Bleomycin-Induced Lung Injury

Abstract

Bleomycin is a chemotherapeutic agent commonly used to treat curable diseases such as germinative tumors and Hodgkin’s lymphoma. The major limitation of bleomycin therapy is pulmonary toxicity, which can be life threatening in up to 10% of patients receiving the drug. The mechanism of bleomycin-induced pneumonitis (BIP) involves oxidative damage, relative deficiency of the deactivating enzyme bleomycin hydrolase, genetic susceptibility, and the elaboration of inflammatory cytokines. Ultimately, BIP can progress to lung fibrosis. The diagnosis of BIP is established by the combination of systemic symptoms, radiological and histological findings, and respiratory function tests abnormalities, while other disorders should be excluded. Although the diagnosis and pathophysiology of this disease have been better characterized over the past few years, there is no effective therapy for the disease. In general, the clinical picture is extremely complex. A greater understanding of the BIP pathogenesis may lead to the development of new agents capable of preventing or even treating the injury already present. Physicians who prescribe bleomycin must be aware of the potential pulmonary toxicity, especially in the presence of risk factors. This review will focus on BIP, mainly regarding recent advances and perspectives in diagnosis and treatment.

Full text

Hindawi Publishing Corporation
Journal of Cancer Research
Volume , Article ID , pages
http://dx.doi.org/.//
Review Article
Bleomycin-Induced Lung Injury
Tomás Reinert, Clarissa Serodio da Rocha Baldotto, Frederico Arthur Pereira Nunes, and
Adriana Alves de Souza Scheliga
Servic¸o de Oncologia Cl´
ınica, Instituto Nacional de Cˆ
ancer (INCA), Prac¸a da Cruz Vermelha 23, 20230-130 Rio de Janeiro, RJ, Brazil
Correspondence should be addressed to Tom´
as Reinert; tomasreinert@hotmail.com
Received  April ; Accepted  September 
Academic Editor: Rainald Knecht
Copyright ©  Tom´
as Reinert et al. is is an open access article distributed under the Creative Commons Attribution License,
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Bleomycin is a chemotherapeutic agent commonly used to treat curable diseases such as germinative tumors and Hodgkin’s
lymphoma. e major limitation of bleomycin therapy is pulmonary toxicity, which can be life threatening in up to % of patients
receiving the drug. e mechanism of bleomycin-induced pneumonitis (BIP) involves oxidative damage, relative deciency of
the deactivating enzyme bleomycin hydrolase, genetic susceptibility, and the elaboration of inammatory cytokines. Ultimately,
BIP can progress to lung brosis. e diagnosis of BIP is established by the combination of systemic symptoms, radiological and
histological ndings, and respiratory function tests abnormalities, while other disorders should be excluded. Although the diagnosis
and pathophysiology of this disease have been better characterized over the past few years, there is no eective therapy for the
disease. In general, the clinical picture is extremely complex. A greater understanding of the BIP pathogenesis may lead to the
development of new agents capable of preventing or even treating the injury already present. Physicians who prescribe bleomycin
must be aware of the potential pulmonary toxicity, especially in the presence of risk factors. is review will focus on BIP, mainly
regarding recent advances and perspectives in diagnosis and treatment.
1. Introduction
Bleomycin is one of the rst described chemotherapeutic
agents and has been used for cancer treatment for many
years. Despite the development of new drugs in oncology,
bleomycin remains an important component of chemother-
apy regimens for curable diseases such as germinative tumors
and Hodgkin’s lymphoma. ese neoplasias commonly aect
youngindividuals,whomaysurviveforlongperiods.In
this regard, early diagnosis and treatment, and prevention
of limiting toxicities such as bleomycin-induced lung injury,
is crucial. is review addresses this important side eect,
focusing on recent advances and perspectives on diagnosis
and treatment.
2. Bleomycin Pharmacology
An antibiotic agent with antitumor activity, bleomycin was
discovered by Umezewa in  and was originally isolated
from the fungus Streptomyces verticillus. Bleomycin exerts
its antitumor eect by inducing tumor cell death, while
inhibition of tumor angiogenesis may also be important. It is
most commonly used as part of adriamycin, bleomycin, vin-
blastine, and dacarbazine (ABVD), the standard chemother-
apeutic regimen for the treatment of Hodgkin’s disease,
and bleomycin, etoposide, and cisplatin (BEP), used for
the treatment of germ-cell tumors. It is also used in the
treatment of several tumor types, such as Kaposi’s sarcoma,
cervical cancer, and squamous cell carcinomas of the head
and neck []. Recently, percutaneous sclerotherapy by using
bleomycin is being successfully used to provide symptomatic
relief to patients with craniofacial venous malformations and
lymphangiomas [].
As small peptide with a molecular weight of ,,
bleomycin contains a DNA-binding region and an iron-
binding region (at opposite ends of the molecule). Iron is an
essential cofactor for free radical generation and the cytotoxic
activity of bleomycin. Bleomycin forms a complex with Fe2+,
which is subsequently oxidized to Fe3+,resultinginthe
reduction of oxygen to free radicals. ese free radicals cause
single- and double-strand DNA breaks, which ultimately lead
to cell death []. Moreover, bleomycin mediates the oxidative

Journal of Cancer Research
degradation of all major classes of cellular RNA. e eects
of bleomycin are cell cycle specic, with its main eects
occurring during the G and M phases of the cell cycle [].
Aer intravenous administration, there is rapid biphasic
disappearance from the circulation. e terminal half-life is
approximately  h in patients with normal renal function.
Bleomycin is rapidly inactivated in tissues, especially the
liver and kidneys, by the enzyme bleomycin hydrolase.
Elimination of bleomycin primarily occurs via the kidneys,
with –% of a given dose being excreted unchanged
in the urine. Patients with impaired renal function may
experience increased drug accumulation and are at risk of
increased toxicity. Dose reduction is required in the presence
of renal dysfunction. Phenothiazines enhance the activity of
bleomycin by competing with liver P enzymes. Cisplatin
reduces the renal clearance of bleomycin and in doing so may
enhance toxicity [].
3. Common Side Effects
Skin reactions are the most common side eects and include
erythema, hyperpigmentation of the skin, striae, and vesic-
ulation. Skin peeling, thickening of the skin and nail beds,
hyperkeratosis, and ulceration may also occur. ese mani-
festations usually occur in the second and third weeks aer
treatment, when the cumulative dose has reached – U.
Directly aer its administration, fever chills and sometimes
hypotensioncanoccur.Othercommonsideeectsare
alopecia, stomatitis, and fatigue. Vascular events, including
myocardial infarction, stroke, and Raynaud’s phenomenon,
areoccasionallyreported[,].
e major limitation of bleomycin therapy is usually
pulmonary toxicity, which can be life threatening and has
been described in up to % of patients receiving the drug.
One of the potential determinants of bleomycin toxicity is
bleomycin hydrolase, the enzyme that is primarily respon-
sible for metabolizing bleomycin to nontoxic molecules.
Interestingly, the two organs that are the most common sites
ofbleomycintoxicity(thelungsandtheskin)havethelowest
levelsoftheenzyme.Duetothefeasibilityofcloningthegene
that encodes bleomycin hydrolase, studies are now needed
to determine whether genetic variability in this enzyme
accounts for individual susceptibility to or protection from
bleomycin-induced pulmonary toxicity [].
4. Clinical Features
Several distinct pulmonary syndromes have been linked to
the use of bleomycin, including bronchiolitis obliterans with
organizing pneumonia (BOOP) [], eosinophilic hypersensi-
tivity, and, most commonly, interstitial pneumonitis, which
may ultimately progress to brosis []. e latter, bleomycin-
induced pneumonitis (BIP), occurs in  to % of patients
treated with bleomycin-containing chemotherapy, depending
on the diagnostic criteria used [].Areasonableestimateof
BIP incidence is %. e mortality of patients with BIP has
been reported to be approximately –% in patients who
develop bleomycin-induced lung injury (-% of all patients
treated with bleomycin) []. To our knowledge, there are no
reported cases of BIP secondary to the use of intralesional
bleomycin for the treatment of vascular anomalies [].
While BIP normally develops gradually during treatment,
the development of BIP up to two years aer discontinuation
of bleomycin therapy has also been reported []. e clinical
diagnosis of BIP is dicult and sometimes delayed by its
similarity to other conditions that are oen encountered
in cancer patients, such as respiratory tract infections, pul-
monary metastasis, and lymphangitic carcinoma. Bleomycin-
induced hypersensitivity pneumonitis may present with more
rapidly progressive symptoms.
e most common symptoms are exertional dyspnea
and nonproductive cough. With progressive pneumonitis,
dyspnea at rest, tachypnea, and cyanosis may occur. Physical
examination of the lungs may be normal or may reveal end-
inspiratory bibasilar crepitations or rhonchi. Pleural rubbing
and nger clubbing are unusual [].
BecauseoftheresemblanceofthesymptomsofBIPwith
other diseases, the diagnosis of BIP is oen one of exclusion.
Infectious diseases are oen excluded by culture and Gram-
staining of sputum, polymerase chain reaction analysis of
pathogens such as viruses, serology, or identication of
antigens of pneumonia-causing pathogens. Patients have
oen been treated unsuccessfully with antibiotics because the
suspicion of pneumonia before the diagnosis is established.
Pneumocystis jiroveci pneumonia (PJP) should always be
investigated. e clinical and radiological features of PJP
(dyspnea, dry cough, bilateral inltrates, and ground-glass
opacities) may resemble those of bleomycin-induce pneu-
monitis. PJP incidence is increased in patients with non-
Hodgkin’s lymphoma and those receiving long-term steroids.
Empirical treatment of PJP is recommended in cases of
clinical suspicion []. Patients who survive an episode of
BIP almost always recover completely, with disappearance of
symptoms,signs,anddisturbancesofpulmonaryfunction
[].
5. Pathogenesis
e mechanism of bleomycin-induced lung injury is not
entirely clear but likely involves oxidative damage, relative
deciency of the deactivating enzyme bleomycin hydro-
lase, genetic susceptibility, and elaboration of inammatory
cytokines [].
Bleomycin induces the generation of reactive oxygen
radicals by forming a complex with Fe3+.Consistentwith
a direct pathologic role for this mechanism, iron chelators
ameliorate the pulmonary toxicity of bleomycin in animal
models []. Reactive oxygen species can produce direct toxi-
city through participation in redox reactions and subsequent
fatty acid oxidation, which leads to membrane instability.
Oxidants can cause inammatory reactions within the lung.
For example, the oxidation of arachidonic acid is the initial
step in the metabolic cascade that produces active mediators
including prostaglandins and leukotrienes. Cytokines such as
interleukin-, macrophage inammatory protein-, platelet-
derived growth factor (PDGF), and transforming growth

Journal of Cancer Research 
factor (TGF)-𝛽arereleasedfromalveolarmacrophagesin
animal models of bleomycin toxicity, resulting in brosis [].
Damage and activation of alveolar epithelial cells may result
in the release of cytokines and growth factors that stimulate
proliferation of myobroblasts and secretion of a pathologic
extracellular matrix, leading to brosis.
Specically, TGF-𝛽,PDGFreceptor-𝛼(PDGFR-𝛼), and
tumor necrosis factor- (TNF-)𝛼are believed to stimulate the
transformation, proliferation, and accumulation of brob-
lasts, which leads to the deposition of extracellular matrix.
e progressive accumulation of this collagen matrix causes
distortion and destruction of alveolar structures and, even-
tually, loss of lung function. In animal models, it has been
demonstrated that PDGFR-𝛼expression is increased in BIP.
PDGFR-𝛼has also been shown to be increased in epithelial
cellsandalveolarmacrophagesinthelungsofpatientswith
idiopathic pulmonary brosis []. Recent evidence obtained
usingableomycin-inducedlungbrosismodelindicatesthat
some broblasts in brosis may be formed from bone marrow
progenitors, as well as from epithelial cells through epithelial-
mesenchymal transition [].
Cytotoxic drugs may also aect the local immune system.
Because the lung is exposed to numerous substances that can
activate its immune system, there appears to be pulmonary
immune tolerance, which avoids overreactions. is toler-
ance may, in part, be the result of an eector and suppressor
cell balance. Cytotoxic drugs can alter the normal balance,
leadingtotissuedamage[].
Other homeostatic systems within the lung can also
be aected, such as the balance between collagen forma-
tion and collagenolysis. Bleomycin may upregulate collagen
synthesis by modulating broblast proliferation through a
TGF-𝛽response. Excessive collagen deposition may result
in severe, irreversible pulmonary brosis. Bleomycin also
hasprofoundeectsonthebrinolyticsystem,alteringthe
balance between brin deposition and brinolysis on the
alveolar surface, thereby leading to brin deposition [].
e alveolar macrophage is thought to play a central role
in the development of bleomycin-induced lung injury due
to its ability to induce the release of a number of eector
molecules (e.g., cytokines, lipid metabolites, and oxygen
radicals). e mechanism by which alveolar macrophages
are activated is unknown. Bleomycin receptors have been
identied on the surfaces of rat alveolar macrophages, sug-
gesting that macrophage activation may occur via a second
messenger [].
6. Histopathology
Gross lung specimens from subjects with bleomycin-induced
lung injury typically demonstrate subpleural lung injury
and brosis. Various forms of interstitial lung disease have
been described, including end-stage brosis, nonspecic
interstitial pneumonia, diuse alveolar damage, organizing
pneumonia, and hypersensitivity (eosinophilic) pneumonia.
More than one of these patterns may be present at the same
time [].
F 
e main abnormalities in bleomycin-induced pulmo-
nary toxicity occur in endothelial and epithelial cells. De-
struction and desquamation of type I pneumocytes occur, as
does the proliferation of type II pneumocytes. Mononuclear
cell inltration, broblast proliferation, and brosis are com-
mon ndings. Bronchoalveolar lavage studies in patients with
bleomycin-induced pneumonitis have shown the presence of
polymorphonuclear alveolitis [].
Figure  shows histology examination of biopsy proven
BIP, revealing important disarrangement of alveolar archi-
tecture, interstitial brosis, intra-alveolar hemorrhage, and
alveoli coated by hyperplastic type II pneumocytes, beyond
chronic and acute inltrated inammatory.
7. Radiological Findings
Typical chest radiographic ndings are bilateral, bibasilar
inltrates, sometimes followed by diuse interstitial and
alveolar inltrates. Fine nodular densities and subpleural
opacication with volume loss and blunting of costophrenic
angles may also be present. ese early ndings may evolve
to progressive consolidation and honeycombing []Pneu-
mothorax and pneumomediastinum are rare complications
of bleomycin-induced pulmonary brosis [].
High-resolution computed tomography (HRCT) of the
chest is more sensitive than chest radiography in identifying
lung abnormalities in bleomycin-exposed patients. HRCT
patterns usually reect the underlying histopathology [].
Diuse alveolar damage is associated with airspace consolida-
tion and ground-glass opacities. Findings suggestive of end-
stage brosis include extensive reticular markings, traction
bronchiectasis, and honeycombing. Organizing pneumonia
manifests as ground-glass opacities in a bilateral but asym-
metric pattern or by airspace consolidation with a subpleural
or peribronchial distribution. Organizing pneumonia may
occasionally present as one or more nodular densities that
may mimic tumor metastases [].
Figures and show chest X-ray and CT scan demon-
strating diuse interstitial and alveolar damage with the
presence of patchy bilateral air-space consolidation and areas
of ground-glass attenuation.
A recent report evaluated the use of -uorode-
oxyglucose (FDG) positron emission tomography (PET)

Journal of Cancer Research
F 
F 
scanning in patients with BIP. It was shown that FDG uptake
is lost aer successful immunosuppressive treatment, even
if the CT scan still shows abnormalities. is observation
highlights the potential of PET scanning to distinguish
between active inammation and residual lung damage. As
BIPisonlyreversibleintheinammatoryphaseandnotin
the brotic stage, PET might be useful for deciding whether
to initiate/continue treatment with anti-inammatory agents
[].
8. Assessment of Pulmonary Function
Many clinicians obtain a baseline set of pulmonary function
test results before starting bleomycin. is practice is rec-
ommended in guidelines from the National Comprehensive
Cancer Network (NCCN). e most common abnormalities
associated with bleomycin-induced pulmonary toxicity are a
reduced carbon monoxide diusion capacity and a restrictive
ventilator defect []. Isolated gas transport abnormalities,
manifested by a decrease in diusing capacity and/or arterial
hypoxemia, especially with exercise, have been seen. In
a randomized trial comparing a cisplatin plus etoposide
regimen, with or without bleomycin, the reduction in carbon
monoxide diusion capacity was  to % in the bleomycin
arms compared to  to % without bleomycin [].
e usefulness of serial pulmonary function tests (PFTs)
for identication of patients who are developing BIP was
assessed by Wolkowicz and colleagues []. Fiy-nine
patients with nonseminomatous testicular carcinoma were
treated with bleomycin-containing regimens. Serial PFTs,
chest radiography and medical assessments were performed
prior to each course of bleomycin. Nine patients (.%)
developedpulmonarysymptomsduetobleomycinand
(%) had signicant changes in chest X-ray lms. e car-
bon monoxide diusion capacity decreased signicantly aer
bleomycintreatmentandwasthemostsensitiveindicator
of its pulmonary eects. However, it failed to dierentiate
patients with BIP from those without BIP. Total lung capacity
was found to be a much more specic indicator of BIP
because its reduction correlated with the development of
pulmonary symptoms and radiographic changes.
So far, no standard guidelines address restriction of
bleomycin prescription according to pulmonary function
test results. Most clinicians tend to avoid its use in patients
who have previously suered from moderate impairment
of pulmonary function or extensive lung disease that could
potentially compromise respiratory performance.
9. Risk Factors
Many studies have been performed to identify risk factors
for the development of bleomycin-induced lung toxicity.
However, most of these studies used dierent diagnostic
criteria. Furthermore, to establish BIP diagnoses, many
studies used lung function assessments that have since been
shownnottobespecicforBIPwhenbleomycinisused
in a multidrug regimen. erefore, comparison of studies
is severely hampered; indeed some are not suitable for the
purpose for which they were designed [].
e risk of bleomycin-induced lung toxicity is higher
in older patients. A British study reported that, among
 patients with germ-cell tumors who were treated with
bleomycin-containing regimens, age over  years was asso-
ciated with a .-fold higher risk of pulmonary complications
[]. In a study of  patients with Hodgkin’s lymphoma who
underwent regimens including bleomycin, the mean age of
those with and without lung toxicity was  and  years,
respectively (Martin, ). Cumulative doses of > U
are also associated with higher rates of pulmonary toxicity.
Although high-grade lung injury is very rare with cumulative
doses < U, injury can occur at doses less than  U. Rapid
intravenous infusion may also increase the risk of pulmonary
toxicity [].
Concomitant use of other chemotherapeutic agents is
associated with an increased risk of pulmonary toxicity. is
association is classically demonstrated with cisplatin, but
there are reports of an increase in the risk of lung toxicity with
regimens containing cyclophosphamide and gemcitabine. At
least some data suggest that high cumulative doses of cisplatin
also contribute to late impairment of pulmonary function
andrestrictivelungdiseaseinlong-termtesticularcancer
survivors. Since more than % of bleomycin is eliminated
by the kidneys in normal individuals, renal insuciency is
an established risk factor for bleomycin toxicity [].

Journal of Cancer Research 
e evidence that inhalation of high oxygen concentra-
tions may increase the risk of pulmonary toxicity in humans
islargelyanecdotal.Nonetheless,theanecdotaldatafrom
humans, combined with the results of laboratory studies
in animals, have led to widespread recommendations for
lifelong avoidance of high concentrations of supplemental
oxygen in patients previously exposed to bleomycin, unless it
is necessary to maintain adequate arterial oxygen saturation
[].
oracic irradiation increases the risk of bleomycin-
induced lung toxicity. It is unclear whether a long interval
between irradiation and administration of bleomycin elim-
inates the increased risk of lung injury. However, preliminary
evidence from a study of  patients with advance-stage
Hodgkin’s lymphoma suggests that the risk of pulmonary
toxicity during consolidative irradiation is low when there is
an interval of at least four weeks between chemotherapy and
irradiation [].
Concomitant treatment with granulocyte colony-
stimulating factor (G-CSF) was identied as a possible risk
factor for the development of bleomycin-induced lung injury
in animal studies. However, human data are conicting. One
reason for the conicting results may be the confounding
inuence of age on the incidence of bleomycin-induced
lung toxicity. Regardless, many clinicians avoid using G-
CSF in conjunction with regimens containing bleomycin,
particularly ABVD [].
O’Sullivan et al. described a prospectively collected se-
ries of  patients with germ-cell tumors treated with bleo-
mycin-containing regimens. Fiy-seven patients (.%)
had bleomycin pulmonary toxicity, ranging from X-ray/
computed tomography (CT) changes to dyspnea. Deaths in
eight patients (% of treated patients) were directly attributed
to bleomycin-induced lung toxicity. e median time from
the start of bleomycin administration to documented lung
toxicity was . months (range .–. months). In a mul-
tivariate analysis, the factors that independently predicted
increased risk of bleomycin-induced pulmonary toxicity
were GFR < mL/min [hazard ratio (HR ., % CI .–
.)], age > years (HR ., % CI .–.), stage IV disease
at presentation (HR ., % CI .–.), and cumulative
dose of bleomycin >, IU (HR ., % CI –) [].
10. Prevention and Treatment
e most eective way to manage pulmonary toxicity associ-
ated with chemotherapeutic agents is to prevent it. One of the
most ecient ways to prevent bleomycin-induced lung injury
is to lower the total cumulative dose of bleomycin. Studies
in patients with good-prognosis germ-cell cancer showed
that bleomycin could not be omitted completely from com-
bination chemotherapy without compromising results [].
However, Einhorn et al. showed that lowering the total dose of
bleomycin from  to  mg does not reduce the ecacy of
treatment of good-prognosis disseminated testicular cancer
[]. In patients with an unacceptably high risk of develop-
ing bleomycin-induced pulmonary toxicity, physicians can
consider treating with nonbleomycin-containing regimens.
In the treatment of germ-cell cancer, a regimen containing
etoposide, ifosfamide, and cisplatin had the same ecacy as
BEP but increased bone marrow suppression [].
e other malignancy for which bleomycin is oen
applied is Hodgkin’s disease. e total cumulative dose of
bleomycin is  mg/m2. Although the main cause of pul-
monary toxicity during treatment is the applied radiotherapy,
in patients at high risk of BIP, a non-bleomycin-containing
regimen such as mechlorethamine, vincristine, procarbazine,
andprednisone(MOPP)canbeused[]. e etoposide, vin-
blastine, and doxorubicin (EVA) regimen appears to have an
overall survival (OS) outcome comparable to that of ABVD
and unexpected lung toxicity []. Omitting radiotherapy
in patients with early-stage Hodgkin’s disease is a strategy
that is gaining acceptance and that would signicantly reduce
the incidence of bleomycin-induced lung injury. A recently
published trial showed that, among patients with stages I and
IIA nonbulky Hodgkin’s lymphoma, ABVD therapy alone,
as compared with treatment that included subtotal nodal
radiation therapy, was associated with higher OS owing to
a lower rate of death from other causes. PET-CT is also
becoming an important tool for safely suppressing the need
for radiotherapy [].
In animals, agents including soluble Fas antigen [], IL-
receptor antagonists [], dexrazoxane [], amifostine [],
and antibodies against TNF-𝛼[]andTGF-𝛽[]havebeen
successfully tested for the prevention or attenuation of BIP.
Recently, Dackor et al. showed that prostaglandin E2(PGE2)
protects murine lungs from bleomycin-induced pulmonary
brosis and lung dysfunction. PGE2prevented the decline
in lung static compliance and protected against lung brosis
when it was administered before bleomycin challenge but
hadnotherapeuticeectwhenadministeredaerbleomycin
challenge []. However, to our knowledge, no published
studies have identied agents that may prevent bleomycin-
induced pulmonary toxicity in humans.
Bleomycin should be discontinued in all patients with
documented or strongly suspected bleomycin-induced lung
injury. Treatment with glucocorticoids is reserved for patients
withsymptomaticlungtoxicityasspontaneousresolution
of asymptomatic radiographic opacities has been described
[]. Although no controlled studies in humans have sys-
tematically examined the ecacy of corticosteroids, a trial
oftheseagentsisprobablywarranted.Casereportsandcase
series have described substantial recovery when signicant
inammatory pneumonitis was present. e optimal dos-
ing and duration of glucocorticoid therapy for bleomycin-
induced lung injury are not known. Based on data from case
series, most authors recommend initiating treatment with
prednisone at . to mg/kg. Aer four to eight weeks, the
dose of prednisone is gradually tapered over an additional
four to six months, in accordance with the patient’s condition
and clinical response. Short-term improvement occurs in
 to % of glucocorticoid-treated patients, but symptoms
may relapse when therapy is tapered []. Unlike the most
common form of pulmonary pneumonitis, patients who
present with disease patterns compatible with organizing

Journal of Cancer Research
pneumonia and hypersensitivity pneumonia are known to
respond much better to corticosteroid therapy.
Clinical response usually occurs within weeks rather
than days and is most likely in those with a signicant
inammatory component. Doses can be tapered slowly over
weeks based on clinical response, with radiological improve-
ments and improvements in pulmonary function lagging
behind. Some clinicians argue that the improvements seen
with corticosteroids in small study groups may well be
due to incorrect diagnoses. Bleomycin-induced pneumonitis
closely resembles cryptogenic organizing pneumonia, which
is known to respond to corticosteroid therapy [].
Bleomycin-induced pneumonitis is thought to resolve in
the majority of patients over time, with improvements in
pulmonary function and radiology at > months. Complete
resolution of symptoms, signs, and abnormal radiology and
pulmonary function test results are less likely if the diagnosis
is delayed, if bleomycin therapy is continued,or if established
brosis occurs []. erefore, early suspicion is very impor-
tant and may guarantee a better prognosis.
11. Future Perspectives
Increased knowledge of the pathogenesis of bleomycin-
induced lung injury may lead to the development of agents
capableofpreventingortreatingestablishedBIP.Preclinical
studies reporting promising results with therapies such as
immunomodulators, tyrosine kinase inhibitors, monoclonal
antibodies, anti-inammatory agents, and transplantation of
human amnion epithelial cells were recently published. Some
of these therapies will be reviewed here.
Sirolimus, an immunosuppressant used to prevent rejec-
tion of transplanted organs, was eective in reducing brosis
score in a bleomycin-induced pulmonary brosis model,
especially in the early phases of the disease [].
A study by Wang et al. recently showed that getinib
reduces pulmonary brosis induced by bleomycin in mice
and suggested that administration of small-molecule epider-
mal growth factor receptor (EGFR) tyrosine kinase inhibitors
has the potential to prevent pulmonary brosis by inhibiting
the proliferation of mesenchymal cells and that targeting
tyrosine kinase receptors might be useful for the treatment
of pulmonary brosis in humans [].
Montelukast, a cysteinyl-leukotriene type  receptor an-
tagonist used in the treatment of inammatory lung disorders
such as asthma, was studied in a mouse bleomycin-induced
lung injury model. Treatment with montelukast signicantly
reduced the brotic area and hydroxyproline content in
the brotic lungs of bleomycin-exposed mice. Montelukast
exhibits its benecial eects by inhibiting the overexpression
ofIL-,IL-,IL-,andTGF-𝛽[].
Nilotinib has been approved for the treatment of chronic
myeloid leukemia in patients with resistance or intolerance
to imatinib. Like imatinib, nilotinib selectively inhibits the
tyrosine kinase activity of PDGFR. In a therapeutic model,
nilotinib showed more potent antibrotic eects than ima-
tinib [].
A recent report evaluated the inuence of the renin-
angiotensin system (RAS). Angiotensin-converting enzyme-
(ACE-) generated angiotensin II contributes to lung injury.
ACE, a recently discovered ACE homolog, acts as a negative
regulatoroftheRASandcounterbalancestheactionofACE.
Treatment of mice with intraperitoneal recombinant human
(rh) ACE ( mg/kg) for  days improved survival, exercise
capacity, and lung function and reduced lung inammation
andbrosis.rhACEmayhavethepotentialtoattenuate
respiratory morbidity in patients with bleomycin-induced
lung injury, as well as patients with acute respiratory distress
syndrome of other causes [].
Pravastatin is best known for its antilipidemic action.
Recent studies have shown that statins have immunomod-
ulatory and anti-inammatory eects. In one recent study,
pravastatin eectively attenuated histopathological changes,
the accumulation of neutrophils, and the production of TNF-
𝛼in a mouse model of bleomycin-induced lung injury and
pulmonary brosis [].
e importance of HER/HER signaling in reducing the
eects of lung injury was recently demonstrated. Transgenic
mice unable to signal through HER/HER had signicantly
less bleomycin-induced pulmonary brosis and showed a
survival benet []. A recent preclinical study that evaluated
the administration of C, a monoclonal antibody directed
against HER, demonstrated that HER/HER blockade
reduced collagen deposition and changes in lung morphol-
ogy. In addition, it resulted in a signicant survival advantage
with  versus % at  days. ese results conrm that
HER is a potential target that could be pharmacologically
targeted to reduce lung brosis and remodeling aer injury
[]. Human amnion epithelial cells (hAECs) have attracted
recent attention as a promising source of cells for regen-
erative therapies, with reports suggesting that cells derived
from human term amnion possess multipotent dierenti-
ation ability, low immunogenicity, and anti-inammatory
properties. Specically, in animal models of lung disease
characterized by signicant loss of lung tissue secondary
to chronic inammation and brosis, the transplantation of
hAECs has been shown to reduce both inammation and
subsequent brosis. A recent study performed using a mouse
model of bleomycin-induced pulmonary brosis showed that
transplantation of hAECs  h aer the administration of
bleomycin reduced expression of the genes encoding the
proinammatory cytokines TNF-𝛼,TGF-𝛽,IFN-𝛾,andIL-
. It also decreased subsequent pulmonary brosis, reducing
pulmonary collagen deposition, levels of 𝛼-smooth muscle
actin, and inammatory cell inltration. It was shown that
hAECs are able to prevent the decline in pulmonary function
associated with bleomycin-induced lung damage [].
To our knowledge, the rst publication reporting success-
fultreatmentofbleomycin-inducedlunginjurywasastudy
describing a case of complete resolution of life-threatening
bleomycin-induced pneumonitis aer treatment with ima-
tinib mesylate, a potent and specic receptor tyrosine kinase
inhibitor of ABL, BCR-ABL, KIT, and PDGFR. A patient
with Hodgkin’s lymphoma who developed severe BIP aer
undergoing an ABVD regimen was completely cured with

Journal of Cancer Research 
imatinib mesylate aer steroids and all other therapies had
failed [].
12. Conclusion
Bleomycin-induced lung injury is a major pulmonary toxic-
ity. e mortality of this complication is high, ranging from
 to %, and signicantly impacts quality of life and ve-
year OS. e diagnosis of interstitial lung disease and BIP
is particularly challenging and oen depends on clinical,
radiological, and cytological ndings. Progress in under-
standing the mechanisms behind the therapeutic ecacy
and unwanted toxicity of bleomycin, as well as elucidation
of its biosynthetic pathway, may lead to the development
of agents capable of preventing or treating BIP. Until then,
physicians administrating bleomycin should be aware of
potential lung toxicity, especially in the presence of risk
factors.
Conflict of Interests
ere is no conict of interests.
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