The Evidence and Molecular Mechanism

of Pulmonary Remodeling

Prof. Dr. Hening Laswati dr., Sp. KFR-K

Dr Soetomo General Academic Hospital,
Faculty of Medicine , Universitas Airlangga
Remodeling, is a pathological feature that contributes to the clinical manifestations of
the disease, for example :

1. Airway remodeling in Asthma (intra pulmonary remodeling)

Asthma is currently recognized as a chronic inflammatory disorder of the airways
that leads to tissue injury and subsequent structural changes collectively called
airway remodeling

2. Peripheral Muscle Fiber Remodeling in Patients With COPD

(extra pulmonary remodeling)
Skeletal muscle dysfunction is manifested by abnormal fiber type distribution,
reduced muscle fiber size, and diminished muscle capillarity and activity of oxidative
enzymes
The 3 R’s (repair –remodeling – regeneration) of lung homeostasis

In many cases of parenchymal lung

diseases both intrinsic and extrinsic
sources of injury combine in a “multiple
hit” process to produce resident cell
(epithelial or endothelial) dysfunction.

Local responses by affected cell

populations can preserve normal
homeostasis or repair, but, if these are
unsuccessful, resident cell death ensues,
and a decision either to regenerate
(restoring normal architecture and
physiology) or to remodel (producing the
resultant dysfunctional disease state) is
initiated

Vogiatzis et al, CHEST 2011; 140(3):744–752

The events in the pathogenesis of parenchymal lung disease and
injury can be divided into 3 basic phases

1. Initiation, resulting from intrinsic and/or extrinsic events to produce epithelial

dysfunction and damage
2. Amplification, mediated in part by the resulting inflammatory response;
3. Response stage, in which epithelial cells undergo decision to either repair
appropriately via activation of proliferative and differentiation programs and
regenerative pathways for proper repopulation of lost epithelial cells or
undergo inappropriate or aberrant remodeling, which might include excessive
apoptosis, epithelial-mesenchymal transition, or reprogramming to a defective
and dysfunctional state of differentiation which represent the final pathways
for many types of parenchymal pulmonary disease

Multiple microinjuries damage
and activate alveolar epithelial
cells
Repair via reepithelialization is attempted using either
local proliferation/transdifferentiation of AT2 cells
or regional expansion of progenitor cell populations
such as BASCs (regeneration).
ER stres
activating signals in AEC cells
release of chemokines/ cytokines,
migration of inflammatory
effector cells into the distal lung
In IPF, the local milieu (including high TGF-β and high VEGF levels) In emphysema, low VEGF and low TGF-β levels,
promotes proliferation of fibroblasts, activation of myofibroblasts, airspace enlargement takes place.
increases in basement membrane disruption, and neovascularization,
with resulting formation of a collagen scar.
Vogiatzis et al, CHEST 2011; 140(3):744–752
Airway remodeling in Asthma

Airway remodeling in asthma constitutes cellular and extracellular matrix changes in the
large and small airways, epithelial cell apoptosis, airway smooth muscle cell proliferation,
and fibroblast activation.

These pathological changes in the airway are orchestrated by crosstalk of different cell
types within the airway wall and submucosa

Airway remodeling may explain persistent airflow obstruction present in some

asthmatic patients, attributed to goblet cell hyperplasia, decreased epithelial cell and
cartilage integrity, sub-epithelial collagen deposition with increased thickness of the
reticular basement membrane, increased airway smooth muscle mass and angiogenesis
of the airways

Three integrated and dynamic processes in airway remodeling: (1) initiation by epithelial
cells; (2) amplification by immune cells; and (3) mesenchymal effector functions
Airway Epithelial Cells as “Initiators” of Airway Remodeling
Epithelial cells respond by secreting soluble factors that recruit, and activate
immune cells. The amplification of the immune response involves macrophages, Hough et al, Frontiers in Medicine May 2020/vol 7/article 191
dendritic cells, neutrophils, mast cells, eosinophils, and lymphocytes.

Immune Cells as “Amplifiers” of Airway Remodeling

Th2 cytokines, such as IL-4 and IL-13 enhance Mesenchymal Cells as “Effectors” of Airway Remodeling
subepithelial fibrosis, mucous hyperplasia, and
collagen deposition. TGF-β and FGFs secreted by the mesenchyme instruct the growth
Both the epithelium and immune cells produce
and differentiation of epithelial cells. Resident ASM cells and
paracrine signals that induce proliferation,
fibroblasts drive key cellular and structural features (increase in
expansion, and activation of the submucosal
ASM mass and subepithelial fibrosis). Submucosal resident
mesenchyme that include resident Airway smooth
fibroblasts that proliferate and differentiate into myofibroblasts
muscle cells and fibroblasts.
 Bronchoconstriction and bronchospasms

Compressive forces of epithelial cells

Mechanostimulation

Activate epithelial cells

to produce TGF-β

Recruited & activation immune system

Homer and Elias , Physiology 20: 28-35,2005

Facilitating the inflammatory process
 Peripheral Muscle Fiber Remodeling
Signal & stimuli that initiate the
muscle loss & wasting process : Intrinsic cellular processes:
1. Ubiquitin-proteasome pathway
1. Immobilization
2. Lysosomal-autophagy pathways
2. Malnutrition
3. Smoking 3. Anabolic suppression
4. Infections/exacerbations 4. Calcium desensitization
5. Hypoxemia 5. Muscle injury
6. Oxidative stress and
6. Hypercapnea
mitochondrial dysfunction
7. Corticosteroids

Skeletal muscle dysfunction

in COPD
Extrinsic processes
1. Hyperinflation-associated diaphragmatic
dysfunction
2. Bony thoracic remodeling
3. Lactate hyperproduction & lower exercise
tolerance
Pathophysiology of COPD-associated muscle dysfunction

Jaitovich and Barreiro, American Journal of Respiratory

And Critical Care Medicine vol 198, number 2, July 15 2018
Study Population
Forty-six clinically stable patients with COPD (42 men and 4 women) classified
by GOLD as stage II (n = 14), III (n = 18), and IV (n = 14)

Exercise Training Program

Similarly to our previous rehabilitation studies, patients were instructed to exercise
at an intensity that was initially equivalent to 80% and progressively to 100% of the
peak work rate (WRpeak) for 30 s alternated with 30 s of rest for a cumulative period
45 min/d, 3 d/wk for 10 consecutive weeks. Training intensity was increased on a
weekly basis
A significant relationship was found between distribution of
A signifi cant improvement in exercise tolerance in patients in all
muscle type I fiber and FEV 1 % predicted ( r 5 0.38, P 5 .009)
across patients with COPD of all three stages, as well as GOLD stages as indicated by the higher WRpeak and the greater
patients with COPD and the healthy age-matched group ( r 5 distance walked during the 6MWT compared with prerehabilitation
0.45, P 5 .001)

The capillary to fiber and capillary to CSA ratios significantly increased following rehabilitation
in patients with COPD with GOLD stages II to IV disease
Exercise training as the cornerstone for enhancing exercise capacity & QoL

improve muscle fiber morphologic & structural characteristics

improved muscle strength &endurance,
partially reverses the abnormal fiber type distribution,
increases the cross-sectional area (CSA) &
the activity of oxidative enzymes of the muscle fibers,
increases capillary density

Intermittent exercise improves muscle blood flow and oxygenation, reduces lactate
concentration & ventilatory demands, activates at the same proportion muscle fiber types I
and II, lower severity of exercise-induced leg fatigue and dyspnea,

Pulmonary rehabilitation should be implemented in patients at all COPD stages

Conclusions

• Airway remodeling may occur in parallel with chronic inflammation, and not simply
as a (serial) consequence of the inflammatory response, will be critical to
developing novel therapeutic strategies

• Advances in bioengineered materials should lead to further insights for lung repair
and regeneration
THANK YOU