibrosis, the incit-
ing agent is well-known (e.g. silica dust, Mycobacte-
rium tuberculosis (Mtb), bleomycin chemotherapy).
While the fibrotic response is certainly beneficial for
the host as a mechanism for walling off infections (e.
g. TB [33]), progressive interstitial fibrosis is certainly
detrimental to the host via impairment of efficient gas
exchange and reduction in lung compliance. The
mechanisms that promote progressive fibrosis are
also poorly understood, but a common theory is that
the accumulating matrix causes mechanical stiffen-
ing of the tissue, which in turn may promote ongoing
activation of mesenchymal and epithelial cells via
mechanotransduction [34,35]. Little is understood
about the biology of progressive fibrosis presenting
the need for computational modeling to study poten-
tial cellular interactions and the potential impacts of
therapies.
In clinical pulmonary medicine, diseases of the
lung are grouped into obstructive versus restrictive
physiology, based on measurement of total lung
capacity and dynamic airflow through the bronchi
and bronchioles using pulmonary function testing
[36,37]. In diseases such as cancer, tuberculosis
(TB), or other infection such as pulmonary abscess,
fibrosis occurs in a patchy distribution directly adja-
cent to the areas affected by the primary disease
process. This form of fibrosis is reactive to the
underlying disease and thought to have some adap-
tive function by walling off infection or tumor invasion
[33,38,39]. Physiology is often normal or may be
3
obstructive if tumor(s) or TB granulomatous infiltra-
tion causes air trapping, resulting in high lung vol-
umes, or dynamic airway collapse with exhalation,
resulting in low air flow [40
42]. Less commonly,
cancer or TB presents with restriction (abnormally
low lung volumes and high air flow) due to pleural
disease or diffuse spread of tumor or granulomas
[43,44]. In contrast, all ILDs, including IPF, presents
with restrictive physiology, or sometimes restriction
mixed with a mild to moderate amount of overlap-
ping obstruction. ILD is an umbrella term for approxi-
mately 200 different forms of pulmonary fibrosis in
which fibrosis is not reactive to a specific pathologic
nidus as in cancer or TB, but rather occurs diffusely
in the interstitial connective tissue compartment
between alveoli [16]. This results in classic restric-
tive physiology, with small, stiff lungs and high air
flow on exhalation due to increased elastic recoil.
Pulmonary fibrosis in patients with ILD may be asso-
ciated with systemic connective tissue diseases
such as scleroderma or rheumatoid arthritis, envi-
ronmental exposures such birds or mold antigen, or
drugs such as methotrexate [45]. IPF is one form of
ILD with no known cause [46]. It is the most fre-
quently studied ILD today due to the historical forma-
tion of key research cohorts, and its poor median
survival rate of 3 years after diagnosis in most
patients [47,48]. Whereas fibrosis in diseases such
as cancer or TB is limited and may be functionally
beneficial, patients with ILD suffer from diffuse man-
ufacture of extracellular collagen matrix that is physi-
ologically and functionally maladaptive. This results
in highly diminished exercise capacity and poor oxy-
gen diffusion across alveolar membranes; hence,
shortness of breath on exertion and oxygen desatu-
ration with ambulation are two key bedside findings
in patients with ILD [48].
The fundamental differences in fibrotic disease
mechanisms has led to the development and use of
distinct computational models for each disease.
Therefore, we will review a variety of computational
models that have been developed to study healthy
lung function and two major lung diseases where
fibrosis is a critical component, idiopathic pulmonary
fibrosis (IPF), and tuberculosis (TB). In so doing, we
will point out the differences and similarities across
the range of computational modeling approaches
that have been used to simulate lung fibrosis. We
will also suggest opportunities for future adaptation
and integration of computational models to study
lung diseases that differ from that which they were
originally devised to investigate.
Computational models of lung fibrosis
Computational models provide researchers with
tools for interrogating complex biological systems

offering both quantitative descriptions and predictive
4 Multi-scale models of lung fibrosis
power that is unattainable through experimental
investigation alone. Pairing of computational models
with experimental data is essential to specify and
constrain them for biological relevancy, computa-
tional models of the lung have been developed to
simulate processes that occur at specific levels of
spatial scale, including molecular [49], cellular [50],
and tissue [51]. These models require the use of
specific computational modeling techniques to rep-
resent the biological processes at a unique level of
scale, and these techniques necessarily abstract or
coarse grain the biological details from higher and/or
lower levels of scale that are not explicitly repre-
sented by the model. For example, in their paper
evaluating the role of airway heterogeneity in
asthma, Tgavalekos et al. abstract the molecular
and cellular details of the condition to focus on the
whole tissue airway interactions that leads to
changes in lung mechanics and ventilation distribu-
tion [52].
Computational modeling approaches can be
broadly divided into two categories based on how
the biological components of the system (e.g., mole-
cules or cells) are represented by the model: (1) dis-
crete models represent individual biological
components using a one-to-one mapping between
the biological component and a simulated represen-
tation of it, and (2) continuum models use generaliz-
able descriptions to represent the effects of
biological components that can reasonably be
assumed to be homogenous to the extent that their
contributions to the biological processes being mod-
eled are sufficiently similar. Within these two catego-
ries, there are many different mathematical and
computational techniques to simulate biological sys-
tem, including ordinary differential equations
(ODEs), partial differential equations (PDEs), and
agent-based models (ABMs), among others [53]
(Fig. 1). ODE models are continuous and typically
Fig. 1. Visual overview of different types of modeling. A) Recreation of process modeled by Hao et al. [6]. B) Recreation
of agent-based model set up from Warsinske et al. [38].
represent the change in concentration of a variable
(e.g. protein) over a spatial or temporal scale (e.g.
protein concentration over time in a system). PDEs
explicitly represent changes in space and over time.
A common method for solving PDEs is finite element
modeling where the geometrical space can be
mapped to smaller elements that are easier to solve
the PDEs over. These models are ideal for modeling
large geometries, such as a pair of lungs, to study
perturbations on a macro-scale [53,54]. Finally,
agent-based models can be solved over space and
time like PDEs but do so by enforcing a set of “rules”
on individual “agents”, such as cells or cytokines.
Rules can be in the form of differential or algebraic
equations, probabilistic expressions, and/or logic-
based conditional statements. The environment the
agents interact with is partitioned into a grid where
each grid-space has its own ruleset which it obeys
when interacting with agents or over time [55,56].
These modeling techniques and others have been
used to model lung fibrosis and will be discussed in
the next section of this paper.
An emerging class of computational models can
simulate mechanisms that bridge spatial and tempo-
ral scales, and these are termed “multi-scale compu-
tational models” [53]. Multi-scale computational
models provide insights into how events at one level
of scale (e.g., changes in cytokine concentrations at
the molecular scale) affect outcomes at another
level of scale (e.g. diameter expansion of a multi-cell
TB granuloma) by representing the interconnections
between spatial scales (Fig. 1B). Given the variety
of mechanisms that play out across the molecular,
cellular, and tissue scales to drive different fibrotic
lung diseases, it is easy to appreciate how multi-
scale models can help researchers simulate and
learn more about lung fibrotic disease progression.
Modeling interconnections between mechanisms
across spatial scales and temporal scales is typically
Multi-scale models of lung fibrosis
achieved by coupling different types of computa-
tional modeling approaches together, and examples
of this will be provided in the following sections. As a
result, these models fall into the category of “hybrid
models”, which intentionally combine discrete and
continuum modeling approaches within a single
model framework (Fig. 2). Just as multi-scale mod-
els present new opportunities for exploration, they
also present unique challenges, not the least of
which is that they tend to require a tremendous
amount of computing power.
Computational models of healthy lung function
Modeling the lung can be approached, broadly
speaking, in two distinct ways
inverse modeling
and forward modeling [57]. Inverse modeling
involves fitting structurally simple models to appro-
priate data sets in order to evaluate parameters of
physiological interest. At the most basic level the
lung can be viewed as a linearly elastic homoge-
neous unit served by a conduit of fixed resistance to
airflow; these two structures representing the paren-
chymal tissues and conducting airway tree of the
lung, respectively. Fitting this model to pressure and
Fig. 2. A subset of references cited in this review, organized according to condition, and classified by the biological
scales they span. [Evans, submitted to Frontiers in Immunology].
5
flow signals measured at the entrance to the lungs
of a mechanically ventilated patient, for example,
can provide estimates of the elastance of the unit
and the resistance of the conduit, which represent
stiffness of the lung tissue and resistance of the air-
ways [57]. Models of greater complexity may provide
more accurate representations of lung behavior, but
at the expense of increased ambiguity about the
physiological meaning of their more numerous
parameters as well as reduced confidence in their
best-fit parameter values. In fact, the number of dis-
tinct compartments that can be identified in an
inverse model of the lungs is never more than a
handful, even with the most precise experimental
data [57], so the amount of structural detail that can
be linked to function is very limited. Forward model-
ing, on the other hand, is not constrained by any limi-
tations on structural complexity, computational
expense aside. All that is required to make a forward
model of arbitrary complexity is knowledge of the
equations that describe its individual components
and their interactions [58-60]. From a basic science
perspective, however, it is perhaps forward model-
ing that has the most to offer in the future. There are
a number of hypotheses about mechanisms that
6 Multi-scale models of lung fibrosis
forward modeling can help to investigate, especially
in IPF which will be discussed in the next section.
Computational models of idiopathic pulmonary
fibrosis
In the context of idiopathic pulmonary fibrosis
(IPF) models are inherently multi-scale as there is
currently no single overwhelming factor controlling
disease initiation or progression. For that reason,
many models attempt to model interactions between
different biological scales to elucidate what compo-
nents are crucial to the diagnosis of IPF.
Wellman et al. chose to use a hybrid physics and
agent-based model to recapitulate the peripheral
“honeycomb” structure seen in computed tomogra-
phy (CT) images of IPF lungs. To test their hypothe-
sis that this pattern arose from spatial interactions
between fibroblasts and stiff ECM, the authors mod-
eled alveolus cross sections from a single lobe of
the lung as a two-dimensional pre-stretched springs
that were aligned hexagonally and surrounded by a
border of springs representing the pleura. The
agents in this model were fibroblast cells that could
travel between nodes of the network and modify the
stiffness of a spring based on a set of rules. Agents
moved in a random walk and were activated over
time through interactions with physiologically stiff tis-
sue which resulted in the deposition of collagen and
stiffening of the agent’s current spring. Agents also
randomly undergo apoptosis and are replaced by a
deactivated fibroblast agent when removed from the
system. In order to compare model results with CT
images the resulting networks were coarse-grained
and transferred to a square grid. Authors defined
two adjoining pixels with Hounsfield Units (HU)
greater than
650 as an area of fibrosis or high-
attenuation area (HAA) and used this value in a
power law equation to calculate the cumulative num-
ber of clusters [61].
The primary goal of this paper was to provide
insight into why the honeycomb pattern in IPF is
most prevalent on the periphery. The current hypoth-
esis is that the fibrotic signal begins on the periphery
which is confirmed by the model in the higher HAA
probability distribution with longer tails at the pleural
border indicating that they are larger than those
in other areas. If agents started the simulation
already activated, then the formation of fibrosis was
distributed throughout the lung rather than the
sub-pleural pattern that is characteristic for IPF. In
cases of severe fibrosis, there were larger HAAs
which resulted from the inverse relationship of the
power law exponent for HAAs and the overall
degree of fibrosis. Overall the authors combined cell
and tissue dynamics to correctly recapitulate the
“honeycomb” phenotype used to clinically diagnose
IPF [61].
Multi-scale models also allow researchers to test
different potential drug targets before using an ani-
mal model or evaluate the pathways of drugs cur-
rently on the market. Hao et al. built a mathematical
model to achieve these, including key molecular and
cellular pathways that lead to the formation of scar
on the tissue level. A schematic of the interactions
included in the model can be seen in Fig. 1A. The
authors used a simplified model of a lung as a cube
containing spatially distributed smaller cubes con-
taining the smallest level of cube representing the
alveoli. Equations are then derived for macrophage
density, AEC density, fibroblast density, myofibro-
blast density, ECM density, scar formation, MCP-1,
and cytokine concentrations (PDGF, MMP, TIMP,
TGF-b, TNF-a and IL-13). Each equation is then
homogenized by assuming that all variables have
zero flux on the boundary. The system spans two
dimensions and is solved by the Runge-Kutta
method in the time direction and using a finite differ-
ence scheme in the spatial direction [6].
The simulations were validated using human lung
tissue samples from patients with IPF and healthy
patients. Simulations demonstrate that MMP 7 con-
centration is four times higher in IPF accompanied
by doubling in levels of MMPs 1,2,9 and 13. TIMP
concentration also increases 20% over the thirty-
day model period. TGF-b levels are twice the levels
seen in a healthy patient in the IPF patient, however,
it is noted that the model cannot confirm if the TGF-
b is activated post transcriptionally or just produced.
Additionally, PDGF and TNF-a concentrations
increase in the IPF patient simulations as expected.
The authors repeated this simulation for a longer
time span of 300 days and saw similar trends
although the disease progressed at a slower rate [6].
Five potential treatments were tested: anti-TNF-a,
anti-PDGF, anti-IL-13, anti-TGF-b and a combina-
tion treatment of anti-IL-13 and anti-TGF-b. These
were chosen based on treatments that were in clini-
cal trial or approved to treat IPF at the time of publi-
cation [6]. Treatment was simulated for both mild
and severe cases of IPF for 300 days after an initial
100-day simulation to get the model into equilibrium.
Treatment efficacy was measured by concentration
of ECM over time. Both the mild and severe cases
responded best to anti-TGF-b as well as the combi-
nation treatment of anti-IL-13 and anti-TGF-b. Both
treatments appear to slow or stop the formation of
fibrosis, possibly even reducing ECM concentration
over time. The combination treatment proved to be
the most effective and had not yet been used in clini-
cal trials at the time, introducing a new potential ther-
apy [6].
A recent article in The Journal of Clinical Investi-
gation Insight used a data driven computational
model to correlate results from histology, RNA
sequencing and microRNA analysis in healthy and
IPF lungs at different stages of disease progression.
Multi-scale models of lung fibrosis
Samples from ten IPF lungs and six healthy donor
lungs were classified by principal component analy-
sis of surface density and collagen I and III volume
fractions then clustered based on expectation-maxi-
mization. IPF was divided into three groups early-
stage with normal lung histology (IPF1), moderate-
stage (IPF2), and late-stage (IPF3). A linear mixed-
effects model was used to identify genes that were
differentially expressed in at least one IPF group
compared to the control. The Dynamic Regulatory
Events Miner (DREM) uses a graphical model-
based machine-learning method to identify branch
points in gene expression profiles where co-
expressed genes begin to be expressed differen-
tially. Branch points are classified by specific tran-
scription factors or microRNAs that serve as
regulators [62].
The major insight provided by the model was that
genetic differences occur in IPF cells before tissue
level changes become evident. It was found that
908 genes were common across samples from all
stages of IPF, even early IPF where the tissue
appears histologically normal. Unsurprisingly, sixty-
seven of the most overexpressed genes were
related to collagen and ECM, with COL1A1 being
the highest expressed gene in all stages of IPF. In
analyzing microRNA changes the authors targeted
those they deemed significant (P<0.05 and a 2-fold
change in expression in IPF compared to the con-
trol) 4 microRNAs were identified and were able to
downregulate 20 genes from the core gene set. The
DREM analysis then organized these changes in
gene expression and microRNAs into thirteen possi-
ble pathways originating from one of four nodes in
the IPF1 phase. An in-depth discussion of each
track and its unique pathway can be found in the
original manuscript. Shifts in cell populations that
may have contributed to each of these tracks was
also studied. Finally, the authors prove their model
is mechanistically relevant by doing a case study on
POU2AF1, a key regulator in node 6 of their model,
demonstrating that POU2AF1 knockout mice were
more resistant to bleomycin induced pulmonary
fibrosis than their wildtype litter mates [62]. Data
driven models offer unique insight through the use
of statistical methods to identify emergent patterns
in large data correlations between experimental
parameters sets that may not be achievable through
mechanistic modeling alone.
Computational models of fibrosis in tuberculosis
Fibrosis in TB occurs at the level of lung granu-
lomas. Granulomas are spheroid collections of
immune cells, ECM, and bacteria that serve to
physically contain and immunologically restrain
M. tuberculosis the bacterium that causes TB.
Fibrosis in TB is associated with both good and
bad disease outcomes. Fibrosis serves to both
7
isolate infected tissue from healthy tissue and
also lower bacterial burdens [63]; however, fibro-
sis also leads to lung scaring that negatively
impacts breathing and lung contraction/expansion.
Little is known about the role of fibrosis in TB and
what drives its formation. A combination of non-
human primate models and systems biology
approaches have begun to shed light into both
cause and effect [38,64].
To begin to explore the role of fibroblasts and
myofibroblasts Warsinske et al. used a computa-
tional agent-based model, GranSim, that describes
the formation and function of lung granulomas in
TB (http://malthus.micro.med.umich.edu/GranSim,
http://malthus.micro.med.umich.edu/GranSim)
[38,65,66]. GranSim captures spatio-temporal
dynamics of the immune response to infection with
Mtb. This model was updated to include fibroblasts
and myofibroblasts types along with TGF-b1 [38],
(called GranSim-Fibrosis, or GramSim-F). Applying
sensitivity analysis to this model (through the calcu-
lation of partial-rank correlation coefficients
(PRCCs)) [67], they demonstrated that fibrosis in
granulomas is associated with anti-inflammatory
response, and that myofibroblast and fibroblast
numbers correlate with levels of TGF-b1 produced
by activated macrophages [38]. However, the same
study showed that the total amount of TGF-b1 could
not explain the development of fibrosis. The authors
concluded that the spatial distributions of active
TGF-b1 in specific areas of a granuloma may be key
to whether or not fibroblasts proliferate or differenti-
ate to become a collagen-producing myofibroblast.
Additionally, they showed that active TGF-b1 is a
necessary but not sufficient condition for inducing
fibrotic outcomes. The role of other anti-inflamma-
tory cytokines has also been highlighted in the con-
text of granuloma-associated fibrosis. In early TB
infection, the roles of the cytokines IL-10 and IL-13
have been shown to be associated with increasing
levels of fibrosis within granulomas in a non-human
primate model of TB [64].
One common theme to granuloma-associated
fibrosis is that fibrosis tends to be associated with
a peripheral pattern, surrounding a granuloma
[33]. This is true in many, but not all cases. A fur-
ther computational study focused on peripheral
granuloma-associated fibrosis. In this work the
GranSim-F model [38] was extended to include
non-fibroblast origins for myofibroblasts in the
granuloma and lung environment via Macrophage
to Myofibroblast Transformation (MMT). Like the
previous studies, this work also identified a link
between anti-inflammatory cytokines and fibro-
blast counts suggesting that in the case of TB
fibrosis is a healing, and not disease exacerbat-
ing response [Evans, submitted to Frontiers in
Immunology]. The computational results in this
work were supported by non-human primate
8 Multi-scale models of lung fibrosis
(NHP) studies, and identified macrophages that
have previously received inflammatory signals as
a potential candidate for MMT in the granuloma.
This study also demonstrated, using GranSim-F,
that traditional fibroblast to myofibroblast differen-
tiation produced a fibrosis phenotype representa-
tive of lung fibrosis; however, without
recapitulating peripheral granuloma fibrosis. With
the addition of MMT, peripheral fibrosis could
manifest. Sensitivity analysis via PRCCs showed
that inflammatory cell types were negatively cor-
related with fibrosis, whereas anti-inflammatory
cytokines such as active TGF-b1 were positively
correlated.
Case study on signaling and fibroblast
differentiation
The molecular mechanisms of fibrosis represent a
vast field. Here we discuss a case study whereby at
a molecular scale, a combination of in vitro experi-
mentation, mathematical modeling, and statistical
analyses are combined to identify key mechanisms
driving fibroblast differentiation and dysregulation
[4]. Warsinske et al. developed a nonlinear ordinary
differential equation model that tracks the temporal
concentrations of three molecules known to be influ-
ential in the development of fibrosis; aSMA, prosta-
glandin E₂ (PGE2), TGF-b1 and contains a single
term for the free surface receptors for TGF-b1 [67].
Fig. 3. Venn diagram summarizing the current state of the multi-scale modeling field with focus on multi-scale modeling
of lung fibrosis.
Using sensitivity analyses on this model [67] the
authors demonstrated that the strength of PGE2-
induced inhibition of adhesion signaling is the most
important factor in regulating fibroblast differentia-
tion, and that high levels of PGE2 inhibit fibroblast
proliferation. In addition, the model predicted that
rates of active TGF-b1 degradation and receptor
recycling are also important to fibroblast differentia-
tion. These specific parameters contribute to either
the actual concentration of TGF-b1 and PGE2 in the
media or to concentration levels at which the recep-
tor
ligand interaction becomes saturated. Taken
together, this suggests that PGE2 and TGF-b1
receptor
ligand signaling dynamics simultaneously
contribute to fibroblast regulation and together dic-
tate the differentiation of the cell. The authors con-
clude that treatment strategies to reduce tissue
damage in fibrosis need to target multiple mecha-
nisms, rather than individually, to affect epithelial
cells as well and fibroblasts and myofibroblasts.
The results of the previous study were echoed by
a similar study that used mathematical modeling
alongside in vitro co-culture experiments of fibro-
blasts and epithelial cells to predict that simulta-
neous targeting of fibroblasts and epithelial cells is
necessary for treatment of pulmonary fibrosis [5]. In
this work, a hybrid-multiscale agent-based model
describing the behavior of both fibroblasts and epi-
thelial cells in culture was developed. This study had
two main aims, which included identifying molecular
Multi-scale models of lung fibrosis
and cellular scale mechanisms driving fibroblast pro-
liferation and differentiation as well as epithelial cell
survival in the context of fibrosis. Their results dem-
onstrated that periodic dosing with PGE₂ temporarily
renders fibroblasts incapable of differentiation and
resistant to TGF-b1 stimulation, increasing epithelial
cell and fibroblast cell death and reducing the rate of
fibroblast proliferation for a temporary period. Con-
versely, periodic dosing with TGF-b1 in the pres-
ence of PGE₂ induces a reduced signal response
that can be further inhibited by the addition of more
PGE₂, and causes the death of epithelial cells. This
study concludes that regulation of both TGF-b1 and
PGE₂ signaling levels are essential for preventing
fibroblast dysregulation. Both of these studies high-
light the utility of combining mathematical modeling
studies with in vitro experiments to help elucidate
mechanisms of fibrosis development at cellular and
molecular scales.
Computational modeling beyond lung
fibrosis
Different computational modeling approaches
have been used to study other lung conditions in
addition to fibrotic disease and this can provide
insight to improving models studying fibrotic lung
disease. Fig. 3 summarizes some of the major areas
of this research
Multi-Scale modeling of lung outside of fibrotic
disease
There have been many studies utilizing multi-
scale modeling to evaluate lung diseases that do not
focus on the role of fibrosis. For example, other mod-
els of TB in lungs not focused on the fibrosis process
have been studied for 15 years [56]. Asthma and
Chronic Obstructive Pulmonary Disease (COPD)
are popular topics for computational modeling utiliz-
ing finite element or computational fluid dynamics
methods. One example of multi-scale model is the
model of airway hyperresponsiveness in asthma
developed by Politi et al. At the lowest level there is
a sliding filament model of smooth muscle cell acti-
vation by Ca2þ which results in an active force at the
cellular level that influences the airway-lumen radii
at the tissue level. At the macroscopic level, the
organ model uses finite element methods to account
for deformations in the lung from breathing and grav-
ity. Both of these then influence the cell and tissue
level, respectively. The cell and tissue levels
exchange information about contractile velocity and
force generated to yield the emergent phenomena
that led to the hyperresponsiveness [68]. For further
reading on computational modeling in these condi-
tions, please refer to Burrowes et al. [69].
9
Few computational models of lung cancer exist,
one notable study being that of Wang et al. which
used an agent-based model to evaluate metastasis
in non-small cell lung cancer (NSCLC). Each cell
functioned as an agent and within it contained a set
of kinetic equations describing their internal molecu-
lar signaling, specifically the Epidermal Growth Fac-
tor (EGF) and Phospholipase Cg (PLCg) pathways.
These molecular signals were influenced by the con-
centrations of external cues: glucose, EGF and oxy-
gen tension; and resulted in one of four tumor cell
phenotypes: proliferation, migration, quiescence
and death. There were four primary rules dictating
agent behavior based off of the resultant concentra-
tion of PLCg and Extracellular signal-regulated
kinase (ERK), a downstream signal of EGF, the last
of which was varied in the study to either preference
migration or proliferation. The model was found to
be more sensitive to the migration preference over
proliferation as it corresponded with experimental
data from human breast cancer cells. Another
intriguing finding was that cells exposed to the high-
est levels of nutrient source underwent a phase tran-
sition resulting in abolishment of a proliferative
phenotype, resulting in a strong migratory pheno-
type. It has been shown previously that EGF stimu-
lation increases the spatial expansion of cancer
systems which explain this emergent phenomenon
of the model [70].
In the field of cystic fibrosis, much of the current
research is focused on mucus transport dynamics
and the microbiota present in the mucus that lead to
infection [71
73]. In the computational modeling
space, there have been many studies investigating
different aspects of CF from large scale studies of
airway constriction at birth [74] to small scale protein
folding [75] and microbiota metabolomics models
[76]. All of these have the potential to contribute to
the formation of fibrosis in CF but no models have
investigated the link directly.
A final area of consideration for multi-scale model-
ing in the lung is the inhalation of substances,
whether they are small molecules for treatment or
harmful particles. Modeling of fibrosis after exposure
to harmful particles, such as tobacco smoke or air
pollutants, was performed by Brown et al. found that
the percentage of exposure time could be used to
break up the fibrosis into three distinct states: self-
resolving, localized damage and persistent damage.
The persistent damage stage was marked by a
steep increase in macrophages, collagen deposition
and fibroblast fluctuation. The primary agents in the
model were particulate matter, macrophages and
fibroblasts which could react to TNF-a and TGF-b
distributions along the patches by either secreting
more cytokines or laying down collagen. This was
an interesting model of lung fibrosis that simulated
similar cellular and molecular processes as the mod-
els discussed previously [77]. For further reading on
10
computational models of aerosol deposition in the
lungs, please refer to the review by Rostami et al.
[78]. Overall, these models and others [79,80] pro-
vide valuable insight on techniques for incorporating
lung mechanics at the macroscopic level as well as
signaling pathways at the microscopic level that can
aid in future development of computational models
of lung fibrosis.
Multi-scale modeling of fibrosis in other organ
systems
Just as computational and mathematical models
of lung diseases in addition to fibrosis can provide
both computational, mathematical and biological
insight examining published models of fibrotic dis-
ease in other organs (beyond the lung) can also pro-
vide valuable information. For example, extensive
modeling has been done on cardiac fibroblasts and
the formation of fibrosis in the heart [81]. One recent
study focusing on cardiac fibroblast signaling com-
bined a logic-based differential equation (LDE)
model of intracellular signaling cascades in fibro-
blasts with an ABM of multi-cellular remodeling by
fibroblasts to study the formation of fibrosis tempo-
rally and spatially. The extensive molecular scale
model contained 10 signaling pathways with 11 bio-
chemical or mechanical cues in a 91-node network
connected by 142 reactions. These signaling cas-
cades led to the activation of myofibroblasts causing
ECM remodeling. This was coupled with an ABM
where each fibroblast agent was exposed to differ-
ent environmental cues including collagen and
inflammatory cytokines. At each one-hour time step
the ABM inputted extracellular cues into the LDE
model which in turn signaled for the agent to secrete
latent TGFb, IL-6, deposit collagen and migrate.
Authors found that collagen deposition correlated to
changes with parameters affecting production, acti-
vation and degradation of TGFb as it affects mRNA
activity downstream that lead to collagen I and II
deposition. The study validated experimental results
by demonstrating the antagonist effect of IL-1b on
TGFb- induced collagen I mRNA. Another intriguing
result was that the collagen profile was affected by
the speed of migration of the fibroblasts, with slower
speeds resulting in more heterogenous profiles than
faster migration speeds. However, the overall colla-
gen content was dependent only on fibroblast den-
sity. This model exemplifies how connecting across
molecular and cellular scales can provide significant
insights into fibrosis [82].
The hierarchical structure of muscles from actin-
myosin bridges to muscle fiber bundles has made it
an attractive subject for multi-scale modeling. In their
paper from 2015 Virgilio et al. used a combined
agent-based and finite element model to identify
how microstructural changes as a result of Duch-
enne Muscular Dystrophy (DMD) affect stress in cell
Multi-scale models of lung fibrosis
membranes and muscle integrity and mechanics.
The agent-based model generated randomized
muscle fascicle cross-sections whose initial condi-
tions, including density of transmembrane proteins,
variation of fiber cross-sectional area and pseudohy-
pertrophy, contributed to fibrosis formation and fat
infiltration into the muscle. In order to use this geom-
etry in the finite element model it was mapped to an
initialized finite-element mesh and smoothed. For
the constitutive model the authors assumed the
muscle fibers, ECM and boundary layer to all be
transversely isotropic, nearly incompressible, and
hyper-elastic. This model serves as an excellent
example of how many layers of interaction multi-
scale modeling can potentially combine, spanning
from transmembrane proteins to an overall muscle
cross section, and what connections can be eluci-
dated with a more complete snapshot of these inter-
actions. Results showed that the nature of fibrosis
and density of transmembrane proteins affected the
overall stiffness of the muscle and its sensitivity to
membrane damage [83].
Computational modeling has been used exten-
sively to study the liver from large-scale models of
metabolism [84] to identifying correlations between
genetic markers and fibrosis progression [14]. One
multi-scale agent-based model evaluated how fibro-
sis progressed into cirrhosis in the liver after toxic
injury and the effects of two possible treatments on
progression. Interactions between live and dead
hepatocytes, inflammatory cells, structural elements
and collagen-producing cells such as fibroblasts led
to the secretion of diffusible factors that further prop-
agate a fibrotic response and force some agents
exert on one another. CCl4 was the toxic agent used
to induce hepatocyte apoptosis and the cascade of
downstream events including phagocytosis of dead
hepatocytes by Kupffer cells. In addition to modeling
the progression of fibrosis the authors tested two
potential therapies, anti-TNF-a and enhancement of
Kupffer cells expressing M2 phenotype. Anti-TNF-a
treatment successfully lowered activation of fibrotic
cells, however, an M2 phenotype shift had the oppo-
site effect and worsened fibrosis. These results
accurately reflected what had been found in previ-
ous experiments demonstrating that the model was
robust [15].
Overall, there has been great progress toward
developing multi-scale models of fibrotic diseases in
other organs and lung function in different diseases
which can help aid our design process in creating
new multi-scale models of lung fibrotic disease. As
we have demonstrated it is crucial to consider
modeling different spatial and temporal scales, from
microscopic signaling pathways to large scale finite
element models, as the more holistic the model is
able to recapitulate disease, the better it can guide
future modeling and experimentation. Fig. 3 organ-
izes the current literature in the field of lung fibrotic
Multi-scale models of lung fibrosis
disease modeling and the areas from which this field
can draw to further accelerate discovery. There are
many models that do not address fibrosis [85
90] or
utilize multi-scale techniques [91
94] that were not
discussed in the present review but still offer insight
to the field.
Challenges to studying lung fibrosis and
opportunities for computational and
mathematical modeling to help
overcome them
Researchers in the field of lung fibrosis are faced
with a number of challenges stemming from the fact
that fibrosis is a complex, multi-cell process that
involves dynamic interactions between different cell
types and biochemical and mechanical cues in the
environment that are spatially heterogeneous. More-
over, experimental models tend to fall short of accu-
rately representing all aspects of disease. For
example, standard cell culture models oversimplify
the micro-anatomical organization of cells and lack
the diversity of cell types (e.g., epithelial, endothelial,
mesenchymal, and inflammatory and immune cells
[46,95]) and the dynamic interplay between them
that is present in vivo. While lung organoids devel-
oped from stem cells, lung on a chip platforms and
other 3-D culture types are gaining traction as more
sophisticated in vitro experimental model systems,
carrying out longer-term mechanistic studies with
these models systems are prohibitive [96-98]. In
vivo models may more authentically recapitulate the
more complex disease state during injury and
inflammation; however, murine models are often
self-resolving and fail to develop honeycomb cysts
and fibroblastic foci that are characteristic of human
IPF, for example [99,100].
Despite these limitations in the experimental
model systems, the field of lung fibrosis is rapidly
expanding and evolving. But, translation of under-
standing from the research bench to the clinic (and
back) remains a challenge because the clinical pre-
sentation of lung fibrotic disease progression is
highly variable from patient to patient (e.g. due to
genetic differences between patients), and attempts
to sub-classify IPF into different disease phenotypes
have been made to categorize different manifesta-
tions of pathology [101]. Bronchoalveolar lavage or
lung biopsy procedures were research goldmines
for determining potential pathogenic mechanisms
[24]. However advances in radiologic classification
of IPF have made it less likely that patients will be
subjected to these procedures. Recently there has
also been a push to determine reliable biomarkers
that can be measured non-invasively to corroborate
findings from CT scans [102].
11
The uncertainties, complexities, and limitations in
available experimental and clinical data create new
opportunities for discovery that can be accessed by
marrying computational and mathematical modeling
with experimental approaches. In particular, many of
the major unanswered questions in the field of fibro-
sis — and lung fibrosis, in particular — relate to the
fact that there is prevailing uncertainty about the
identification and definition of fibroblasts as a unique
cell population. Fibroblasts are broadly defined as
cells with a pronounced tissue remodeling pheno-
type, usually demarked by elevated amounts of
engaged integrins and secretion of ECM, as well as
a responsiveness to TGF-b. However, epithelial,
endothelial, perivascular, hematopoietic, and other
mesenchymal populations also demonstrate this
chemo-mechanical responsiveness and extracellu-
lar remodeling capacity that classically defines fibro-
blasts [103,104]. Moreover, there are few, if any,
reliable surface makers for fibroblasts (that can be
targeted in flow cytometry and immunohistochemis-
try with labeled-antibody, for example) that uniquely
label them [105]. And, the most widely used markers
for fibroblasts (smooth muscle alpha-actin, for exam-
ple) are often unreliable because their expression
levels vary widely with the phenotypic state of the
cell [106]. Indeed, the variety of cells which can take
on characteristics of fibroblasts, according to the
definition above, is driving intense study of fibroblast
heterogeneity, which uses new high-throughput
screening techniques to more fully characterize the
remarkably diverse populations of fibroblasts [107].
Moreover, the specific responsiveness of fibroblasts
to remodeling cues
their sensitivity to stiffness,
cytokines, and other local chemo-mechanical factors

has been found to vary greatly between and within
tissues, and heterogeneity can develop even within
clonal fibroblast populations in vitro. The variety of
outcomes in fibroproliferative diseases and the
diversity in their underlying etiologies likely has
much to do with these tissue- and site-specific heter-
ogeneities [108,109].
Computational modeling, however, is not without
its limitations and challenges. Defining the scope of
a computational or mathematical model remains a
major challenge in the field, as no model is able to
account for the copious amount of interactions that
happen at every physiological and temporal scale in
a biological system. More importantly, models are
not intended to be a reflection of reality but an
abstraction, similar to an in vitro experiment. Com-
puting power is another factor, as researchers must
balance creating biologically relevant models with
computational time required to run simulations. As a
result, biological questions being addressed drives
determination of both physical scale and time con-
straints of a model. Interactions deemed less essen-
tial are excluded from the model to prioritize those
most relevant to the model outcomes under question
12
[110]. Scope is also affected by the experimental
limitations in validating a model. When more varia-
bles are considered in a model, it becomes increas-
ingly difficult to isolate and validate each prediction
[111]. Data and software sharing also remain major
issues in a field with limited standardization of soft-
wares, dissemination of models and public sharing
of experimental data sets [112]. While less compli-
cated models are able to be run on personal com-
puters and laptops [5,82,113], more expansive and
complicated models require parallelization through
the use high performance computing [114], which
can be prohibitive for non-experts in the field to
engage with computational models. Sharing of mod-
els with domain experts and non-experts has
enabled by publicly available model sharing web-
based platforms, such as SimTK [https://simtk.org/]
and Git [https://git-scm.com/].
So, how can computational and mathematical
modeling help provide a more accurate and compre-
hensive understanding about fibroblast identity, phe-
notype, fate, and contribution to fibrotic disease in
the lung? We and others [65,113,115] have devel-
oped computational models, like agent-based mod-
els, that explicitly represent the phenotypic states of
individual cells within a heterogeneous population of
cells, and we have used these models to simulate
and record the transitions between phenotypic
states that are driven by internal and environmental
signals (e.g. accumulation of collagen or DAMPs in
the immediate neighborhood). These models have
allowed us to examine — and track individual (simu-
lated) cells within a population — a broader spec-
trum of fibroblast phenotypic identity than what can
be ascertained using experimental approaches,
which are reliant on fixed markers and stationary
analysis time points. Computational and mathemati-
cal models also provide the opportunity to precisely
control the simulated extracellular environment (e.g.
by simulating gradients of chemokines and growth
factors) to evaluate how environmental cues, and
combinations thereof, might drive resident cells into
a fibrotic program [82]. There is also opportunity to
combine data driven and mechanistic modeling by
allowing insights gained through data driven
approaches to directly impact the boundary condi-
tions or parameters for a mechanistic model. Clus-
tering analyses performed on RNASeq data
obtained from populations of fibroblasts harvested
from fibrotic lung, for example, may lead to the iden-
tification of subpopulations of fibroblasts which can
then be used to specify different types of fibroblast
agents in an agent-based model of IPF. By compar-
ing computational and mathematical model predic-
tions to experimental data, we can validate (or
invalidate) predictions and develop more informed
hypotheses about how changes in fibroblast pheno-
typic state contribute to fibrotic disease. These
computational and mathematical models can also
Multi-scale models of lung fibrosis
be used to test the effects of different drugs (and
drug doses) in a high-throughput and cost-efficient
manner, without having to run as many experiments.
Analyses of this type can reveal, for example, how
drugs could invoke subtle phenotypic shifts in sub-
populations of fibroblasts that might be undetectable
using current experimental measurement techni-
ques but are highly influential in disease progres-
sion.
Conclusions
This review summarizes published computational
and mathematical models that have been developed
in recent years to study different aspects and types
of lung fibrotic disease. We contend that some of the
insights that have been gained from these models
could not have been obtained through the use of
experimental approaches in isolation, although the
computational and mathematical models them-
selves are dependent (to various degrees) on the
use of experimental data to parameterize and vali-
date them. The use of computational and mathemat-
ical modeling to study fibrotic diseases in the lung
may slightly be lagging the use of computational and
mathematical modeling to study fibrosis beyond the
lung, in organs such as skeletal muscle, heart, and
liver. Hence, borrowing, sharing, and cross-validat-
ing computational tools and mathematical
approaches that have been developed to study
fibrosis in other organ systems may accelerate the
deployment of computational and mathematical
modeling in lung fibrosis. The process of lung fibro-
sis is complex, heterogeneous, and highly dynamic,
and these characteristics pose challenges to study-
ing and treating it clinically. By explicitly represent-
ing, through simulation, aspects of disease that are
particularly difficult to track and measure in real time
(like different fibroblast phenotypic states), computa-
tional and mathematical models provide the
research community with a way to more deeply and
thoroughly investigate the underlying drivers of lung
fibrosis in different disease states.
Acknowledgments
This research was supported by NIH grants: U01
HL-124052, Awarded to J.H.T.B., R01AI123093 and
U01 HL131072 awarded to D.E.K., HL144481
awarded to B.B.M., K23HL143135 awarded to C.A.
B., HL127283-05 awarded to T.H.B. Support from
UVA Pinn Scholars to S.M.P and the UVA Fibrosis
Initiative awarded to T.H.B. The authors would like
to thank Susan Leonard-Duke for her contributions
to Fig. 1.
Multi-scale models of lung fibrosis
Declaration of Competing Interest
The authors declare that there are no commercial
or financial relationships that could be construed as
a potential conflict of interest affecting the objectivity
of this review.
Received 5 February 2020;
Received in revised form 13 March 2020;
Accepted 15 April 2020
Keywords:
Lung fibrosis;
Multi-scale computational models;
Fibroblast
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