JOURNAL OF THE AMERICAN COLLEGE OF TOXICOLOGY

Volume 12, Number 1,1993

Mary Ann Liebert, Inc., Publishers

Drug-Induced Lung Toxicity

MANNFRED A. HOLLINGER

ABSTRACT

The number of blood-borne chemotherapeutic agents implicated in drug-induced lung toxicity

continues to increase, although problems in detection remain. The initiation of drug-induced
lung injury can have an immunologic or nonimmunologic basis. If endothelial cells are injured,
interstitial pulmonary edema may result. Regardless of the source of injury, the progression of
drug-induced lung toxicity is often quite similar, involving (1) parenchymal damage, (2)
recruitment of inflammatory cells, and (3) progression of the inflammatory process. If the
inflammatory reponse is sufficiently severe and disperse, increased collagen can be deposited in
interstitial and intra-alveolar areas. The resulting attenuation of gas exchange can induce
dyspnea and possibly death. Recent research suggests mediation of the fibrogenic process via
cytokines such as transforming growth factor+ and tumor necrosis factor. Preliminary results
demonstrating amelioration of cytokine mediated lung-induced fibrosis in animal models with
appropriate antibodies suggest a possible future modality of therapy. Certain amphiphilic drugs
are capable of eliciting a more specificform of lung toxicity. This class of drugs can interfere with
phospholipid metabolism in pulmonary macrophages. In these cases, phospholipidosis results
from phospholipid accumulation. The physiologic sequelae in human phospholipidosis is still
uncertain.

INTRODUCTION

I n order for a chemical substance, whether a therapeutic agent or not, to produce lung injury, it must gain access
to pulmonary tissue, either directly via the respiratory system or indirectly via the circulatory system. With
regard to agents that enter the respiratory system, the number of respirable, xenobiotic chemicals that a human can
be potentially exposed to is undoubtedly on the order of thousands. Most of these are nontherapeutic chemicals,
although the respiratory tract is also becoming more popular as a port of entry for drugs. Factors effecting transfer
of respirable xenobiotics, including drugs, from the airways to the lung have recently been reviewed by Taylor
(1990) and Gonda (1990a,b). Previously, Kehrer and Kacew (1985)reviewed the damaging effects of systemically
applied chemicals per se on the lung, while Witschi (1990) has analyzed toxicologic interactions in the
pathogenesis of lung injury. Cooper et al. (1986a.b) and Cooper and Matthay (1987). most recently, have
specifically reviewed the deleterious effects of drugs.
The present review will focus on pulmonary toxicity produced exclusively by drugs that reach the lungs via the
systemic circulation and primarily affect pulmonary parenchymal cells (i.e., alveolar type I and type II epithelial,
capillary endothelial, and interstitial mesenchymal)as well as rnacrophages. Although parenchymal cells comprise
only 5 of approximately40 cell types in the human lung, they represent more than 90% of the total cell population
(Crapo et al., 1982). The goals of this review are to update developments, primarily over the last 6 years, in our

Chairman, Department of Medical pharmacology & Toxicology, School of Medicine, University of California, Davis, CA.

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 HOLLINGER

understanding of (1) the number of drugs associated with lung injury, as well as (2) possible mechanisms of
drug-induced pulmonary injury. Particular consideration will be placed on three specific aspects of lung damage;
pulmonary edema, fibrosis, and phospholipidosis. In all cases, emphasishas been given to those drugs that produce
toxicity in humans and, when possible, citation to more extensive reviews on specific areas are also provided.

PHYSIOLOGIC AND ANATOMIC CONSIDERATIONS

The human lung has several features that make it a likely target for blood-borne toxicants. For example, it is the
only organ in the body that receives 100% of the cardiac output. Furthermore, it receives a rapid blood flow of
approximately 5Uminutes (Renwick, 1982) and its extensive pulmonary vasculature contains 10 to 20% of the
total body blood volume (Roth and Wiersma, 1979). Another important aspect is that, in humans, approximately
one-half of the total body endothelial cell mass is located in the lung (Nunn, 1987). This vascular arrangement
represents the most dense capillary network in the body and provides a total endothelial cell surface area of
approximately 125 M2 in a 70 kg adult. The significance of this large lung endothelial surface area is that it
represents a potential for exposure to blood-borne toxic agents that is approximately 70 times that of skin.
The lung also has active uptake processes that can concentrate certain drugs from the capillaries into
parenchymal cells (Gillis and Pitt, 1986). Uptake of drugs from lung capillaries is facilitated further by (1) the
permeability of the capillary endothelium itself, which is 10 times greater than the alveolar epithelium (Staub,
1974); (2) junctions between endothelial cells that are 5 times wider than those between epithelial cells (5 nM vs.
1 nM) (Nunn, 1987); and (3) the thickness of the total absorption barrier (endothelium and epithelium) being less
than 0.5 pm in parts of the alveolar region (Weibel, 1973).

INCIDENCE OF DRUG-INDUCED LUNG TOXICITY

Historical considerations
Drug-induced lung disease appears to be an increasingly frequent clinical problem (Martin, 1991), and the
number of drugs associated with parenchymal pulmonary injury in humans continues to grow. In 1972, 19 drugs
were identified as pneumotoxins (Rosenow, 1972);in 1986the list had increased to 37 (Cooper et al., 1986a,b) and
in 1987, to 40 (Cooper and Matthay, 1987). In 1992the number reached more than 50. In addition, at least 2 drugs
are known to specifically produce phospholipidosis in humans, and nearly 3 dozen to induce pulmonary edema.
Some authors, in fact, have suggested that as many as 80 different drug substances are liable to generate lung
disease (Pannier, 1983).

Problems in detecting drug-induced lung injury

For a number of reasons, the actual incidence of lung damage caused by drugs is somewhat difficult to ascertain.
For many drugs, actual harmful reactions in the lungs are still so relatively rare that they are published as anecdotal
reports. Even when a specific form of lung toxicity, such as bleomycin-inducedfibrosis, is estimated, the reported
frequency can range from 2 to 46% (DeLena et al., 1972) although it is usually considered to be 4% (Physician’s
Desk Reference, 1991). The overall incidence of pulmonary toxicity for the antiarrhythmic drug amiodarone is
estimated at 5 to 15%, with a reported mortality rate of 5 to 10% (Martin and Rosenow, 1988; Dunn and Glassroth,
1989; Mason, 1989; Dusman et al., 1990).
Delayed appearance of pneumotoxicity can also be a problem. For example, the ill-fated appetite suppressant
Aminorex@was on the European market for several years in the mid- 1960s before severe pulmonary hypertension
was associated with its use. Most cases of drug-related fibrosis are usually seen days, weeks, and even months after
chemotherapy. However, some patients have become symptomatic as many as 17 years after exposure to the drug
(Hasleton et al., 1991).
The reason(s) why the response to some drugs is sporadic and unpredictable is not known, although undoubtedly
multifactorial. Genetic predisposition, which has been demonstrated in animals, is an example of one factor that
may play a Ale in certain situations (Harrison and Lam, 1988). In pulmonary fibrosis, it has been demonstrated

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 DRUG-INDUCED LUNG TOXICITY

that there are clones of fibroblasts with individual growth characteristics (Jordana et a]., 1988). Some cases of
drug-induced lung injury are, in all likelihood, undiagnosed and incorrectly classified as idiosyncratic. Other
factors influencing drug-induced lung injury include dose, gender, age, concurrent ionizing radiation, interaction
with other drugs, and concomitant disease (e.g., renal and liver failure).

TYPES OF INJURY

Acute injury
Acute lung injury is often manifested as pulmonary edema. This occurs when the rate of transvascular fluid
filtration by the capillary endotheliumexceeds the rate of fluid removal by the lymphatics. Both cardiogenic and/or
noncardiogenicfactors can play a role in drug-induced pulmonary edema (Reed and Glauser, 1991). With regard
to the former, agents such as cocaine are believed to produce pulmonary edema as a consequence of pulmonary
hypertension, by virtue of impairing left ventricularcontractility(Lang and Maron, 1991). If retrograde pulmonary
vascular pressures rise sufficiently, there may occur a correspondingelevation in capillary permeability.
At least 34 drugs have been reported to produce noncardiogenicpulmonary edema (Table I). Noncardiogenic
pulmonary edema may be produced directly or indirectly via neurogenic or immunologic mechanisms. Unfortu-
nately, there are relatively few studies dealing with mechanisms of either type. Recent studies suggest that
cytokines may be involved in directly increasing vascular permeability following their release from pulmonary
cells (Hocking et al., 1990) possibly via destabilizing endothelial actin bands (Madara et a]., 1986), and
intercellularjunctional proteins (Johnson et al., 1989).
Tumor necrosis factor (TNF) appears to have a key role in the pathophysiology of diverse inflammatory states
(Cerami, 1992). Infusion of TNF into guinea pigs produces a significant increase in pulmonary permeability
(Stephens et al., 1988). In the isolated guinea pig lung, TNF-induced pulmonary edema appears to be
neutrophil-dependent,with platelet activating factor mediating the increased vascular permeability (Hocking et al.,
1990). The participation of neutrophils appears to be facilitated by TNF induction of cell surface adhesion
molecules such as ICAM and ELAM-1 on endothelial cells that bind to the CD18 integrin receptor on neutrophils.
Subsequent activation of neutrophils produces pulmonary edema as a result of both increases in vascular
endothelial cell permeability and pulmonary capillary hydrostatic pressure (Lo et al., 1992).
Central neurogenic disturbances produced by drugs such as the phenothiazinesmay result from a disturbanceof
hypothalamic function (Li and Gefter, 1992).
Reactive oxygen molecules have been implicated in endothelial damage (Henning et al., 1988) and edema
formation (Tate et al., 1982). In cultured monolayers of endothelial cells, enzymatically generated oxidants
produce changes in cell shape characterizedby a retraction of cells and the formation of numerous intercellulargaps
as well as an increase in permeability (Lofton et al., 1991). These changes are associated with a reduction in
cytoskeletal F-actin stress fiber length and number. In perfused rabbit lung, H,O, exposure produces an increase in
vasoconstriction mediated by thromboxane B, resulting in edema formation (Corten et al., 1991).

Chronic injury
Interstitial lung injury, if allowed to progress unrestrained, is frequently associated with the development of
pulmonary fibrosis, a process in which the normal pulmonary parenchyma is replaced by a collagenous matrix
(Crystal et al., 1984; Rennard et al., 1984a; Rennard et al., 1984b) incapable of gas exchange. Interstitial
pulmonary fibrosismay result from known (e.g., toxins inhaled via the airway or systemicallyadministered drugs)
or unknown (idiopathic) causes. However, it must be emphasized that to qualify for the latter there should be no
history of exposure to inhalants or drugs known to cause interstitiallung disease (Crystal et al., 1978). The intensity
of chronic lung inflammation and fibrosis following drug-induced lung injury is directly related to the severity of
acute injury (Shen et al., 1988) and has been associated with over 50 different drugs (Table 2). Development of
fibrosiswithin the alveoli appears to occur only under conditionsof significant disruption of the epithelial basement
membrane (Crouch, 1990).
Regardless of the variety of agents or conditions associated with this disease, the pathogenesis and ultimate
morphologic changes within the lung are quite similar. The classical pattern of lung injury can be divided into

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 HOLLINGER

TABLE1. DRUGSASSOCIATED
WITH NONCARDIOGENIC
PULMONARY EDEMA

Drug Reference
Amiodarone Satz et al., 1991
Amphotericin B Wright et al., 1981
Aspirin Heffner and Shan, 1981
Carbamazepine Begley, 1989
Chlordiazepoxide Demeter et al., 1979
Chlorothiazide Bowden, 1989
Chlorpromazine Li and Gefter, 1992
Cocaine (freebase smoked) Efferen et al., 1989; Kline and
Hirasuna, 1990
Colchicine Hill et al., 1975
Cytosine arabinoside Jehn et al., 1988
Dextran Kitziger et al., 1990; Choban
etal., 1991
Diltiazem Humbext et al., 1991
Ethchlorvynol Conces, 1986
Glycerol Almog et al.. 1986
Haloperidol Mahutte et al., 1982
Heroin Steinberg and Karliner, 1968
Hydrochlorothiazide Grace et al., 1989
Interleukin-2 Conant et al., 1989; Saxon et al.,
1991
Lidocaine Howard et al., 1982
Methadone Frand et al., 1972
Methamphetamine (crystal) Nestor et al., 1989a, b
Monooctanoin Shustack et al., 1986; Hine et al.,
1988
Morphine Lust and Maloley, 1988; Bruera
and Miller, 1989
Nalbuphine Stadnyk and Grossman, 1986
Naloxone Schwartz and Koenigsberg, 1987;
Wride et al., 1989
Naproxen Reeve et al., 1987
Nifedipine Prigogine et al., 1991
Ornithine-8-vasopressin Borgeat et al., 1990
Propoxyphene Bogartz and Miller, 1971
Prostaglandin F, alpha Wein et al, 1989
Pyrimethamine Pang, 1989
Radiocontrast medium Vandenplas et al., 1990;
Bouachour et al., 1991
Ritodrine Gupta et al., 1989; Chu and Hsu,
1990
Salbutamol Watson and Morgan, 1989
Terbutaline Mabie et al., 1983; Azarnivar
et al., 1991
Tocolytic agents Pisani and Rosenow, 1989

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 DRUG-INDUCED LUNG TOXICITY

AGENTSTHATCAUSEPULMONARY
TABLE2. PHARMACOLOGIC PARENCHYMAL
INJURY

Cytotoxic Drugs Noncytotoxic Drugs

Antibiotics Antibacterial Agents

Bleomycin Nitrofurantoin
Mitomycin Amphotericin
Neocarzinostatin Gentamicin (PDR, 1991 )
Alkylating agents Sulfasalazine
Busulfan Rifampicin (Umeki, 1988)
Cyclophosphamide Analgesics
Chlorarnbucil Acetylsalicylic acid
Ifosfamide (Baker et al., 1990) Opiates
Melphalan Heroin
Nitrosoureas Propoxyphene
Carmustine (BCNU) Methadone
Semustine (methyl CCNU) Sedatives
bnostine (CCNU) Ethchlorvynol
Chlorozotocin Chlordiazepoxide
Antimetabolites Anticonvulsants
Methotrexate Diphen ylhydantoin
Azathiopnne Carbamazepine
Mercaptopurine Mephenytoin (PDR, 1991)
Cytosine arabinoside Diuretics
Fludarabine monphosphate Hydrochlorthiazide
Miscellaneous Bumetanide (Bamett et al., 1990)
Procarbazine Major Tranquilizers
VM-26 Fluphenazine
Vinblastine Haloperidol
Vindesine Antiarrhythmics
Amiodarone
Lidocaine
Tocainide
Mexiletine (PDR, 1991)
An tidepressants
Fluoxetine (PDR, 1991)
Dothiepin (McEwan et al., 1986)
Miscellaneous
Deferoxamine (Freedman et al., 1990)
Gold salts
Penicillamine
Colchicine
Leuprolide (PDR, 1991)
Pergolide mesylate (PDR, 1991)
Methysergide (PDR, 1991)
Bromocriptine (Ward et al., 1987)
Buserelin" (Seigneur et al., 1988)
Nilutamide (Gomez et al., 1992)

Source: Modified from Cooper et al. (1986a,b), with new additions cited in parenthesis.
'Not approved for use in the United States.
Abbreviations: PDR, Physician's Desk Reference.

35
 HOLLINGER

several major stages: injury, disruption of the alveolar-capillary interface, extravasation of an exudate from the
vascular compartment into the air space, invasion of alveoli by fibroblasts and other inflammatory cell types and,
finally, new matrix deposition (Fukuda et al., 1987; Kuhn et al., 1989; Dunnill, 1990). Thus, pulmonary fibrosis
can be considered to be the end result of acute alveolar inflammation (i.e., "alveolitis"). The uptake of neutrophils
'
and other inflammatory cells following acute lung injury forms the basis for the use of "Indium-labeled leukocyte
scintigraphy in diagnosing drug-induced pneumonitis (Palestro et al., 1992).

MECHANISMS

Drug-induced injury to the lung apparently can occur by both immunologic and nonimmunologic means,
although the specific mechanisms of adverse reactions in the lung appear to be as diverse as the drugs themselves.
Histologic examination of the injured lung usually indicates an irregular pattern of inflammation, alveolitis, or
fibrotic development with a corresponding presence of inflammatorycells. Nevertheless, an a priori requirement
is that the causative agent must directly or indirectly interact with some critical lung parenchymal cell
macromolecule to initiate the pathologic process (Snyder et al., 1991).
It is now appreciated that a relatively common underlying mechanism of pathology induced by a number of
diverse xenobiotics is the formation of some type of oxygen-centered free radical (e.g.., superoxide, 0;;
hydroxyl, . OH) or "functional" free radical (e.g., hydrogen peroxide, H,O,) (Bishop et al., 1984; Clark et al.,
1985) in which there is an unpaired electron within the outermost orbital shell of the molecule. Of these, the
hydroxyl radical appears to be the most reactive and damaging chemical species (Halliwell, 1981). There are
various sources of oxygen free radicals within the lung, including polymorphonuclear leukocytes, eosinophils,
mast cells, and macrophages (Babior, 1984; Fantone and Ward, 1982).
We know that a number of pulmonary fibrogenic agents have the ability to generate reactive oxygen species
(Karlinsky and Goldstein, 1980; Shoenberger et al., 1984; Tryka et al., 1982) at least partially mediated by a
microsomal NADPH-dependentcytochrome P-450reductase (Holtzmanet al., 1981)and in the case of bleomycin,
via an iron mediated mechanism (Lown and Kim, 1977) and, for nitrofurantoin by cyclic reductiodoxidation
(Boyd, 1980). Although xenobiotics may initiate a cascade of oxy-radicals by different mechanisms, cells are
usually damaged in a similar fashion.
A possible additional mechanism for the generation of reactive oxygen species is via release from inflammatory
cells. For example, alveolar macrophages and neutrophils, which are the predominant inflammatory cells present
in fibrosing alveolitis (Crystal et al., 1981; Crystal et al., 1984; Reynolds, 1987), can both release reactive oxygen
species as well as proteases (e.g., neutrophil elastase and collagenase) (Gadek, 1992). Of the two cell types,
macrophages are believed to contribute more to the total oxidative burden in the lung because of their superiority
in numbers (Strausz et al., 1990), although neutrophils have been reported to be the prevailing cellular source
recovered in bronchoalveolar lavage samples (Behr et al., 1991). The neutrophil myeloperoxidase/H,O,/chloride
system (which generates hypochlorous acid or chlorinated amines) may also be of some pathogenic significance in
the development of the initial biochemical lesion.
Neutrophils and macrophages are not the only granulocytes present in alveolar tissues. Eosinophils are also
prominent and appear to respond to the same chemotacticsubstances as neutrophils. Tissue damage resulting from
eosinophils has been suggested to be due to cytotoxicity produced by the release of eosinophilic cationic protein,
major basic protein, and eosinophilic peroxidase (Gleich and Adolphson, 1986).
Regardless of their type or source, reactive oxygen species are believed to induce toxicity via lipid peroxidation,
protein degradation, depletion of NADPH, andlor breakage of DNA strands (Minchin and Boyd, 1983). Because
of their short half-life (McCord, 1979), these free radicals can induce lung injury only in areas where they are
generated, which basically means the physical presence of the offending drug molecule is needed to generate these
injurious factors within the tissue. Unfortunately, the lung has a relatively high vulnerability to the generation of
oxy-radicals since the process is dependent, in part, upon oxygen availability, which is, of course, highest in the
lung. Therefore, any drug that can directly or indirectly generate oxy-radicals can be expected to produce lung
injury.

36
 DRUG-INDUCED LUNG TOXICITY

Of the lung parenchymalcell population, endothelialcells appear to be particularly vulnerable to oxygen toxicity
(Crapo et al., 1980; De 10s Santos, et al., 1987), possibly due to either lower levels of endogenous antioxidant
enzymes (Bishop et al., 1984) or a greater proclivity for self-generation of toxic oxygen products (Ward, 1991).
The comparative sensitivity of endothelialcells is indicated by reports that (1) bovine pulmonary artery endothelial
cells are 14 times more sensitive to hydrogen peroxide than alveolar epithelial cells (Simon et al., 1986); and (2)
sheep endothelial cells are more sensitiveto endotoxin than alveolar epithelial cells (Wiener-Kronishet al., 1991).
The time course for oxygen metabolite-inducedtoxicity toward endothelial cells indicates that the oxy-radical
does not need to remain in the system for a prolonged period in order for the injury to evolve (Shasby et al., 1985).
An importantconsequence of endothelialinjury is the thickeningof the alveolar+apillary septa1space at the site of
endothelial injury.

COMPLICATIONS

Extravasation of fluid into alveoli

Following the specific chemical even@) that produces damage to the endothelial-alveolarinterface, extravasa-
tion of fluid occurs into the interstitium and alveolar spaces (Burkhardt, 1989). This alveolar exudate contains
fibrin fragments, fibronectin, and other adhesive and chemotactic substances (Song et al., 1986; Schleimer et al.,
1991), as well as degranulating neutrophils and platelets (Fantone and Ward, 1982; Schraufstatteret al., 1984). A
substantial body of evidence indicates that cytokines are secreted by various inflammatory cells and target cells
within injured lungs (Kroemer and Martinez-A, 1991) and that these factors have the potential to alter subsequent
growth repair of the lung (Bitterman, et al., 1988; Dubaybo and Thet, 1990; Elias, J.A. et al., 1987; Goldstein and
Fine, 1986; Lemaireet al., 1986; Martinet et al., 1987; Rennard et al., 1981; Kelley, 1990.)
Recently, three peptides (1 4-38 KD) related to platelet-derivedgrowth factor (PDGF) have been recovered from
bronchoalveolar lavage samples from patients with severe, acute, diffuse lung injury (Snyder et at., 1991). It has
been hypothesized that these peptide moieties may participate in signaling mesenchymal cell migration and
replication on the alveolar epithelial surface. The glycoprotein vitronectin (which resembles fibronectin
functionally) has also been reported to be elevated in patients with interstitial lung disease (Pohl et al., 1991).
Vitronectin is a normal constituent of the epithelial lining fluid and, by virtue of its capacity to promote cell
substrate and cell-cell interactions, it may be a modulatorof inflammation and repair. Cytokines do not universally
play a proinflammatory role, however, since interleukin-1 can protect against lung toxicity caused by cyclophos-
phamide and irradiation (Done et al., 1991).
Recent studies of idiopathic fibrosis indicate an increase in the expression of the C-sislPDGF-2 proto-oncogene
in epithelial cells of lung tissue (Antoniadeset al., 1990). Localized and sustained production of this mitogen may
represent a significant factor contributing to abnormal fibroblast proliferation and collagen production. In view of
the fact that acute injury can lead to expressionof proto-oncogenesin the epithelium, it is possible that certain drugs
may also produce some of their fibrogenic potential via activation of similar proto-oncogenes. Anticancer drugs,
such as bleomycin, would be the most likely candidates because there is evidence that DNA damage may alter gene
expression (Hollander and Fornace, 1989; Fomace et al., 1989).

Release of chemotactic substances

Although a number of chemoattractantsare undoubtedly released following lung injury, the transforming growth
factor+ (TGF-P) family is an example of a new generation of peptides that have recently been associated with
pulmonary fibrotic diseases (Khalil et al., 1989,1991) and may be important in tissue repair. TGF-P is stored in the
a granules of platelets, which are among the frst cells to reach the site of injury (Assoian and Spom, 1986). as well
as activated macrophages and lymphocytes (Assoian et al., 1987; Kehrl et al., 1986). In platelets, TGF-P occurs
primarily as an inactive precursor that is associatedwith a high-molecular-weightbinding protein (Miyazonoet al.,
1988). However, platelets also release an active form of TGF-P (Slivka and Loskutoff, 1991) that appears to be
associatedwith thrombospondin(Murphy-Ullrichet al., 1992). Transcriptsfor the genes encoding for TGB-P have

31
 HOLLINGER

also been detected in smooth muscle and connective tissue fibroblasts supporting the large airways and blood
vessels in the adult mouse lung (Pelton et al., 1991).
TGF-p is a potent chemoattractant for fibroblasts (McCartney-Francis, et al., 1988), monocytes, and
macrophages and can induce transcription of other growth factors (Wahl et al., 1987; McCartney-Francis,et al.,
1988). TGF-p is also mitogenic for immature fibroblasts (Hill et al., 1986) and can stimulate fibroblasts to
synthesize collagens type I and III (Rossi et al., 1988) and that this stimulating effect is preceded by increased
TGF-p mRNA formation (Hoyt and Lazo, 1988). Recently, TGF-P expression in alveolar macrophages has also
been demonstrated in lung tissue from patients with idiopathic pulmonary fibrosis (Broekelmann et al., 1991).
TGF-p generated in the course of experimental mouse hypersensitivity pneumonitis has also been shown to
contribute significantly to lung collagen synthesis (Denis and Ghadinan, 1992).
The profibrotic property of another cytokine, TNF, has also been indirectly demonstrated. In this case, anti-TNF
antibodies administered to mice protected them against bleomycin- or silica-induced collagen deposition in the
lung (Piguet et al., 1989; Piguet et al., 1990). Recently, direct results demonstrating an increase in lung TNF
mRNA and macrophage TNF activity has been reported in bleomycin-sensitive mice (Phan and Kunkel. 1992).
Release of cytokines such as TNF at sites of inflammation results in augmented cellular expression of intercellular
adhesion molecule-1, which may mediate the accumulation of neutrophils (Barton et al., 1989).
As indicated above, resident macrophages are one of the cell types that secrete factors involved in the mediation
of the fibrotic process. However, until recently there has been relatively little direct evidence for the interaction of
pneumotoxins with pulmonary macrophages, although internalizationof bleomycin into macrophages is known to
occur. Unfortunately, evidence that this process is receptor-dependenthas been lacking. Significantly, the recent
results of Denholm and Phan (1 990) indicate the presence of two populations of specific receptors for bleomycin on
rat alveolar macrophages (presumably membrane sites). The significance of this observation is that the K, of the
high affinity site (528 nM) is within the concentration range reported to produce the release of numerous fibroblast
growth factors from macrophages.

New matrix deposition

In response to injury, the lung, like other organs, has the capacity to respond, by recruitment of myofibroblast
cells into injured sites followed by angiogeneses and reepithelialization. Among the numerous factors influencing
mesenchymal cell activity, it has recently been reported that fibroblast proliferation is stimulated by oxygen-free
radicals (Murrell et al., 1990), thereby providing a common thread whereby drugs may act. When fibroblast
activation does occur within the lungs, there are two areas of proliferation that can be recognized: (1) interstitial
fibrosis in alveolar walls and (2) intra-alveolarfibrosis. The extent to which the fibrotic repair process replaces the
original parenchymal architecture of the lung with collagen determines the degree of “remodeling.” Those areas
that are “remodeled” are relatively disorganized due to the action of local proteases and air spaces tend to be
irregularly shaped with thickened, edematous, fibrotic walls.
The accumulation of collagen within the parenchyma represents the end result of a “repair cascade” (Laurent,
1986), is subject to considerable individual variability, and can be either diffuse or localized, depending on the
nature of the injury and which fibroblastsare activated (Jordana et al., 1988). If fibrosis proceeds beyond a certain
point, the diffusion and mechanical properties of the lung can be compromised by the accumulated collagen,
resulting in hypoxia, dyspnea, or death. For example, mortality from bleomycin pulmonary toxicity, has been
reported to occur in 1 to 2% of those treated (Comis et al., 1979).
Under normal circumstances. the protein collagen represents 15 to 20% of the total mass of an adult human lung
and 60to 70% of the total connective tissue mass (Hance and Crystal, 1976; Horwitz et al., 1976). This steady-state
level of lung collagen is normally regulated by a series of enzymatic biosynthetic steps as well as by degradative
processes (collagenase)within fibroblasts. Both enhanced synthesis and reduced degradation appear to play a role
in the development of pulmonary fibrosis (Selman and Pardo, 1991). Collagen normally functions to provide the
principal architectural frameworkof the lung and is a central component of the fibrous support scaffold. Normally,
the alveolar interstitium contains at least three types of collagen, which have characteristicamino-acid sequences.
Studies in tissue culture suggest that most of the cells within the alveolar unit can produce collagen. For recent
overall comprehensivereviews of the role of collagen in lung fibrosis, see Gin (1990), as well as Lazo and Hoyt
(1990).

38
 DRUG-INDUCED LUNG TOXICITY

DRUG-INDUCED PHOSPHOLIPIDOSIS

In certain cases, drug toxicity can be manifested in the lung in a relatively rare manner. Phospholipidosis, for
example, is a disorder of phospholipidmetabolism associated with amphiphilicamines that have pKavalues greater
than 8. Structurally, amphiphilic drugs are molecules that contain a hydrophobic group (usually an aromatic ring
often substituted with a halogen) connected to a hydrophilicmoiety (an amino group charged at physiologic pH) by
an aliphatic side chain.
While numerous amphiphilic drugs have been shown to produce phospholipidosisin animals (Table 3) only two,
amiodarone and 4,4'-diethylaminoethoxyhexestrol,have been linked to phospholipidosis in humans (Marchlinski
et al., 1982;Akeda, 1972). In the case of amiodarone, its principal metabolite (desethylamiodarone)is also active
(Kannan et al., 1991). In patients, the development of adverse reactions to amiodarone is usually related to dose
and duration of therapy (Hank et al., 1983; Rakita et al., 1983; Heger et al., 1983; Haffajee et al., 1983; Falik et
al., 1987). Some authors have suggested that toxicity is more likely when the daily dose exceeds 400 mg and the
cumulative dose exceeds 100 g (Adams et al., 1988;Kupferschmidet al., 1989) while others have indicated lesser
doses (Rotmensch et al., 1984). For a recent view, the reader is referred to Pitcher (1992).
While phospholipidosis induced by this class of drugs may occur in diverse cells throughout the body (Coulombe
and Bendayan, 1989; Lewis et al., 1989), as well as in the lung (Coulombe and Bendayan, 1989). it is the
pulmonary macrophage that is affected pnmady, and this has been studied most extensively (ffruban, 1984;
Reasor, 1987). Morphologically, the most prominent alteration of the macrophage is hypertrophy; the result of
engorgement with accumulated phospholipid and characterized by lamellar inclusion bodies that originate in
lysosomes. Normally, alveolar macrophages contain only about 3% of the total pulmonary phospholipid in the rat
but, following treatment with chlorphentermine, for example, this is increased to 34% (Heyneham and Reasor,
1986a). In vitro cell culture studies indicate that several specific phospholipids, including phosphatidylinositol,
phosphatidic acid, and bis (monoacylglycerol)phosphate are all significantly increased to a greater extent than
other phospholipids (Martin et al., 1989).
The underlying mechanism(s) for the induction of phospholipidosis by amphiphilic drugs has become clearer
over the last several years. Using amjodaroneas an example, the following sequence of events is believed to take
place. After passive absorption of the nonionized form of the drug across the plasma membrane of endothelial and
epithelial cells, macrophageuptake occurs by either diffusion (Forman et al., 1982; Bend et al., 1985)or facilitated
diffusion(Heyneham and Reasor, 1986b). The drug then passes into macrophage lysosomes, where the relatively
acidic pH of this organelle induces protonation of the amino group nitrogen (Vestal et al., 1980). The positively
charged form of the drug then presumably forms a complex with the negatively charged phosphate moiety of the

TABLE3. DRUGSREPORTED
TO PRODUCE PHOSPHOLIPlWSIS IN
EXPERIMENTAL
ANIMALS

Chlorphentermine Cyclizine
1-Chloramitriptyline Nor chlorcyclizine
Clofex Homo chlorcyclizine
Fluoxetine Hydroxyline
Chlorcyclizine Meclizine
Triparanol Ethyl fluclozepate
4,4'-diethylaminoethoxy hexestrol Tamoxifen
AmiodarAne Chloroquine
Iprindole Haloperidol
Imipramine Citalopram
I-Chloro-l0,l I-dehydroamitriptylline Amboxol
Chlomipramine Fenfluramine
Zimelidine
Source: Adapted from Reasor (1987).

39
 HOLLINGER

phospholipid. In addition, binding of amphiphilic drugs to hydrophilic or hydrophobic moieties of lamellar bodies
has been reported to vary from drug to drug, with the affinitiesof chlorinated analogs being stronger to hydrophilic
sites (Joshi et al., 1989).
A likely consequence of the formation of this new drug-phospholipid complex is that the phospholipid
component of the complex becomes resistant to phospholipase-mediateddegradation. Significantly,the binding of
drugs to lamellar bodies has been shown to correlate with phospholipidosis-inducing capacity (Joshi et a]., 1989).
The formation of the drug-phospholipid complex has several other possible ramifications. First, the level of free
protons within the lysosomes may decrease, leading to an elevation in intralysosomal pH. This elevation in pH may
contribute to a decline in phospholipase A and A, activity (Heath et al., 1985; Hostetler et al., 1986; Martin et al.,
1989). Thus, the complex may not only be more resistant to degradation by phospholipases, but activity of the
enzymes themselves may also be decreased. Furthermore, the formation of the complex would be expected to
induce a shift in the equilibrium from the “free-pool” and thus provide more drug and phospholipid. Hence, the
drug complex will tend to accumulate due to (1) mass-action, as long as free drug is available; and (2) diminished
destruction. The above scenario is consistent with the high tissue-to-plasma levels reported for these drugs. That
the complex is reversible is indicated by the fact that withdrawal of the drug reverses phospholipid accumulationin
the macrophage.
Despite increased understanding of the mechanism of amiodarone-induced phospholipidosis, the question
remains of how this process relates to pneumonitis and fibrosis that may occur following exposure to amiodarone.
Changes in lung mechanics have been observed to occur in experimentalanimals with phospholipidosis (Camus et
al., 1989) and the phospholipidosis has been reported to correlate with pulmonary inflammation (Wilson et al.,
1991). Although foamy macrophages and cytoplasmic lamellar inclusions are characteristic of drug-induced
phospholipidosis, it has been questioned whether their presence alone distinguishes toxic from nontoxic patients
(Meyers et al., 1987). Nevertheless, while they may be present in patients without symptoms of amiodarone
pulmonary toxicity, they are a consistent feature of lung injury associated with amiodarone (Dean et a!., 1987).

ACKNOWLEDGMENT

The author would like to acknowledge the excellent secretarial assistance of Cynthia Nofziger.

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