Intravenous keratinocyte growth factor protects against
experimental pulmonary injury
Jane
Guo1,
Eunhee S.
Yi2,
Andrew M.
Havill1,
Ildiko
Sarosi1,
Lane
Whitcomb1,
Songmei
Yin1,
Scot C.
Middleton1,
Pierre
Piguet1, and
Thomas R.
Ulich1
1 Amgen Preclinical Research,
Thousand Oaks 91320-1789; and
2 San Diego School of Medicine,
University of California, San Diego, California 92103
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ABSTRACT |
Keratinocyte
growth factor (KGF) administered by intratracheal instillation is well
documented to stimulate the proliferation of alveolar and bronchial
cells. In the present study, intravenous KGF was also shown to
stimulate the proliferation of alveolar and bronchial cells in mice and
rats, although to a lesser degree than intratracheal KGF. Despite the
decreased potency of intravenous KGF on pulmonary cell
5-bromo-2'-deoxyuridine incorporation compared with intratracheal
KGF, intravenous KGF was very effective in preventing experimental
bleomycin-induced pulmonary dysfunction, weight loss, and mortality in
either mice or rats and experimental hyperoxia-induced
mortality in mice. The effectiveness of intravenous administration of
KGF in preventing lung injury suggests that the mechanisms of the
protective effect of KGF may involve more than pulmonary cell
proliferation and also suggests the potential use of systemic KGF for
clinical trials in settings of pulmonary injury.
bleomycin; hyperoxia
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INTRODUCTION |
KERATINOCYTE GROWTH FACTOR (KGF or fibroblast growth
factor-7) is a member of the fibroblast growth factor family. KGF is a
fibroblast-derived mitogen that selectively stimulates the
proliferation of epithelial cells in vitro (10, 12) and in vivo (7, 16, 17, 21, 22, 24). The potential therapeutic use of KGF has been
evaluated in disease models associated with damage to epithelial cells
of the skin, digestive tract, and bladder. KGF has shown beneficial
effects in models of dermal injury (11, 13), in chemotherapy or
irradiation-induced oral and gastrointestinal mucositis (3), and in
cyclophosphamide-induced ulcerative hemorrhagic cystitis (15).
KGF instilled intratracheally causes alveolar type II pneumocyte and
bronchial cell proliferation (15). In pulmonary disease models,
intratracheal instillation of KGF has prevented lung injury caused by
radiation and bleomycin (23), hyperoxia (9), acid instillation (20),
and
-naphthylthiourea (8).
The purpose of the present study was to compare the effect of KGF on
pulmonary epithelium after intravenous and intratracheal administration
and to document the protective effect of intravenous KGF in bleomycin-
and hyperoxia-induced rodent models of lung injury. Bleomycin, a
chemotherapeutic agent used clinically in the treatment of a variety of
human malignancies, can cause pulmonary injury and fibrosis both in
animal models and in patients (6). Prolonged exposure to elevated
levels of O2 in animal models and patients also damages the alveolar epithelium, resulting in pulmonary fibrosis and mortality (4).
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MATERIALS AND METHODS |
Animal treatment. The
humane care and use of all experimental animals in this study was
overseen by the institutional animal use and care committee.
KGF and bleomycin instillation.
Male Lewis rats weighing 200-250 g were purchased
from Charles River Laboratories (Cambridge, MA). Female CBA/J and
BALB/c mice (~25 g) were obtained from Jackson Laboratories (Bar
Harbor, ME). Recombinant human KGF was produced at Amgen in
Escherichia coli. Intratracheal
instillation (0.1 ml) of KGF or bleomycin in mice was performed with a
28-gauge needle after blunt dissection of the soft tissues of the neck to expose the trachea. In rats, 0.5 ml of KGF or bleomycin was instilled via intratracheal cannulation with a sterile 18-gauge catheter using a fiber-optic light source. The doses of bleomycin sulfate (Sigma, St. Louis, MO) in Lewis rats (10 U/kg) (23) and CBA/J
mice (2 U/kg) were chosen based on previous studies of
bleomycin-induced fibrosis.
Immunohistochemical detection of proliferating
cells. Animals were injected with 50 mg/kg of 5-bromo-2'-deoxyuridine (BrdU) in 0.2 ml of saline
intraperitoneally 2 h before euthanasia. The lungs were excised and
fixed in 10% neutral-buffered Formalin at a pressure of 20 cmH2O. A midsagittal section was
taken to detect cells undergoing DNA synthesis. Specific BrdU labeling was detected with monoclonal rat (MAS 250ps, Accurate) or mouse (Bu20a,
Dako) anti-BrdU antibody. Rat type II pneumocytes were identified with
polyclonal rabbit anti-bovine surfactant protein B (SP-B) antibody (a
generous gift from Dr. Jeffrey Whitsett, Cincinnati, OH). Indirect
immunohistochemistry was performed with the Vectastain ABC-AP System
(Vector Laboratories, Burlingame, CA) for BrdU labeling. Horseradish
peroxidase and 3,3'-diaminobenzidene as the chromogen (Vector
Laboratories) were used for SP-B staining. Ten to twenty random
×400 microscopic fields of alveolar parenchyma and bronchioles
0.2-0.5 mm in transverse diameter were used for quantification of
BrdU-positive cells in a double-blind fashion by a pathologist. Only
nucleated cells of the alveolar walls with the exclusion of
identifiable alveolar macrophages were considered for the enumeration
of SP-B-positive cells.
Pulmonary function tests.
A noninvasive, bias-flow ventilated whole body
plethysmographic technique was used to quantitate the tidal volume and
frequency of breathing in rats placed in an unrestrained chamber (Buxco
Electronics, Troy, NY). The changes in chamber pressure represent the
difference between thoracic expansion-contraction and tidal volume. The
chamber pressure was differentiated to give a pseudoflow signal with a
transducer connected to a preamplifier. Flow signals were analyzed with
Buxco Biosystem XA software.
Hyperoxia-induced lung injury.
Mice were exposed to >95%
O2 at 3.3 l/min in an airtight
chamber (Schroer, Kansas City, MO). Animals had free access to water
and food and were monitored at least four times daily for respiratory
distress.
Statistical analysis.
Data are presented as means ± SD. When two groups
were compared, the probability value was determined by a two-tailed
t-test (Systat, Evanston, IL).
Comparisons of multiple groups were made with a Newman-Keuls post hoc
test after ANOVA. The significance of survival curves was determined by
Proc GENMOD with a logit link function and Kaplan-Meier method. A
P value
0.05 was considered
significant.
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RESULTS |
Kinetics of alveolar and bronchial cell BrdU
incorporation after intratracheal vs. intravenous KGF administration in
mice and rats. BrdU labeling was
compared in mice (Fig. 1) and rats (Fig.
2) receiving intratracheal or
intravenous KGF (5 mg/kg). The kinetics and magnitude of the response
were dependent on both the route of administration and the
species.

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Fig. 1.
Kinetics of keratinocyte growth factor (KGF)-induced
5-bromo-2'-deoxyuridine (BrdU) uptake in alveolar and bronchial
cells in CBA/J mice (n = 5/group)
treated with 5 mg/kg of KGF intratracheally (it; ) or intravenously
(iv; ). Control mice (n = 2/group)
received saline it ( ) or iv ( ).
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Fig. 2.
Kinetics of KGF-induced BrdU uptake and surfactant protein B (SP-B)
expression in alveolar and bronchial cells in Lewis rats receiving a
single 5 mg/kg treatment of KGF [it ( ) or iv ( ); n = 5 rats/group] or saline [it ( ) or iv ( );
n = 5 rats/group].
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In mice, the stimulation of DNA synthesis, as shown by BrdU
incorporation in alveolar cells, reached a maximum 2 days after either
intratracheal or intravenous delivery of KGF. Bronchial cells displayed much more BrdU incorporation after intratracheal administration of KGF than after intravenous injection. Control mice
injected with saline showed negligible staining for BrdU.
In rats, intratracheal KGF caused peak BrdU incorporation in alveolar
cells at 2 days, whereas intravenous KGF caused a peak effect at 1 day
and no effect at 2 days. The number of BrdU-positive alveolar cells was
much lower in the intravenous group than in the intratracheal group. A
similar level of BrdU incorporation was seen in bronchial cells after
intravenous or intratracheal injection. Intravenous injection of KGF
had a marginal effect on the number of type II pneumocytes as
quantitated by SP-B-positive cells, whereas a large increase in type II
pneumocytes was seen peaking 72 h after intratracheal KGF.
Intravenous KGF prevents bleomycin-induced pulmonary
injury. Mice received intravenous KGF or human serum
albumin (HSA; 5 mg/kg) on days
2 and
3
before intratracheal bleomycin. Four of seventeen control mice (24%)
survived for 26 days after bleomycin administration, whereas 15 of 18 KGF-pretreated mice (83%) survived (P < 0.001; Fig. 3). Surviving control mice
lost weight progressively, whereas KGF-pretreated mice maintained their
weight (Fig. 3).

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Fig. 3.
Intravenous bolus injections of KGF prevent bleomycin-induced mortality
and weight loss in mice. CBA/J mice were treated with KGF (5 mg/kg;
n = 18) or human serum albumin (HSA; 5 mg/kg, n = 17) 2 and 3 days before
instillation of 0.05 U bleomycin.
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In the rat bleomycin model at a dose at which mortality was not
observed, KGF given intratracheally or intravenously at 2 and 3 days
before bleomycin protected against weight loss, although intratracheal KGF was more effective than intravenous KGF for approximately the first 2 wk after bleomycin administration (Fig. 4). The bleomycin-induced deterioration in
respiration rate and tidal volume was ameliorated in KGF-pretreated
rats (Fig. 5) as shown by the normal tidal
volume after intratracheal KGF (P < 0.001 compared with intratracheal HSA) and 75% of the normal tidal volume after intravenous KGF (P < 0.001 compared with intravenous HSA). The respiratory rate was equally
improved, although not completely normalized, after intratracheal or
intravenous KGF administration (P < 0.001 compared with intratracheal or intravenous HSA).

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Fig. 4.
KGF prevents bleomycin-induced weight loss in rats. Rats
(n = 6/group) were treated
with KGF (5 mg/kg) or HSA (5 mg/kb) 2 and 3 days before instillation of
2.5 U bleomycin it.
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Fig. 5.
KGF ameliorates bleomycin-induced loss of pulmonary function as
measured by respiration rate and tidal volume. Rats
(n = 6/group) were treated with KGF (5 mg/kg it or
iv) or HSA (5 mg/kg) 2 and 3 days before instillation of 2.5 U
bleomycin. Pulmonary function was evaluated 15 days after instillation
of bleomycin.
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Intravenous KGF prevents hyperoxia-induced pulmonary
injury. CBA/J mice kept in >95%
O2 for 3.5 days and then reexposed
to ambient air experienced a mortality of ~75% within the first 2 days after their removal from the hyperoxic environment (Fig. 6). A single intravenous injection of KGF
(5 mg/kg) given either on day
2
or
1 or
immediately before O2 exposure
resulted in nearly complete protection against mortality
(~5-15% mortality; P < 0.001 vs. control; Fig. 6). Treatment with KGF on day
3 before O2
exposure resulted in a moderate protective effect (~30% mortality; P = 0.003 vs. control; Fig. 6).

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Fig. 6.
KGF decreases hyperoxia-induced mortality after 3.5 days of
O2 exposure. CBA/J mice were
injected with a single bolus dose of 5 mg/kg of KGF iv
(n = 20) or HSA
(n = 40) either on
day 3, 2, or
1 or immediately before
O2 exposure.
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In dose-response experiments, CBA/J mice were treated with 0.1-5
mg/kg iv of KGF immediately before
O2 exposure (Fig.
7). The mice that did not receive KGF
experienced a mortality of 90%. KGF at a dose of 5 mg/kg showed
complete protection (0% mortality; P < 0.001 vs. control). KGF at doses of 0.5 and 0.25 mg/kg was also highly protective (P
0.001 vs.
control), but the protective effect was lost at a dose of 0.1 mg/kg
(P > 0.05 vs. control).

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Fig. 7.
Dose-response study of KGF shows that a KGF dose of as little as 250 µg/kg iv at time 0 is effective in
preventing hyperoxia-induced mortality. CBA/J mice
(n = 10/group) were injected with KGF
doses of 0.1-5 mg/kg iv immediately before
O2 exposure.
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To study any variability among mouse strains, we also studied BALB/c
mice. BALB/c mice were found to be somewhat more sensitive to
O2, already experiencing a
90% mortality at 2.75 days after exposure to hyperoxia. Nevertheless,
KGF at 5 mg/kg iv on days
1 and
0 before O2
exposure provided dramatic protection against mortality (Fig.
8). By exposing the mice to varying
durations of O2 exposure, we
showed that KGF exhibited a protective effect in mild-to-severe
O2 injury (Fig. 8).

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Fig. 8.
Magnitude of protective effect of KGF against hyperoxia depends on
length of O2 exposure. BALB/c mice
(n = 10/group) were injected
with 5 mg/kg of KGF or HSA iv 1 and 0 days before
O2 exposure of 2.5-3 days.
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Histological examination of the lungs from both control and KGF mice at
the time of removal from the O2
chamber showed acute bronchiolitis, alveolar edema, hemorrhage, and
alveolar neutrophil infiltration. Because most control mice died
shortly after their removal from
O2, long-term histological study
of significant numbers of these mice was not possible. In KGF-treated
mice, histology at 1 wk after removal from the hyperoxic environment
showed a focal organizing pneumonia (Fig.
9). By 2 wk, the pneumonia had largely
resolved, although focal scanty interstitial deposits of collagen were noted in some mice. By 4 wk, the
pulmonary histology of the KGF-treated mice had largely normalized,
although focal mild lesions persisted (Fig. 9).

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Fig. 9.
Lungs of KGF-treated mice show acute neutrophilic and hemorrhagic
pneumonitis on day of removal from
O2 chamber
(day 0), patchy organizing pneumonia
(arrows) on day 7, and resolution to a nearly normal
pulmonary architecture on day 28. Left, whole mounts;
right, low-power histology.
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DISCUSSION |
Intravenous KGF is nearly as effective as intratracheal KGF in
ameliorating bleomycin- and hyperoxia-induced lung injury in rodents.
Although alveolar and bronchial cells in mice and rats incorporate BrdU
after intratracheal or intravenous KGF administration, the intravenous
route is not nearly as potent in causing BrdU incorporation in
pulmonary cells or in causing alveolar cell hyperplasia. Although the
mechanism of the protective effect of KGF is not fully understood,
mechanisms may be involved that are independent of the proliferative
action of KGF on epithelial cells. KGF, for example, has been reported
to upregulate functions such as surfactant protein expression (17, 20)
and sodium-potassium-adenosinetriphosphatase activity (5) and to
decrease permeability between injured epithelial cells (18). Unlike
tumor necrosis factor, which was reported to increase expression of the
antioxidant enzyme superoxide dismutase (14), Panos et al. (9) did not
find an increase in pulmonary superoxide dismutase activity in
KGF-treated rats exposed to O2. Some investigators have proposed effects of KGF on the regulation of
apoptosis. In vitro, KGF did not prevent
H2O2-induced
alveolar cell death or alter Bcl-2 expression (19).
The kinetics of BrdU incorporation in mice and rats are not exactly the
same, and the alveolar cell hyperplasia noted by routine histology in
mice is not as striking as that in rats. It is unclear whether the
magnitude of the pulmonary effects of KGF on cellular proliferation in
rodents can be readily extrapolated to humans.
Different strains of mice appear to have different sensitivities to
O2. In our experiments, BALB/c
mice were more sensitive to O2
than CBA/J mice, but KGF exerted a protective effect in both strains.
In preliminary experiments in our laboratory, the sensitivity of
rats to O2 seems to be greater
than that of mice, and we have not yet shown that KGF is protective
against O2 toxicity in rats after
intravenous administration. Previous work has shown that the ability of
KGF to protect against O2-induced
lung injury is related to the timing of the KGF treatment. In rats,
intratracheal KGF was effective if given at 48 and 72 h before
O2 exposure. Treatment at 24 or 0 h before O2 exposure was
ineffective (2). Similar results have been obtained in a rat model of
bleomycin-induced fibrosis in which pretreatment with intratracheal KGF
was effective in preventing injury but posttreatment with KGF was
ineffective (1).
KGF is currently in clinical trials for the prevention of
chemotherapy-induced mucositis. The effectiveness of intravenous KGF in
preventing lung injury is of importance because intravenous KGF would
be easier to administer than intratracheal KGF if KGF were to prove
effective in the clinical prevention of lung injury.
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ACKNOWLEDGEMENTS |
We are grateful to Louis Munyakazi and Robyn Murphy-Filkins for
performing statistical analysis. We also thank Carol Burgh and Gwyneth
Van for their contribution of histological studies.
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FOOTNOTES |
Address for reprint requests: T. R. Ulich, 1840 DeHavilland Dr.,
Thousand Oaks, CA 91320.
Received 5 November 1997; accepted in final form 8 June 1998.
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