INVITED REVIEW
Keratinocyte and hepatocyte growth factors in the lung: roles
in lung development, inflammation, and repair
Lorraine B.
Ware1 and
Michael A.
Matthay2
1 Division of Pulmonary and Critical Care,
Department of Medicine, University of California, Los Angeles
90024; and 2 Cardiovascular Research Institute,
University of California, San Francisco, California 94143
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ABSTRACT |
A growing body of evidence indicates that
the epithelial-specific growth factors keratinocyte growth factor
(KGF), fibroblast growth factor (FGF)-10, and hepatocyte growth factor
(HGF) play important roles in lung development, lung inflammation, and
repair. The therapeutic potential of these growth factors in lung
disease has yet to be fully explored. KGF has been best studied and has impressive protective effects against a wide variety of injurious stimuli when given as a pretreatment in animal models. Whether this
protective effect could translate to a treatment effect in humans with
acute lung injury needs to be investigated. FGF-10 and HGF may also
have therapeutic potential, but more extensive studies in animal models
are needed. Because HGF lacks true epithelial specificity, it may have
less potential than KGF and FGF-10 as a targeted therapy to facilitate
lung epithelial repair. Regardless of their therapeutic potential,
studies of the unique roles played by these growth factors in the
pathogenesis and the resolution of acute lung injury and other lung
diseases will continue to enhance our understanding of the complex
pathophysiology of inflammation and repair in the lung.
acute lung injury; acute respiratory distress syndrome; epithelial
growth factor
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INTRODUCTION |
SINCE THE DISCOVERY AND
CHARACTERIZATION of the epithelial-specific growth factors
keratinocyte growth factor (KGF) and hepatocyte growth factor (HGF),
their roles in lung development, lung inflammation, and repair have
been widely investigated. Over the past 10 yr, it has become
increasingly clear that KGF and HGF play important roles in both the
normal and the injured lung and ultimately may have therapeutic
potential in lung disease. This review presents a brief history of the
discovery and physical properties of KGF and HGF and then focuses on
current knowledge of the biological effects of KGF and HGF in lung
development and in the injured lung. Fibroblast growth factor-10
(FGF-10), a recently discovered epithelial growth factor with
structural and functional similarities to KGF, will also be discussed.
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KGF |
Background and Basic Properties
Interest in identifying epithelial-specific growth factors that
might be oncogenic led to the isolation of KGF from a human embryonic
lung fibroblast line by Rubin et al. (104) in 1989. The
factor was termed keratinocyte growth factor because of its potent
mitogenic activity on mouse epidermal keratinocytes. Subsequent studies
showed that KGF is a member of the FGF family (and is also designated
FGF-7) and, like other members of the family, has heparin-binding
capability (35, 150). Unlike other members of the FGF
family, KGF has epithelial specificity; KGF is expressed predominantly
by mesenchymal cells, and its receptor (KGF receptor; KGFR) is
expressed only in epithelial cells. This epithelial specificity suggests that KGF may play an important role in mesothelial-epithelial interactions (27).
Attempts to find new FGFs with sequence homology to KGF and other FGFs
led to the discovery of FGF-10 in 1996 (157). Initial studies indicated that its sequence had significant homology to KGF and
that it was expressed preferentially in the lung of adult rats and rat
embryos (157). Like KGF, human FGF-10 is mitogenic for
keratinocytes but not fibroblasts (32) and is highly
induced in the skin after wounding (125). This similarity
to KGF has led some researchers to label it KGF-2. However, in this
review it will be referred to as FGF-10.
A comparison of the basic properties and receptor specificity of
KGF and FGF-10 is shown in Table
1. Unlike other members of the
FGF family that bind to a variety of FGF receptors, KGF binds only to a
splice variant of FGF receptor (FGFR)2 termed FGFR2-IIIb or KGFR
(46). Like KGF, FGF-10 binds with high affinity to
FGFR2-IIIb but has also been shown to have a weaker affinity for
FGFR1-IIIb (8, 53, 55). These receptors are expressed only
in epithelial tissues, thus conferring the unique paracrine epithelial
specificity of these growth factors. KGF also interacts with
low-affinity cell surface heparan sulfate proteoglycan receptors (16). This interaction has a potentiating effect on the
interaction of KGF with KGFR (50). Heparan sulfate
proteoglycan may also bind to the KGFR, further modulating the KGF-KGFR
interaction (50). The interaction of FGF-10 with cell
surface heparan sulfate proteoglycan has not been as well studied but
is likely similar. FGF-10 does have fourfold higher affinity for
pericellular matrix heparan sulfate than KGF (53).
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Table 1.
Comparison of the properties of keratinocyte growth factor, fibroblast
growth factor-10, and hepatocyte growth factor
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Role of KGF in the Developing Lung
A role for KGF in lung development was first suggested when it was
reported that FGFR2 is expressed in the epithelial cells of the
developing lung (97). Targeting a dominant negative FGFR2 to the lung led to the total absence of lung development
(96). KGF is expressed in mesenchymal cells of the
developing lung and other organs (63). Overexpression of
KGF in the mouse lung epithelium either constitutively
(116) or conditionally (130) caused embryonic pulmonary malformation with histological similarities to pulmonary cystadenoma (Fig. 1). Embryonic lungs had
dilated saccules lined with columnar epithelial cells and no normal
alveolar architecture, and the embryos died before reaching term.
Studies in explanted rat lungs have provided further evidence for the
importance of KGF in lung morphogenesis. Both the addition of exogenous
KGF (114) and blocking KGF or KGFR expression using
antisense oligonucleotides (100) disrupt normal
branching morphogenesis in fetal rat lung explants. The effects of KGF
in lung development depend on the stage of gestation. When KGF was
expressed in the mouse liver late in gestation using an apolipoprotein
E promoter, the predominant effect in the lung was type II cell and
bronchiolar cell hyperplasia rather than pulmonary malformation
(83). Interestingly, although these studies suggest a role
for KGF in normal lung morphogenesis, KGF null mice had histologically
normal lung development and survival (41).

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Fig. 1.
Effect of targeted
overexpression of human (h) keratinocyte growth factor (KGF) in the
murine lung using a surfactant protein C (SP-C) promoter. Comparison of
pulmonary development pattern and pulmonary epithelial proliferation
and morphology in a normal mouse at gestational day 16.5 (E16.5; A, C, and E) compared with a
littermate SP-C-hKGF transgenic embryo (B, D, and
F). A: photomicrograph of a saggital section
showing lungs of a normal E16.5 mouse. B: photomicrograph of
a saggital section showing lungs of an E16.5 SP-C-hKGF transgenic mouse
lung. C: staining of lungs from A for Ki-67, an
endogenous marker of cell proliferation. D: Ki-67 staining
of lungs from B. Arrows in C and D
point to proliferating cells staining positive for Ki-67 expression.
E: higher powered photomicrograph of a distal epithelial
airway from A. Note the cuboidal shape characteristic of the
distal airway epithelium in normal embryonic mouse lung. F:
higher powered micrograph of the epithelial cells lining the large
dilated saccules in B. Note the more columnar appearance of
the epithelial cells, characteristic of more primordial or immature
bronchial epithelium. Sections were stained with hematoxylin and eosin.
Bar = 500 µm for A and B; 100 µm for
C and D; and 25 µm for E and
F. [From Simonet et al.
(116).]
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The lack of an effect of the KGF null mutation can now be partially
explained by the discovery that FGF-10 also binds to KGFR and is an
important mediator of branching morphogenesis in the developing lung.
FGF-10 is highly expressed at the sites where distal buds will appear
in the embryonic mouse lung (9) and acts as
chemoattractant for epithelial lung buds in concert with KGF
(95). FGF-10 null mice have striking abnormalities,
including total absence of lung development below the trachea, no limb
bud initiation, and other organ abnormalities including a lack of thyroid, pituitary, or salivary glands and malformation of the teeth,
kidneys, hair follicle, and gut (73, 86). Thus KGF and
FGF-10 have complementary and overlapping roles in the regulation of
branching morphogenesis in the lung in concert with several other
growth factors and signaling molecules (51, 146).
In addition to its role in lung morphogenesis, KGF has important
effects on epithelial differentiation in the developing lung. In
isolated rat fetal lung epithelial cells, type II cell maturation and
surfactant synthesis appear to be under the control of
mesothelial-epithelial interactions. Chelly et al. (25)
recently reported that at least one-half of the stimulation of
surfactant synthesis by fibroblast-conditioned media in isolated rat
fetal lung epithelium could be abrogated by a KGF-neutralizing
antibody. Administration of KGF to fetal rat type II cells led to
increased synthesis of all surfactant components including disaturated
phosphatidylcholine and surfactant proteins A, B, and C
(26). Similar findings have been reported in a
mesenchyme-free lung epithelial culture system where KGF administration
promoted distal epithelial differentiation and surfactant protein
expression (21, 28). In vivo, intratracheal, intravascular, or intramuscular KGF administration to preterm rabbits
significantly increased lung-tissue saturated phosphatidylcholine (47).
Glucocorticoid effects in the fetal lung may also be mediated by KGF.
Administration of dexamethasone, known to enhance fetal type II cell
maturation and surfactant synthesis, was accompanied by a 50% increase
in KGF mRNA in fetal lung fibroblasts (25). In fetal lung
explants cultured with dexamethasone, an increase in KGF and KGFR
expression was measured along with increases in surfactant protein
expression and mature type II cell phenotype (88).
Both KGF and FGF-10 also play an important role in fetal lung fluid
secretion, a process that is closely linked to lung morphogenesis. The
fetal airway and alveoli actively secrete fluid, and normal lung
development is dependent on this process (12).
Experimental studies indicate that active chloride secretion is the
driving force for fetal lung fluid secretion (49, 70, 84)
and that the fetal mesenchyme can produce soluble factors that alter
fetal lung distal epithelial ion transport (98). In fetal
mouse lung explants, administration of KGF led to increased fluid
secretion that was independent of cystic fibrosis transmembrane
conductance regulator (CFTR) and could be inhibited by ouabain and
bumetanide (165). Similar findings have been reported in
the human fetal lung for both KGF and FGF-10 (38). Thus
both KGF and FGF-10 appear to enhance CFTR-independent fluid
accumulation in the fetal lung. A candidate chloride channel for this
effect is CLC-2, a fetal lung epithelial chloride channel that exhibits
increased expression on the apical surface of the respiratory
epithelium after KGF administration (11). KGF also
inhibited expression of the
-subunit of the epithelial sodium
channel (ENaC) in fetal mouse lung explants, suggesting that KGF may
inhibit sodium absorption in the fetal lung in addition to its effects
on chloride secretion (165).
Effects of KGF in the Injured Lung
Endogenous KGF.
The role of endogenous KGF in acute lung injury has not been well
studied. However, it seems likely, on the basis of the key role that
endogenous KGF has been shown to play in wound healing in the skin
(60, 152), that endogenous KGF plays an important role in
epithelial repair in the lung as well. In neonatal rabbits exposed to
hyperoxia, KGF mRNA expression was increased 12-fold in whole lung
homogenates at 6 days compared with controls (22). This
rise in KGF mRNA was followed, at 8-12 days, by an increase in
type II cell proliferation, suggesting that increased expression of KGF
led to alveolar epithelial type II cell hyperplasia in response to
hyperoxic injury. In a rat model of increased permeability pulmonary
edema due to exposure to
-naphthylthiourea (ANTU), pretreatment with
a small dose of ANTU leads to resistance to pulmonary edema when a
larger dose is administered. Barton et al. (6) showed that
a single low dose of ANTU in rats caused an upregulation of KGF gene
transcription in the lung, suggesting that KGF-induced hyperplasia
might underlie the induced resistance to ANTU. Finally, in rats with
acute lung injury due to bleomycin injection, KGF levels in
bronchoalveolar lavage (BAL) increased markedly after injury, peaking
at 7-14 days, coincident with peak type II cell proliferation
(1). Thus in several different injury models, the
available evidence indicates that KGF expression is increased after
acute lung injury and may be an important endogenous stimulus for
alveolar epithelial proliferation and repair. Results from clinical
studies are discussed below.
The molecular mechanisms that upregulate the expression of KGF in the
setting of lung injury have not been well studied. On the basis of in
vitro studies of nonpulmonary fibroblasts, a variety of proinflammatory
cytokines have been shown to upregulate KGF mRNA expression and protein
translation, although the effects depend on culture conditions and cell
lines studied. Proinflammatory cytokines that have a stimulatory effect
on KGF expression include interleukin (IL)-1
(24, 128)
and -1
(17, 24, 128), tumor necrosis factor-
(17, 128), IL-6 (17, 24), transforming growth
factor-
(TGF-
) (24), and platelet-derived growth
factor-BB (PDGF-BB) (24). Whether lung fibroblasts in vivo
also upregulate KGF expression in response to the proinflammatory
cytokines present in early acute lung injury should be investigated.
Interestingly, in vitro administration of dexamethasone downregulated
both constitutive dermal fibroblast expression of KGF (23)
and cytokine-stimulated KGF expression (23, 128).
Furthermore, glucocorticoid-treated mice had a markedly reduced
induction of KGF mRNA after skin injury, despite high levels of serum
growth factors and proinflammatory cytokines (18).
Although observed in models of skin injury, these findings are of
potential interest in the lung because clinical administration of
glucocorticoids early in acute lung injury was not beneficial
(10).
Exogenous KGF.
The protective effect of exogenous KGF in a model of acute lung injury
was first reported in 1995 by Panos et al. (90). In that
study, rats pretreated intratracheally with 5 mg/kg of recombinant
human KGF had far better survival and virtually no histological changes
when exposed to 120 h of hyperoxia compared with untreated
animals. Intratracheal KGF has since been shown to have a protective
effect in a variety of other lung injury models (Table
2). For example, in an acid instillation
model (160), pretreatment with intratracheal KGF 72 h
before intratracheal acid instillation reduced mortality,
histological changes, inflammatory cell influx, procollagen mRNA
levels, and hydroxyproline accumulation (Fig.
2). In an ANTU model of increased
permeability pulmonary edema (39, 62), pretreatment with
KGF reduced alveolar-capillary barrier permeability and pulmonary edema
formation. Similar beneficial effects on vascular permeability and
pulmonary edema formation have been reported in a rat model of
ventilator-induced lung injury (149). Intratracheal KGF
has also been shown to ameliorate radiation pneumonitis
(163), bleomycin-induced lung injury (122, 162, 163), lung injury from bleomycin and radiation (Fig.
3) (163), and
Pseudomonas aeruginosa pneumonia (138),
when given before the insult. Recently, intravenous KGF (5 mg/kg) has
also been shown to protect against bleomycin- and hyperoxia-induced
lung injury in mice (40), even though it stimulated less
alveolar epithelial proliferation than intratracheal KGF. Finally,
subcutaneous administration of KGF in mice ameliorates graft-vs.-host
disease (94) and idiopathic pneumonia syndrome
(93) in allogeneic bone marrow transplant models.

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Fig. 2.
Representative photomicrographs of left lung tissue 7 days after
unilateral HCl instillation. HCl (0.1 N, 0.5 ml) was instilled
intrabronchially into the rat left lung. Left intrabronchial
instillation of KGF (5 mg/kg, 0.5 ml) at 72 h (KGF 72 h/HCl) or
saline (0.5 ml) at 72 h (Saline 72 h/HCl) was completed before HCl
treatment. Microscopic lung injury after the saline 72 h/HCl treatment
varied from severe injury consisting of consolidation,
hemorrhage, inflammatory cell infiltration, fibroblast proliferation,
and obliteration of alveolar architecture (a) to
moderate injury consisting of focal areas of inflammatory cell
infiltration and fibroblast proliferation (b). Pretreatment
with KGF at 72 h before HCl instillation (KGF 72 h/HCl) completely
prevented microscopic lung injury (c) or resulted in only
mild focal areas of inflammatory cell recruitment and cell
proliferation (d). Bar = 40 µm. [From Yano et al.
(160).]
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Fig. 3.
High magnification view of lung
injury caused by the combination of bilateral thoracic radiation (18 Gy) and intratracheal instillation of bleomycin (1.5 U) shows that the
intact pulmonary architecture in KGF-pretreated rats (5 mg/kg
intratracheal) contrasted with the architectural disorganization and
hemorrhage in the lung of a saline-pretreated rat. [From Yi et al.
(163).]
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Several important observations can be made from a comparison of these
studies of KGF in lung injury models. First, KGF was protective for a
wide variety of mechanisms of lung injury, including direct epithelial
injury (e.g., acid aspiration), direct endothelial injury (e.g., ANTU),
and T cell-mediated injury (graft-vs.-host disease). Second, the
beneficial effects of KGF were apparent on multiple levels from
cellular to whole animal. These beneficial effects included reduced or
absent histological changes, decreased fibrosis and deposition of
collagen precursors, reduced physiological indices of lung injury
including vascular permeability and formation of pulmonary edema, and
improved survival. Third, in all studies, pretreatment with KGF was
necessary for the protective effect. Simultaneous or posttreatment was
not efficacious. These observations suggest that the mechanisms by
which KGF exerts its protective effects on lung injury are probably
multiple, not immediate, and affect multiple cell types within the
lung. Putative mechanisms are summarized in Table
3 and will be discussed below.
Mechanisms of protection in acute lung injury.
KGF has a wide variety of effects on lung epithelial cells that may
mediate its protective effect in acute lung injury. One of the earliest
observations was that both in vivo and in vitro administration of KGF
cause alveolar epithelial type II cell proliferation (Fig.
4) (34, 92, 136). In vivo,
intratracheal administration in rats stimulates reproducible type II
cell hyperplasia that peaks at 2-3 days. Proliferation of type II
cells is accompanied by migration to cover the alveolar epithelial
barrier with type II cells, a process that histologically resembles
reactive type II hyperplasia seen in human lungs after an injurious
stimulus (3). Bronchial epithelial hyperplasia also occurs
in response to KGF, both in vitro (72) and in vivo
(72, 136). A similar response to intratracheal KGF has
been observed in mice (40, 57). By 7 days after a single
intratracheal administration of KGF, the lung parenchyma returns to
normal, a process that is mediated by both apoptosis and
differentiation to type I cells (33, 34). In this model,
type II cell proliferation is accompanied by increased expression of
surfactant proteins A, B, and D. Increases in surfactant protein
secretion could have several beneficial effects in lung injury,
including prevention of alveolar collapse by reduction of alveolar
surface tension and augmentation of host defense. However, whereas in
vitro KGF administration enhances surfactant protein expression on a
per cell basis (112, 124), in vivo KGF administration
enhances surfactant protein expression only on a whole lung basis.
Individual type II cell levels of surfactant protein expression are
decreased (161). The differential effect of KGF in vitro
compared with in vivo probably has multiple explanations, including
relative differences in dose and duration of exposure to KGF as well as
complex environmental influences in vivo that are not present in a
simple in vitro system. When KGF expression is increased via
adenovirus-mediated gene transfer either in vitro in rat type II cells
or in vivo, similar findings of type II cell hyperplasia and increased
surfactant proteins A and D production have been reported
(78).

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Fig. 4.
Schematic diagram shows the progression of type II
pneumocyte hyperplasia in the lung after a single intratracheal
injection of KGF (5 mg/kg). [From Ulich et al. (136).]
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One of the histological hallmarks of acute lung injury is
sloughing and necrosis of the alveolar epithelium (2, 3). In addition to type II cell proliferation, regeneration of a normal alveolar epithelium requires migration of type II cells along the
denuded basement membrane to reconstitute an intact epithelium (143). KGF enhances the spreading and motility of alveolar
epithelial type II cells, suggesting that improved alveolar repair may
underlie some of the protective effects of KGF in lung injury. The
beneficial effects of KGF on wound closure were first observed in the
skin (120, 151, 152), bladder (7), gastric
epithelium (126), and cornea (119). In the
lung, KGF enhances wound closure during cyclic mechanical strain in
bronchial epithelial monolayers through enhanced cell spreading and
motility (144). KGF also enhances the alveolar epithelial
repair activity of rat alveolar epithelial type II cells when
administered in vivo (141) or in vitro (M.-P. d'Ortho,
unpublished observations). Altered migration and wound repair in
KGF-treated epithelial cells may, in part, be a function of altered
interaction with the extracellular matrix through increased expression
of matrix metalloproteinases (MMPs) and urokinase-type plasminogen
activator (UPA). These effects have not yet been studied in lung
epithelial cells. In cultured human keratinocytes, KGF increased cell
migration, UPA activity (108, 132), and MMP-10 (stromelysin-2) activity (58). In porcine periodontal
ligament epithelial cells, KGF increased both MMP-13 (collagenase-3)
activity (135), MMP-9 (gelatinase) activity, and UPA
activity (101).
In addition to enhancing epithelial repair after a mechanical injury,
KGF renders epithelial cells more resistant to mechanical injury.
KGF-treated alveolar epithelial cells are inherently more resistant to
injury from mechanical deformation (Fig.
5) (89), a factor that may
contribute to KGF's protective effects in ventilator-induced lung
injury (149). KGF also renders airway epithelial cells
more resistant to both hydrogen peroxide- (145) and
radiation-induced increases in cell permeability (109).
Interestingly, in both of these in vitro studies, the protective effect
was not limited strictly to pretreatment. In the radiation model, KGF
was partially protective when given immediately after radiation
(109). In the hydrogen peroxide model, as little as 1 h of pretreatment with KGF was partially protective, suggesting that at
least some of the KGF effects were posttranslational
(145). In both these studies, KGF's protective effects
were associated with stabilization of the F-actin cytoskeleton and
could be inhibited by blocking protein kinase C. KGF also renders
alveolar epithelial cells more resistant to cell necrosis induced by in
vitro mechanical deformation (89). In that study, KGF
treatment accelerated the in vitro transition from type II phenotype to
type I phenotype, a transition that may have conferred resistance to
mechanical deformation; changes in the actin cytoskeleton and the
secretion of extracellular matrix may have also played a role in that
model.

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Fig. 5.
Enhanced viability after
application of mechanical strain in KGF-treated rat alveolar epithelial
cells. Rats were given KGF (5 mg/kg intratracheal) 48 h before
isolation of alveolar epithelial type II cells. Cytoplasm of viable
cells was stained using calcein-AM (indicated in green), and nuclei of
nonviable cells were stained using ethidium homodimer-1 (indicated in
red). A: saline vehicle-treated unstretched cells.
B: saline vehicle-treated cells after 1 h of cyclic
stretch (25% change in surface area). C: KGF-treated
unstretched cells. D: KGF-treated cells after same 1-h
stretch protocol. [From Oswari et al.
(89).]
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KGF also has effects on alveolar epithelial fluid transport in the
adult lung. Unlike the fetal lung, which is a net secretor of fluid,
the adult lung actively removes fluid from the alveolar space to
maintain the gas exchange interface. Alveolar epithelial fluid
transport is driven primarily by the active transport of sodium across
the alveolar epithelial barrier by alveolar epithelial type II cells
(68). The ability to clear fluid from the alveolar space
is critically important to the resolution of pulmonary edema and to the
restoration of adequate gas exchange in the setting of acute lung
injury (142). Furthermore, in both animal models of acute
lung injury and clinical acute lung injury, alveolar fluid clearance is
impaired (69, 76, 77, 142). KGF has been shown to increase
alveolar epithelial fluid transport in both in vitro and in vivo
studies in both the uninjured and the injured lung. In primary isolates
of rat alveolar epithelial cells, addition of KGF enhanced active ion
transport across monolayers primarily due to increased Na-K-ATPase
1-subunit expression (13). In the normal
rat lung, intratracheal pretreatment with KGF increased alveolar
epithelial fluid transport both in vivo (140) and in the
isolated perfused lung (39). The primary mechanism was by type II cell hyperplasia since expression of the ENaC was diminished on
a per cell basis (140). In rats with lung injury due to
P. aeruginosa pneumonia, KGF pretreatment prevented the
reduction in alveolar epithelial fluid transport observed in the
untreated animals (138). Similar findings have been
reported after ANTU injury in an isolated perfused lung model
(39). The effects of KGF on alveolar epithelial fluid
transport can be additive with other measures to stimulate alveolar
fluid clearance. In one study, KGF treatment combined with the cAMP
agonist terbutaline more than doubled the rate of alveolar fluid
clearance (140) (Fig. 6).

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Fig. 6.
Effect of terbutaline on alveolar liquid clearance over
1 h in rats 72 h after KGF treatment (5 mg/kg intratracheal).
Data are also shown for alveolar liquid clearance over 1 h in
control rats and in control rats treated with 10 4 M
terbutaline. Data are means ± SD. * P < 0.05 compared with control group. P < 0.05 compared with
72 h after KGF treatment and P < 0.05 compared
with terbutaline control. Top: %stimulation (means ± SD) by terbutaline with and without KGF. [From Wang et al.
(140).]
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Several groups have investigated the effects of KGF on DNA repair after
oxidant injury. In A549 alveolar epithelial cells exposed to radiation,
addition of KGF to the media ameliorated the formation of DNA strand
breaks. This protective effect of KGF was blocked by the addition of
inhibitors of DNA polymerases
,
, and
, indicating
that the effect was due to enhanced DNA repair (127).
Similar findings were reported when A549 or primary isolates of rat
alveolar epithelial cells were exposed to H2O2. Again, the protective effect of KGF against DNA strand breaks was
blocked by the addition of inhibitors of DNA polymerases (
,
,
, and
) in this study (153). When rats were exposed
to hyperoxia and allowed to recover before isolation of alveolar
epithelial cells, DNA strand break formation was observed in culture
that could be blocked by adding KGF to the culture medium
(20). This protective effect was associated with the
appearance of proliferating cell nuclear antigen, suggesting that the
KGF may facilitate transition to a point in the cell cycle where DNA
strand breaks can be repaired. KGF may also prevent epithelial cells
from responding to proapoptotic stimuli. In mice, KGF protected against
hepatocyte apoptosis induced by injection of lipopolysaccharide and
D-galactosamine (111). Although there have
been only a few studies in the lung, KGF appears to inhibit
hyperoxia-induced apoptosis of alveolar epithelial cells (20,
54), probably through induction of an antiapoptotic pathway, the
Akt signaling axis (54).
Although KGF has a multitude of direct effects on epithelial cell
proliferation, motility, fluid transport, and repair, some of the
beneficial effects of KGF may be mediated by the release of downstream
mediators that have both autocrine and paracrine effects. For
example, in a rat model of T cell-mediated idiopathic pneumonia after
bone marrow transplantation, KGF administration before bone
marrow transplant suppressed T cell-dependent alveolar macrophage
activation and production of inflammatory mediators (42).
This finding suggests that KGF stimulated the release of an epithelial
cell-derived mediator capable of downregulating macrophage function.
The protective effect of KGF in this model was blocked if a nitrating
species was introduced by adding cyclophosphamide to the conditioning
regimen. The authors hypothesize that the generation of peroxynitrite
disabled downstream signaling from the KGF receptor by disabling
tyrosine phosphorylation (42). KGF may also stimulate
epithelial cells to produce other growth factors. In cultured murine
keratinocytes, KGF stimulated the expression and secretion of TGF-
into the medium (29). Similarly, supernatants from
alveolar epithelial cells isolated from KGF-treated rats stimulated
alveolar epithelial repair (141), consistent with an
autocrine effect of KGF. This effect also appears to be mediated
through the epidermal growth factor (EGF) receptor (K. Atabai,
unpublished observations), perhaps due to the stimulation of production
of soluble factors such as EGF or TFG-
. KGF treatment may also
prevent the release of potentially harmful mediators. In a
bleomycin-induced lung injury model in rats, pretreatment with KGF
prevented the bleomycin-associated increase in profibrotic mediators
including TGF-
and PDGF-BB (162).
The majority of studies of the protective effect of KGF in acute lung
injury have focused on epithelial cells. However, a few recent reports
indicate that KGF may have direct or indirect effects on endothelial
cells that contribute to protection from acute lung injury. Gillis et
al. (36) reported that subnanomolar concentrations of KGF
induced neovascularization in the rat cornea. In this study, KGF
induced chemotaxis in capillary but not large vessel endothelial cells
in culture. FGF-10 had similar effects. KGF also helped to maintain the
barrier function of capillary endothelial cell monolayers, protecting
against hydrogen peroxide- and vascular endothelial growth
factor-induced increases in permeability. However, KGFR could not be
localized to endothelial cells. The authors hypothesize that KGF may be
acting through an as yet undiscovered high affinity receptor on
endothelial cells since KGF administration led to rapid rises in
mitogen-activated protein kinase activity in capillary endothelial
cells (36). A protective effect of KGF on the endothelium
was also suggested in an in vivo hyperoxia study. In this study, KGF
administration prevented damage by hyperoxia to both the alveolar
epithelium and capillary endothelium as measured by electron microscopy
(5). The mechanism of the protective effect for the
endothelium was not defined, although whole lung levels of the cell
death-associated proteins p53, Bax, and Bcl-x all declined, as did
levels of plasminogen activator inhibitor-1. In an isolated perfused
rat lung model, intravenous KGF attenuated hydrostatic pulmonary edema,
a finding that was associated with decreased alveolar-capillary barrier
permeability and may have been due to effects on endothelial
permeability (148).
Clinical Studies of KGF in the Lung
There have been very few clinical studies evaluating the role of
endogenous KGF in human acute lung injury. Verghese et al. (137) measured levels of KGF in undiluted pulmonary edema
fluid sampled from patients with early acute lung injury. Although KGF was detected (0.3-2.1 ng/ml) and was bioactive, there was no
difference in levels in patients with acute lung injury compared with
control patients with hydrostatic pulmonary edema. However, because KGF is a heparin-binding protein, measurements in the soluble phase may not
be the optimal way to detect changes in KGF expression after lung
injury in humans. Stern et al. (121) collected BAL fluid
from patients with acute respiratory distress syndrome (ARDS) later in
their course than in the Verghese study. KGF was detected in BAL fluid
in 13 of 17 patients with ARDS vs. only 1 of 8 patients with
hydrostatic pulmonary edema. Mechanically ventilated patients without
ARDS or hydrostatic edema did not have detectable levels of KGF in BAL.
Detectable levels of KGF were associated with measurable levels of type
III procollagen peptide and death, but only when both ARDS and non-ARDS
patients were considered together.
The use of exogenous KGF as a treatment for human acute lung injury has
not been studied. Because KGF has only been effective as a pretreatment
in animal models, there has been little enthusiasm for clinical trials
in acute lung injury. In humans, the development of acute lung injury
is rarely predictable. Thus a preventive therapy lacks appeal. However,
it should be noted that the available animal models of acute lung
injury do not adequately reproduce the clinical situation. In humans
with acute lung injury, ventilatory and hemodynamic support along with
treatment for the underlying inciting clinical disorder may provide a
prolonged interval for KGF to exert its therapeutic effects, a
situation that cannot be reproduced in animal models. Furthermore,
there are some patients for whom a preventive therapy might be useful
such as patients receiving chemotherapy and/or radiation therapy with
potential lung toxicity.
Although KGF is not currently being evaluated as a treatment for
clinical acute lung injury, other therapeutic uses are being explored.
Phase I/II studies are underway to evaluate recombinant human KGF as an
agent to prevent oral and gastrointestinal mucositis. In a phase I
trial in healthy volunteers, a 3-day administration of systemic KGF was
safe, well tolerated, and induced a dose-dependent increase in oral
mucosal proliferation (27). Topical KGF is also undergoing
study for acceleration of wound healing in the skin. Although FGF-10
has shown promise in animal models of gastrointestinal mucositis and
wound healing in the skin, it is still in preclinical evaluation.
 |
HEPATOCYTE GROWTH FACTOR |
Background
The identification of HGF was the result of a concerted
effort to identify the growth factor responsible for hepatic
regeneration after hepatectomy (102). Initially isolated
from multiple sources (37, 71, 80, 105), it was later
recognized that HGF was identical to another growth factor, scatter
factor, which had been independently isolated and cloned
(147). Like KGF, HGF has heparin-binding capability, but
it is not a member of the FGF family. HGF is expressed as a single
chain molecule of 728 amino acids that is cleaved proteolytically to an
active heterodimer (14). The active heterodimer has four
kringle domains and an inactive serine protease site and belongs to a
group of fibrinolytic and coagulation-related proteins, which includes
plasminogen and other blood proteases (14). The HGF
receptor (Table 1) is a membrane-spanning tyrosine kinase that was
identified as the c-met protooncogene product in 1991 (15, 81). Unlike the KGFR, c-met expression is
not confined to the epithelium, although epithelial expression
predominates. In addition to normal epithelial cells of almost every
organ, c-met has been detected on fibroblasts, endothelial
cells, microglial cells, neurons, and hematopoietic cells. Like KGF,
HGF binds to cell surface heparan sulfate proteoglycans (56) that serve as low-affinity receptors and modulate the
interaction between HGF and the c-met receptor (103,
107).
Role of HGF in the Developing Lung
HGF and its receptor are expressed in many developing organs. HGF
expression is usually confined to the mesenchyme, and HGF receptor
expression is usually confined to the epithelium (118). HGF null mice die in utero due to abnormalities of the liver and placenta (110, 134). However, lung development is normal
at the time of death in these embryos. Brinkmann et al.
(19) tested the effect of HGF on various epithelial cell
lines and found that HGF could induce endogenous morphogenetic programs
in epithelial cells from a variety of organs including the lung (LX-1
carcinoma cells). In embryonic rat lung organoids grown on
three-dimensional collagen matrices, antisense HGF oligonucleotides
blocked alveolar and bronchial morphogenesis (48). In rat
fetal lung explants, exogenous HGF stimulated branching organogenesis
(85). However, when fetal lung epithelial explants were
grown in the absence of mesenchyme, HGF alone was insufficient to
restore branching morphogenesis, whereas KGF alone or acidic FGF
alone was sufficient. HGF had a synergistic effect with KGF or acidic
FGF in this mesenchyme-free system (85). Thus while HGF
appears to play an important role in branching morphogenesis in the
lung, it is not essential, perhaps due to redundancy in the repertoire
of mediators of mesenchymal-epithelial interactions.
In humans, amniotic fluid from women up to 31 wk pregnant had a
motogenic effect on a fetal feline lung cell line (48). This motogenic activity could be abolished by anti-HGF neutralizing antibodies, suggesting that HGF is present and probably functional in
human lung development as well. After 31 wk, human amniotic fluid was
no longer motogenic for fetal lung cells.
Effects of HGF in the Injured Lung
Endogenous HGF.
HGF is present in the BAL fluid of normal adult rats and is
responsible for most of the mitogenic effects of lavage fluid on
alveolar epithelial cells (65). In the first published
study to examine the effect of acute lung injury on HGF expression in the lung, Yanagita et al. (158) reported that HGF mRNA and
HGF activity increased in whole lung at 3-6 h after injury with
intratracheal hydrochloric acid. This increase in HGF expression was
followed at 24 h by a peak in bronchial epithelial DNA synthesis
and at 48 h by a peak in alveolar epithelial DNA synthesis. An
increase in whole lung HGF expression has also been reported in a rat
model of ischemia-reperfusion. In that model, whole lung HGF mRNA
increased by 24 h after ischemia-reperfusion. This was followed by
an increase in whole lung HGF protein that peaked at day 3 after ischemia-reperfusion. Administration of an anti-HGF antibody
aggravated ischemia-reperfusion lung injury and reduced postinjury DNA
synthesis in the lung, suggesting that endogenous HGF plays a role in
the reparative response to lung injury. In a recent study, Morimoto et
al. (79) attempted to localize the cellular source of HGF
in a rat model of P. aeruginosa pneumonia. Whole lung HGF
mRNA increased at 3 h after bacterial instillation and again
at 24-72 h. Immunohistochemistry suggested that the cellular
source of HGF for the early peak was bronchial epithelial cells. This
finding is surprising and was not confirmed by in situ hybridization
but is in keeping with a report that normal human bronchial epithelial
cells can produce HGF in culture as an autocrine motogenic factor
(131). The cellular source for the later peak of HGF
production appeared to be alveolar macrophages and, in particular,
those that had phagocytosed apoptotic neutrophils (79).
Fibroblasts isolated from rats exposed to hyperoxia also have increased
HGF expression (139).
The lung may also be a source of HGF after injury to other
organs. For example, after partial hepatectomy, unilateral nephrectomy, or induction of hepatitis in rats, HGF mRNA in the intact lung increased at 6 h (159). In the setting of acute
pancreatitis in rats, HGF mRNA and protein increased in the lung,
liver, and kidney (133). These findings suggest that the
lung may contribute to organ repair and regeneration in an endocrine
fashion through production of circulating HGF.
The factors that lead to upregulation of HGF expression in the setting
of lung injury or other organ injury have not been fully elucidated.
The human HGF gene has an IL-6 response element and a potential binding
site for nuclear factor IL-6 near the transcription initiation site,
suggesting that IL-6 may promote transcription (74). This
is potentially important because plasma levels of IL-6 are elevated in
patients with acute lung injury (129). IL-1
and IL-1
have both been shown to increase HGF mRNA in cultured human skin
fibroblasts (66). In addition to transcriptional regulation, local proteolytic activation of HGF may control its activity. Miyazawa and coworkers (75) showed that an
enzymatic activity that proteolytically activated the HGF precursor
could be induced in the liver in response to tissue injury.
Exogenous HGF.
Compared with KGF, there have been relatively few studies of the
effect of exogenous HGF in lung injury. In bleomycin-induced lung
injury in the mouse, concomitant treatment with a continuous infusion
of HGF repressed fibrotic morphological changes at 2 or 4 wk after
initiation of bleomycin (Fig. 7)
(154). Interestingly, HGF infusion was also effective if
it was started 2 wk after the bleomycin was started, suggesting that
HGF may be able to reverse some of the fibrotic changes induced by
bleomycin. Dohi et al. (30) recently reported that
intratracheal HGF given at 3 and 6 days after (but not before)
bleomycin could also reduce fibrotic changes in the mouse lung. This
reduction in fibrosis was associated with increased bronchial
epithelial and alveolar epithelial proliferation.

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Fig. 7.
Microscopic findings in murine
lungs 2 and 4 wk after treatment with bleomycin and/or low-dose
hepatocyte growth factor (HGF). A: bleomycin (100 mg/kg,
continuous subcutaneous administration from days 0 to 7)
alone at 2 wk. B: bleomycin and low-dose HGF (50 µg/mouse,
continuous intraperitoneal administration from days 0 to 7)
at 2 wk. C: bleomycin alone at 4 wk. D: bleomycin
and low-dose HGF at 4 wk. Lungs were stained with elastica-Masson.
Original magnification, ×10. [From Yaekashiwa et al.
(154).]
|
|
Although HGF effects have been studied extensively in other organs, the
mechanisms by which HGF may be protective or facilitate recovery from
acute lung injury have not been thoroughly explored. As with KGF,
proliferation of alveolar epithelial type II cells may be an important
mechanism. Alveolar epithelial type II cells express the
c-met receptor, and HGF is a potent mitogen for rat alveolar
epithelial cells, both in vitro (64, 113) and in vivo (91). Human adult lung fibroblast-conditioned media are
also mitogenic for rat alveolar epithelial type II cells. This
mitogenic activity is predominantly due to HGF and KGF
(92). HGF is also a potent in vitro mitogen for human
bronchial epithelial cells (117). Unlike KGF, however,
addition of HGF to primary isolates of alveolar epithelial cells
inhibited the synthesis and secretion of phosphatidylcholine surfactant
components (139). In addition to its potent mitogenic
effects on alveolar epithelial cells, the addition of exogenous HGF may
also modulate the alveolar epithelial response to other growth factors.
For example, TGF-
is a potent growth factor associated with acute
lung injury (99), fibroblast proliferation, and lung
fibrosis (164) that is known to inhibit epithelial cell
proliferation. TGF-
dramatically downregulates HGF expression
in human lung fibroblasts (67) through regulation at the
posttranscriptional level (43). In primary isolates
of rat alveolar epithelial type II cells, addition of TGF-
did not inhibit HGF-induced proliferation (113). Thus exogenous
HGF may restore a proliferative phenotype in type II cells that is
downregulated by TGF-
.
Another interesting mechanism by which HGF may ameliorate lung injury
is through modulation of fibrinolysis. Clinical acute lung injury is
associated with fibrin deposition and a reduction in fibrinolytic
capacity in the airspace (45). An intact fibrinolytic system is also important to recovery from experimental lung injury. For
example, intact fibrinolysis is required for recovery from bleomycin-induced lung injury (31, 87) and
hyperoxia-induced lung injury (4). The alveolar epithelium
is an active participant in maintaining the fibrinolytic balance in the
lungs (61, 115). Dohi et al. (30) reported
that administration of HGF to A549 alveolar epithelial cells in culture
enhanced cell surface plasmin generation and expression of urokinase
activity, thus enhancing the fibrinolytic capacity of this cell line.
Clinical Studies of HGF
To date, the only clinical studies of HGF in lung disease have
focused on measuring HGF in biological fluids such as serum, BAL fluid,
or pulmonary edema fluid in patients with various lung diseases. In
patients with either idiopathic pulmonary fibrosis or collagen vascular
disease-associated pulmonary fibrosis, both serum (59,
156) and BAL fluid (106) levels of HGF were
elevated. Patients with bacterial pneumonia also had elevated serum
levels of HGF (59), although in one study, levels in
nonsurvivors were normal (82). Elevated serum HGF levels
have also been measured in patients with clubbing (44),
after thoracotomy with unilateral ventilation (155), or
after pneumonectomy (123).
In patients with acute lung injury, both BAL fluid levels
(121) and undiluted pulmonary edema fluid levels
(137) of HGF are elevated, and higher levels are
associated with increased mortality (Fig.
8). This association with increased
mortality does not imply causality but rather may indicate that high
levels of HGF in the lung are associated with more severe lung injury and inflammation and thus a worse outcome. Pulmonary edema fluid levels
were sevenfold higher than simultaneous plasma levels, indicating some
local production of HGF in the lung (137). Thus although
there is ample evidence that lung disease can increase HGF levels in
biological fluids, the clinical studies to date have not explored the
mechanistic role of HGF in human lung disease nor have there been any
therapeutic trials.

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Fig. 8.
Relationship between pulmonary edema fluid levels of HGF
and hospital mortality in 26 patients with acute lung injury or acute
respiratory distress syndrome. Analysis was done by ANOVA of data
normalized by log transformation. [From Verghese et al.
(137).]
|
|
 |
CONCLUSIONS |
The epithelial-specific growth factors KGF, FGF-10, and HGF
are important mediators of mesenchymal-epithelial interactions during
lung development, lung inflammation, and lung repair. Whether these
growth factors will also have therapeutic use in lung disease is not
yet clear and requires further study. Regardless of any therapeutic
potential, future studies of KGF, FGF-10, and HGF will undoubtedly
deepen our understanding of the pathogenesis and resolution of
acute lung injury and other lung diseases.
 |
ACKNOWLEDGEMENTS |
This work was supported by National Heart, Lung, and Blood
Institute Grants HL-51856 and K08 HL-70521.
 |
FOOTNOTES |
Address for reprint requests and other correspondence:
M. A. Matthay, CVRI Box 0130, 505 Parnassus, San Francisco,
CA 94143-0130 (E-mail: mmatt{at}itsa.ucsf.edu).
10.1152/ajplung.00439.2001
 |
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