Laboratory of Pulmonary Pathobiology, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina 27709
AIRWAY
REMODELING during chronic inflammatory disease processes such as
asthma and chronic obstructive pulmonary disease involves a variety of
morphological changes, including mucous cell metaplasia and airway
fibrosis. Over the past several years, an intense effort has been aimed
at elucidating the cellular and molecular mechanisms that contribute to
this complexity. Increasing evidence has revealed potentially important
roles for the epidermal growth factor receptor (EGFR) in mediating
several aspects of airway disease. In particular, the EGFR system has
been postulated to play important roles in the growth and
differentiation of epithelial and connective tissue cell types in the lung.
It is clear that EGFR and its ligands are elevated during the
pathogenesis of asthma, and induction of this system correlates with
goblet cell hyperplasia in the airways of asthmatics (1, 16). Therefore, understanding the mechanisms that regulate the EGFR and its ligands in mediating mucous hypersecretion by airway epithelial cells has become an active area of research in attempts to
understand airway remodeling in asthma. The role of EGFR and its
ligands in orchestrating epithelial growth, repair, and differentiation during airway remodeling is complex and involves 1) the
cleavage and release of membrane-bound EGFR ligands [transforming
growth factor- A seminal paper by Takeyama and coworkers (14) identified
the EGFR system as a regulatory axis for mucin production in airways. Before this work, it had been reported that neutrophils mediate goblet
cell degranulation, and this was associated with increased elastase
activity (13). Moreover, Voynow and coworkers
(18) demonstrated that neutrophil elastase increases the
mRNA stability of MUC5AC (a major respiratory mucin) and increased
production of MUC5AC glycoprotein. More recently, Fischer and Voynow
(4) reported that neutrophil elastase induces MUC5AC gene
expression in airway epithelium via the generation of ROS. Although
neutrophil elastase and ROS generated by neutrophils had been shown to
increase mucin production by airway epithelial cells, until now the
connection to EGFR signaling had not been established.
The study by Kohri et al., one of the current articles in focus (Ref.
6, see page L531 in this issue), makes an
important advance by connecting the concept of neutrophil
elastase-induced mucin production to EGFR activation. Using
NCI-H292 cells, they show that human neutrophil elastase-induced MUC5AC
production was preceded by EGFR tyrosine phosphorylation and was
inhibited by selective EGFR kinase inhibitors and by a neutralizing
antibody raised against TGF- Other cytokines that are upregulated during airway remodeling may also
exert their biological effects via the EGFR system. It is increasingly
recognized that interleukin-13 (IL-13), a Th2 cytokine, plays an
critical role in the pathogenesis of asthma, and recent reports have
linked IL-13-induced airway epithelial cell proliferation and mucin
production to EGFR activation. Booth et al. (2) reported
that IL-13 stimulates the release of TGF- Although the work by Kohri and colleagues (6) demonstrates
a role for TGF- Inhaled pollutants that cause airway inflammation and remodeling also
have the capacity to trigger EGFR phosphorylation through ligand-independent mechanisms. Ligand-independent receptor activation is a mechanism wherein exogenous stressors (e.g., ROS, metals) enter
the cells and bypass the extracellular, ligand-binding domain of the
EGFR to activate the intracellular domain of the receptor (19,
23). A variety of environmental agents that generate oxidative
stress can activate EGFR via ligand-independent activation, and this is
most likely achieved through inhibition of phosphatase activity
associated with the kinase domain of the EGFR. For example, metals
associated with air pollution particulates such a vanadium are potent
EGFR activators in bronchial epithelial cells and pulmonary myofibroblasts (19, 20, 22). Asbestos fibers stimulate
apoptosis of pleural mesothelial cells via EGFR activation
(21), and cigarette smoke induces mucin synthesis by
airway epithelial cells via activation of EGFR (17).
Collectively, these studies identify the EGFR as a common target of
pollutant-induced oxidative stress.
Fibrosis is another component of airway remodeling that involves
activation of the EGFR. In particular, the paracrine signaling between
epithelial cells and peribronchiolar myofibroblasts appears to be
important in mediating myofibroblast proliferation and subsequent collagen deposition. Zhang et al. (22) showed that human
bronchial epithelial cells exposed to metal-induced oxidative stress
release HB-EGF, and this EGFR ligand was found to be a major mitogen
for human lung myofibroblasts in culture. They also showed that HB-EGF induction by metal-induced oxidative stress is dependent on the phosphorylation of EGFR and downstream mitogen-activated protein kinases, indicating that EGFR activation plays a role in growth factor
expression. Animal models of fibrosis also support a role for the EGFR.
Rice et al. (11) reported that a tyrphostin inhibitor of
EGFR tyrosine kinase reduces metal-induced pulmonary fibrosis in rats.
Madtes and coworkers (8) reported that TGF- In summary, the EGFR system appears to play a central role in mediating
airway remodeling during diseases such as asthma and fibrosis. Some of
the recent studies summarized in this editorial focus underscore the
complex mechanisms wherein the EGFR is a central convergence point or
crossroad in cellular signaling that mediates mucous cell
hypersecretion by airway epithelial cells and the enhanced growth of
epithelial cells and myofibroblasts. It should be noted that, while
many studies implicate the EGFR in the pathobiology of airway disease,
it is also recognized that the EGFR may play an important role in
bronchial epithelial repair in diseases such as asthma
(10). New discoveries in other organ systems, such as the
discovery that prostaglandin E2 promotes colon cancer
growth through EGFR (9), should be investigated as
possible mechanisms of EGFR-mediated airway disease. Future research in
this exciting area should identify the balance between EGFR activation
in mediating airway repair versus aberrant EGFR activation that leads
to chronic airway inflammation and remodeling.
ARTICLE
TOP
ARTICLE
REFERENCES
(TGF-
), heparin-binding epidermal growth factor
(HB-EGF)] from the cell membrane by a variety of endogenous
mediators that activate metalloproteinases, 2) inflammatory
cytokines [e.g., tumor necrosis factor (TNF)-
] produced by
leukocytes that have the potential to induce EGFR expression, and
3) the ligand-independent activation of EGFR by reactive
oxygen species (ROS) generated by leukocytes or by inhaled pollutants.
. Moreover, they show that neutrophil
elastase treatment depleted pro-TGF-
and increased TGF-
in cell
culture supernatant. Thus their findings show that neutrophil elastase triggers cleavage of membrane-tethered TGF-
to bind and
phosphorylate EGFR in an autocrine manner, resulting in downstream
signaling pathways that culminate in the expression of MUC5AC. Although this is potentially an important mechanism for increasing mucin hypersecretion in airways, it should be mentioned that the NCI-H292 cells are a human pulmonary mucoepidermoid carcinoma cell line. It
would be important to know whether or not normal human bronchial epithelial cells, maintained in air-liquid interface cultures to
promote mucociliary differentiation (5), would respond to neutrophil elastase via the same mechanism as described for NCI-H292. It is also noteworthy that paracrine signaling involving TGF-
released from other cell types could also be important in driving MUC5AC expression and mucin production by airway epithelial cells. For
example, eosinophils are a predominant inflammatory cell in asthma, and
activated eosinophils release mature TGF-
(3).
from the membranes of
human bronchial epithelial cells, which then binds to the EGFR and
initiates proliferation. Shim et al. (12) demonstrated
that intratracheal instillation of IL-13 into the lungs of rats causes
goblet cell metaplasia and increases mucin production via a complex
mechanism wherein IL-13 induces the production of IL-8, thereby causing
neutrophil recruitment. In that study, the authors proposed that
TNF-
secreted by recruited neutrophils induces EGFR expression in
the airway epithelium. Finally, they proposed that the release of
oxygen free radicals by neutrophils contributes to EGFR phosphorylation
via a ligand-independent receptor activation mechanism (12,
15).
in neutrophil elastase-mediated mucin production, a
novel mechanism for increasing MUC2 expression and mucin production by
human airway epithelial cell lines was reported by Lemjabbar and
Basbaum (7) that involves cleavage of HB-EGF in response to lipoteichoic acid (LTA), a bacterial cell wall component of the
gram-positive bacteria Staphylococcus aureus. LTA was shown to bind the platelet-activating factor receptor (PAFR), and PAFR transduced the signal to EGFR via a metalloproteinase
(ADAM10)-dependent proteolysis of transmembrane HB-EGF. This research
emphasized clear differences between EGFR-dependent gram-positive
bacterial responses and EGFR-independent gram-negative bacterial
responses. Lipopolysaccharide (LPS) from gram-negative bacteria has
been reported to bind and activate the Toll-like receptor (TLR) 4 via a
mechanism that does not involve the EGFR (7). However,
signaling by EGFR activation in response to LTA and TLR4 activation
driven by LPS converge at the level of Ras to mediate downstream
activation of nuclear factor-
B, which then turns on the
transcription of MUC2. This work provided an important step for future
treatment strategies of antibiotic-resistant strains of S. aureus and suggested that the PAFR-ADAM10-EGFR axis should be
targeted to block S. aureus infections.
null mice
are resistant to bleomycin-induced pulmonary fibrosis. Collectively, these studies indicate that both HB-EGF and TGF-
contribute to pulmonary fibrosis by serving as mitogens for myofibroblasts.
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FOOTNOTES |
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Address for reprint requests and other correspondence: J. C. Bonner, Laboratory of Pulmonary Pathobiology, National Inst. of Environmental Health Sciences, NIH, Research Triangle Park, NC 27709 (E-mail: bonnerj{at}niehs.nih.gov).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
10.1152/ajplung.00126.2002
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