232 Endocrine, Metabolic & Immune Disorders - Drug Targets, 2007, 7, 232-236

Tetracyclines and Pulmonary Inflammation

*
S. Rempe, J.M. Hayden, R.A. Robbins and J.C. Hoyt

Research Service, Carl T. Hayden VA Medical Center Phoenix, AZ, University of Arizona, Tucson, AZ, USA

Abstract: Tetracycline and its derivatives, such as chlortetracycline, oxytetracycline, minocycline, doxycycline, methacy-
cline and lymecycline, are naturally occurring or semi-synthetic polyketide compounds that exhibit a well known broad-
spectrum antibacterial activity that interferes with prokaryotic protein synthesis at the ribosome level. In addition to this
well known antibacterial activity these compounds also exhibit a variety of additional, less well known properties. Among
them are separate and distinct anti-inflammatory properties. Tetracycline and related compounds have been shown to be
effective chemotherapeutic agents in a wide variety of chronic inflammatory diseases and conditions. These include pe-
riodontitis, rosacea, acne, auto-immune diseases such as rheumatoid arthritis and protection of the central nervous system
against trauma and neurodegenerative diseases such as stroke, multiple sclerosis and Parkinson disease. Tetracycline and
related compounds appear to be beneficial for treatment of several chronic inflammatory airway diseases. Among them
are asthma, bronchiectasis, acute respiratory distress syndrome, chemical induced lung damage and cystic fibrosis. The
clinical use of tetracycline-type drugs in treatment of chronic airway inflammation is becoming a topic of intense interest.
Recent findings in this area have led to an understanding of the myriad physiological, cellular and molecular mechanisms
of the inflammatory response and how this response may be controlled to limit damage to host cells and tissues. This re-
view presents a brief summary of the recent research in the area of tetracycline and its derivatives in control of pulmonary
inflammation.
Key Words: Tetracycline, doxycycline, lung, inflammation.

INTRODUCTION well known antibiotic or antibacterial actions. Presently a

Tetracyclines, discovered in 1948, are a group of poly-
ketide antibiotic compounds, produced in the soil by several
members of the bacterial genus Streptomyces. In 1954 the
first member of the tetracycline family to be characterized,
chlortetracycline Fig. (1), was isolated from fermentation
broths of Streptomyces aureofacians [1]. Clinical studies
with this newly discovered antibiotic demonstrated advan-
tages over penicillin such as a greater spectrum of antibacte-
rial activity and fewer adverse effects. Since the discovery of
chlortetracycline (1) other naturally occurring derivatives
such as tetracycline (2) and oxytetracycline (3) have also
been isolated. Modification of these naturally occurring anti-
biotics has lead to the development of a series of clinically
useful semi-synthetic tetracycline derivatives Fig. (1). Among
these derivatives are minocycline (4), doxycycline (5),
methacycline (6) and lymecycline (7). These semi-synthetic
tetracycline derivatives often exhibit increased absorption,
decreased bacterial resistance and increased efficacy over the
naturally occurring analogs [2] The biosynthesis, chemical
and physical properties of the tetracycline compounds has
been well described in several review articles [2,3] and will
not be covered in this brief review.
During the 1980s Golub et al. [4] observed that mino-
cycline decreased gingival collagenase levels and retarded
alveolar bone loss in germ-free diabetic rats giving the first
indication that tetracycline-type compounds exhibit a second
mode of action, anti-inflammatory action, in addition to their
*Address correspondence to this author at the Carl T. Hayden VA Medical
Center, Research (RS/151), Building 27, 650 East Indian School Road,
Phoenix, AZ 85012, USA; Tel: (602) 277-5551; Fax: (602) 212-2047;
E-mail: jeff.hoyt2@va.gov
subantimicrobial dose of doxycycline is an approved treat-
ment for inflammation associated with periodontal disease
[5].
Since this first demonstration of anti-inflammatory action
in periodontal disease, the tetracycline and related com-
pounds have been examined in additional clinical settings.
Inflammation and underlying tissue destruction caused by
two potentially disfiguring diseases acne vulgaris and ro-
sacea has been shown to be dramatically reduced by low
dose doxycycline therapy [6]. O’Dell et al. [7] demonstrated
that doxycycline with methotrexate was a superior treatment
over methotrexate alone in the treatment of early seroposi-
tive rheumatoid arthritis patients. However, little benefit was
observed if treatment was delayed for a substantial time. It is
thought that anti-inflammatory action of doxycycline is
caused by inhibition of the collagenase activity of one or
more matrix metalloproteinase enzymes. In a similar study
lymecycline was demonstrated to be of possible benefit in
the treatment of reactive arthritis [8]. Minocycline has re-
ceived attention as a possible protective agent in neurologi-
cal injury and disease in part because of its ability to diffuse
into the central nervous system and reach therapeutic con-
centrations. Minocycline has been shown to decrease proin-
flammatory cytokine production and decrease neural cell
death leading to improved functional outcomes of spinal
cord injured rats [9]. Other studies have shown that mino-
cycline reduces inflammation in the brain by inhibition of
matrix metalloproteinases and microglial activation [10].
Other neurological diseases that may benefit from the anti-
inflammatory action of minocycline include stroke, multiple
sclerosis, Parkinson disease, amyotrophic lateral sclerosis,
Alzheimer disease and Huntington disease [10]. Using a sim-
ian immunodeficiency model of human immunodeficiency

1871-5303/07 $50.00+.00 © 2007 Bentham Science Publishers Ltd.

Tetracyclines and Pulmonary Inflammation Endocrine, Metabolic & Immune Disorders - Drug Targets, 2007, Vol. 7, No. 3 233

R4 R2 R3 R1 R
OH
6 5 4
8 7 3
D C B A O
9 10 11 12 2
1

OH HN
OH O OH O R5

R R1 R2 R3 R4 R5
1 Chlortetracycline -N(CH3)2 -H -CH3 -H -Cl -H
2 Tetracycline -N(CH3)2 -H -CH3 -H -H -H
3 Oxytetracycline -N(CH3)2 -OH -CH3 -OH -H -H
4 Minocycline -N(CH3)2 -H -H -H -N(CH3)2 -H
5 Doxycycline -N(CH3)2 -OH --CH3 -H -H -H
6 Methacycline -N(CH3)2 -OH =CH3 -- -H -H
7 Lymecycline -N(CH3)2 -H -CH3 -OH -H -N-
-Methylene Lysine
8 CMT-8 -H -H -H -H -H -H

Fig. (1).

virus (HIV) central nervous system disease Zink et al. [11]
have demonstrated that minocycline treatment reduced se-
verity of encephalitis, suppressed viral load and decreased
expression of various inflammatory markers. This fascinat-
ing work indicates that minocycline may be a possible anti-
inflammatory therapy for HIV disease.
PULMONARY INFLAMMATION AND TETRACY-
CLINES
Common airway diseases are the result of injury to the
lung, are characterized by changes in lung function, tissues
and fluids and are associated with chronic inflammation.
Current thinking suggests that this inflammation is caused by
chemical attractants, such as cytokines and lipid factors, that
lead to the migration and accumulation of inflammatory cells
in the lung tissues and airspaces. The type of injury (e.g.
infectious, allergy or smoke/chemical inhalation) will deter-
mine the pattern or type of cell infiltration [12]. This cell
migration is followed by lung tissue inflammation and dam-
age. Despite considerable research, the role of these chemi-
cal attractants and conditions that control their function in
airway diseases remain unclear. This brief review covers
research findings concerning tetracycline-type antibiotics
and their effect on inflammatory pulmonary diseases.
Distribution of Drugs in Lung Tissues
Whether antibiotic compounds are used to treat bacterial
infections or to treat inflammation their ultimate disposition
in tissues and cells must be considered. Oral or systemic
administration of antibiotics leads to their accumulation
through out the body including lung tissues. However, many
factors or mechanisms effect the ultimate disposition of these
agents in the lungs. Among these mechanisms are transport
of the agent into the respiratory tract tissues from the cardio-
vascular system, host-related factors such as inflammation
and mechanical injury and antibiotic-related factors such as
molecular weight, hydrophobicity, degree of protein binding,
biotransformation or destruction of the drug, the speed of
absorption and excretion and the final concentration achieved
[13]. These factors influence the choice of antibiotic, includ-
ing tetracycline and its derivatives, used in the treatment of
pulmonary inflammation.
Effect of Tetracyclines on Pulmonary Inflammation
The inflammatory response consists of a diverse, com-
plex series of chemical messengers and cellular events that
can occur throughout the lung. The anti-inflammatory effects
of tetracyclines may occur at a variety of different sites and
in differing ways and tetracycline-type drugs exhibit good
tissue penetration exceeding therapeutic concentrations [13-
15] making these drugs possible anti-inflammatory agents.
Inflammation is a continuous process in lung tissues. It
serves as a host defense to protect the lungs from infectious
and noxious agents. However, it is a thin line between in-
flammation protecting the lungs and inflammation actually
causing tissue destruction [16]. Matrix metalloproteinases,
nitric oxide and neutrophil elastases are some of the many
potentially damaging mediators found in inflamed lung tis-
sues.
Matrix Metalloproteinases
Matrix metalloproteinases (MMP) are a family of zinc
dependent endopeptidase isozymes which are able to degrade
the extracellular matrix and are responsible for tissue remod-
eling and damage in many situations. They are involved in
wound healing, cancer progression and have also been im-
plicated in causing lung damage in various lung diseases.
There are more than 20 MMPs known. In the lung two MMP
isozymes, MMP-2 (gelatinase A) and MMP-9 (gelatinase B),
have roles in lung tissue remodeling and damage. Both
isozymes are released from non-inflammatory cells, while
inflammatory cells mainly produce MMP-9 [17-19]. These
two isozymes degrade gelatin and collagen localized to the
endothelial basement membrane and basement membranes
of smooth muscle cells of the intima and media. MMPs have
been implicated in the pathogenesis of many lung disorders.
Increased levels of MMPs have been found in bronchoalveo-
lar lavage (BAL) fluid of acute respiratory distress syndrome
(ARDS) patients and it has been suggested that they play a
234 Endocrine, Metabolic & Immune Disorders - Drug Targets, 2007, Vol. 7, No. 3
major role in ARDS and in its development of capillary leak
syndrome [20,21]. MMPs also play a role in chronic in-
flammation in cystic fibrosis (CF). Sagel et al. [22] showed
that induced sputum levels of MMP-9 were significantly
increased in children with CF compared with healthy con-
trols. They also showed that the ratio of MMP-9 to its inhibi-
tor, TIMP-1, was higher in cystic fibrosis patients compared
with controls and that there was a significant inverse rela-
tionship between MMP-9 and FEV1. Similarly Ratjen et al.
[23] showed increased levels of MMP-8 and -9 in pulmonary
lavage fluid of children with cystic fibrosis. Excessive levels
of MMP-8 and -9 have also been found in patients with hos-
pital-acquired pneumonia [24] and an abundance of MMPs
have been found in sarcoid granulomas [25].
Given the role of MMPs in these and many other lung
disorders it appears crucial to apply some therapeutic inter-
vention. Golub et al. [4] demonstrated that minocycline in-
hibited collagenase (one form of MMP). Since then tetracy-
cline and several of its derivatives have been shown to in-
hibit the activity of a variety of MMP isozymes indicating a
possible treatment for inflammation and inflammatory lung
diseases. Recent work by Garcia et al. [26] examined the
mechanism of doxycycline inhibition of matrilysin (MMP-7)
using deuterium exchange mass spectroscopy. Matrilysin
inhibition is apparently not due to binding of doxycycline to
the enzyme’s active site but rather by its interaction with
enzyme bound zinc or calcium atoms that are required for
structural stability of the enzyme. Binding of doxycycline to
these metal atoms apparently destabilizes the enzyme struc-
ture leading to loss of activity.
Lee et al. [27] examined the effect of doxycycline on
airway hyper-responsiveness and inflammatory mediators in
toluene diisocyanate-induced (TDI) asthma using a murine
system. TDI is a common cause of occupational asthma
which is characterized by airway hyper-responsiveness and
inflammation. Doxycycline (20 mg/kg) was administered by
gavage daily for six days before TDI challenge. Doxycycline
was found to reduce MMP-9 mRNA and protein levels, de-
crease the number of lymphocytes, eosinophils and neutro-
phils in airway lumen and reduce airway hyper-responsive-
ness compared to untreated controls.
Palei et al. [28] examined the role of MMP-2 and MMP-
9 during acute pulmonary embolism (APE) in rats. Doxycy-
cline, 30 mg/kg injected i.v., was found to decrease MMP-9
activity but not MMP-2 activity after embolization. MMP-9
is involved in regulation of vascular tone through endothelin-
1 release [29]. It is possible that APE enhanced production
of MMP-9 is responsible for increased activation of endo-
thelin-1 and that doxycycline inhibition of MMP-9 may ac-
count for endothelin-1 mediated hemodynamic changes dur-
ing APE [30].
The severity of bronchiectasis has been found to correlate
with the levels of neutrophil collagenase (MMP-8) contained
in bronchoalveolar lavage (BAL) fluid [31]. A correlation
between the levels of active MMP-8 and severity of lung
tissue damage in bronchiectasis was confirmed. Exposure to
doxycycline inhibited MMP-8 activity further suggesting
that it may be a possible therapeutic intervention to prevent
long term tissue damage in bronchiectasis.
Rempe et al.
Guignabert et al. [32] used guinea pigs to induce respira-
tory epithelial lesions via intra-tracheal administration of
sulfur mustard. Sulfur mustard, a vesicant, is a chemical war-
fare agent that causes severe blistering when it makes contact
with tissues and cells. They demonstrated increased levels of
gelatinase in BAL fluid 24 hours after exposure by zy-
mographic analysis of biotinylated substrate degradation.
Treatment with subcutaneous administration of doxycycline
(30 mg/kg) 3 hours before exposure to sulfur mustard de-
creased gelatinase activity, inflammation and epithelial le-
sions. Rappenau et al. [33] used the human bronchial epithe-
lial cell line 16HBE14o- to demonstrate that a combination
of N-acetyl cysteine and doxycycline provided improved
protection against sulfur and nitrogen mustard vesicants over
each separate treatment.
Nitric Oxide
Nitric oxide (NO) is constitutively produced at low basal
levels by many pulmonary cells by the constitutive nitric
oxide synthase (NOS) type I or type II isozymes or can be
produced in larger amounts during inflammation by the in-
ducible form of NOS (iNOS or type II NOS). NOS catalyzes
oxidation of L-arginine to NO and L-citrulline. NO is a free
radical which under physiological conditions is responsible
for controlling the smooth muscle tone in vessels and air-
ways. It also acts as a proinflammatory mediator. NO can
react with superoxide produced by activated macrophages to
produce peroxynitrite, a powerful oxidizing agent, which
may cause wide spread, severe lung damage. NO production
has been implicated in the pathogenesis of many inflamma-
tory lung diseases including ARDS, reactive airway disease
and cystic fibrosis. It is also believed to be involved in silica-
induced lung disease [34]. Genovese et al. [35] examined the
role of NO in bleomycin-induced lung disease. Mice that
lacked the iNOS gene and that had received bleomycin de-
veloped less severe lung injury, namely decreased edema and
PMN induced inflammation, leading to a decrease in rate of
mortality.
The effect of doxycycline on NO production by LA4
murine lung epithelial cells has been examined [36]. Doxy-
cycline decreased iNOS catalyzed production of NO via a
reduction in iNOS protein and iNOS mRNA. In addition
doxycycline decreased production of p38 MAP kinase which
in turn decreased the stability of iNOS mRNA ultimately
leading to decreased production of NO. In similar work
D’Agustino et al. [37] found that doxycycline treatment re-
duced mortality arising from endotoxemia in a murine
model. Doxycycline was found to reduce synthesis of iNOS
in endotoxin-stimulated macrophages by an IL-10 independ-
ent mechanism, and the reduction of NO production after
exposure to endotoxin may have reduced inflammatory dam-
age from septic shock.
Neutrophil Elastase
Neutrophil elastase (NE) is a serine protease located in
azurophil granules of leukocytes. NE degrades elastin, an
extracellular matrix protein of the lung, which gives lungs
their elastic recoil. This degradation, if uncontrolled, may
cause severe inflammation and tissue damage. NE has been
implicated in various inflammatory lung diseases including
Tetracyclines and Pulmonary Inflammation
ARDS [38], chronic obstructive pulmonary disease (COPD)/
emphysema [39] and cystic fibrosis [40]. An imbalance be-
tween NE and its inhibitors, such as alpha-1-antitrypsin,
seems to play a key role in these diseases [41]. Tetracycline
derivatives have been reported to prevent MMP-catalyzed
degradation of NE inhibitors protecting the extracellular ma-
trix from extensive destruction [42].
Effect on Cytokines
Monocyte chemoattractant protein-1 (MCP-1) is a major
pro-inflammatory chemokine found in chronic pulmonary
disease and is a potent chemoattractant for monocytes. Using
A549 human lung epithelial cells Raza et al. [43] were able
to show that doxycycline, 30
g/ml, decreased production of
MCP-1. Expression of MCP-1 mRNA was found to be de-
pressed by doxycycline treatment. In a similar fashion inter-
leukin-8 (IL-8) production was also determined to be de-
pressed by doxycycline treatment of stimulated A549 epithe-
lial cells (Hoyt, unpublished results). Tigecycline is the first
clinically available drug in a new glycylcycline class of anti-
biotics. Tigecycline is a derivative of minocycline with a
- - - -
(CH3)3C NH-CH2 C(O) NH moiety on position 9 of the D
ring. Salvatore et al.1 examined the effect of tigecycline in a
murine model of Mycoplasma pneumoniae induced pneumo-
nia. In BAL fluid from infected mice tigecycline was found
to decrease concentrations of proinflammatory cytokines and
chemokines including TNF-
, IFN-, IL-1, GM-CSF,
MCP-1 and others relative to uninfected controls.
Chemically Modified Tetracyclines
Tretment of chronic inflammation often requires long-
term exposure to various pharmacologic agents. Various
tetracycline derivatives have been demonstrated to possess
anti-inflammatory properties in addition to their better
known antibacterial activities. Thus, long term exposure to
tetracycline derivatives may lead to accumulation of tetracy-
cline-resistant bacteria ultimately leading to cessation of
treatment. Realization that antibiotic activity of tetracycline
resides only in one portion of the molecule lead Golub et al.
[44] to chemically modify the basic tetracycline structure in
order to abolish this activity. Removal of the dimethylamino
group from position 4 of the A-ring Fig. (1) abolished anti-
bacterial activity [44] and lead to the synthesis of a series of
chemically modified tetracyclines or CMTs [45]. The vari-
ous CMTs have been examined in a variety of systems for
anti-inflammatory activity.
Steinberg, et al. [46] examined the effect of COL-3, also
known as CMT-3 (8), on septic shock and ARDS in a por-
cine model. Occlusion of the superior mesenteric artery was
used to induce sepsis. As septic shock developed, lung tissue
revealed damage typical of ARDS, accompanied by an ob-
served increase in concentration of plasma IL-1 and IL-6 and
BAL IL-6, IL-8, IL-10 and NE. Pretreatment with COL-3
prevented the onset of septic shock (as determined by a sig-
nificant fall in arterial blood pressure), ARDS (as determined
by a fall in PaO2/FiO2 ratio and an increase in lung water
(expressed as a wet to dried tissue ratio) and decreased se-
1
Salvatore, C.M.; Katz-Gaynor, K.; McCracken, R.D. and Hardy, R.D. Meeting Ab-
stract B-401, ICAAC Conference, San Francisco 2006.
Endocrine, Metabolic & Immune Disorders - Drug Targets, 2007, Vol. 7, No. 3 235
rum and BAL fluid levels of the aforementioned cytokines
and NE.
Carney et al. [47] used endotoxin-induced ARDS to ex-
amine the effect of COL-3 on lung function and activity of
MMP-2 and MMP-9. Pretreatment with COL-3 decreased
sequestration of neutrophils and monocytes in lung tissues,
reduced the wet/dry weight ratio of the lung and decreased
the destructive proteolytic activity of both MMP-2 and
MMP-9.
Although CMTs do not exhibit antibacterial activity,
there is evidence that they may be effective antifungal agents
[48,49]. The chemically modified tetracycline used these
studies, CMT-3, was found to be a more effective fungicide
against filamentous fungi than against yeasts. In contrast, the
often used fungistatic compound amphotericin B was found
to be effective against most filamentous fungi and yeast
tested. The viability of two filamentous fungi that can cause
lung infections, Aspergillus fumigatus and Rhizopus sp. was
reduced approximately 60% after treatment with CMT-3 on
SABHI agar; however, a greater viability of both organisms
was seen in similar experiments using amphotericin B.
CONCLUSIONS
The use of tetracycline and its derivatives in the treat-
ment of a variety of inflammatory conditions beyond the
lung is becoming increasingly apparent. The therapeutic po-
tential of this class of antibiotic in pulmonary inflammation
is especially important in chronic conditions such as bron-
chiectasis, COPD, cystic fibrosis, and many others. The ac-
tion of these compounds is multi-factorial in nature and ef-
fects numerous, diverse parts of the inflammatory cascade
such as MMPs, neutrophil elastase, NO and pro-inflammatory
chemokines for example. In many cases the exact mecha-
nism by which tetracycline-type compounds exert their anti-
inflammatory effects remains undiscovered and demon-
strates great promise for future therapy.
ABBREVIATIONS
APE = Acute Pulmonary Embolism
ARDS = Acute Respiratory Distress Syndrome
BAL = Bronchoalveolar Lavage
CF = Cystic Fibrosis
CMT = Chemically Modified Tetracycline
COPD = Chronic Obstructive Pulmonary Disease
HIV = Human Immunodeficiency Virus
IL = Interleukin
iNOS = Inducible Nitric Oxide Synthase Isozyme
MAP Kinase = Mitogen Associated Protein Kinase
MCP-1 = Monocyte Chemoattractant Protein-1
MMP = Matrix Metalloproteinase
NE = Neutrophil Elastase
NO = Nitric Oxide
236 Endocrine, Metabolic & Immune Disorders - Drug Targets, 2007, Vol. 7, No. 3 Rempe et al.

NOS = Nitric Oxide Synthase
TDI = Toluene Diisocyanate-Induced
REFERENCES
[1] Stephens, C.R.; Conover, L.H.; Pasternack, R.; Hochstein, F.A.;
Moreland, W.T.; Regna, P.P.; Pilgrim, F.J.; Brunnings, K.J. and
Woodward, R.B. (1954) J. Am. Chem. Soc., 76 (13), 3568-3575.
[2] Nelson, M.L. (1998) Adv. Dental Res., 12 (2), 5-11.
[3] Sapadin, A.N. and Fleischmajer, R. (2006) J. Am. Acad. Dermatol.,
54 (2), 258-265.
[4] Golub, L.M.; Lee, H.M.; Lehrer, G.; Nemiroff, A.; McNamara,
T.F.; Kaplan, R. and Ramamurthy, N.S. (1983) J. Periodontol.
Res., 18 (5), 516-526.
[5] Preshaw, P.M.; Hefti, A.F.; Jepsen, S.; Etienne, D.; Walker, C. and
Bradshaw, M.H. (2004) J. Clin. Periodontol. Res., 31 (9), 697-707.
[6] Bikowski, J.B. (2003) Skinmed., 2 (4), 234-245.
[7] O’Dell, J.R.; Elliott, J.R.; Mallek, J.A.; Mikuls, T.R.; Weaver,
C.A.; Glickstein, S.; Blakely, K.M.; Hausch, R. and Leff, R.D.
(2006) Arthritis Rheum., 54 (2), 621-627.
[8] Lauhio, A.; Sorsa, T.; Lindy, O.; Suomalainen, K.; Saari, H.;
Golub, L.M. and Konttinen, Y.T. (1992) Arthritis Rheum., 35 (2),
195-198.
[9] Stirling, D.P.; Koochesfahani, K.M.; Steeves, J.D. and Tetzlaff, W.
(2005) Neuroscientist, 11 (4), 308-322.
[10] Zemke, D. and Majid, A. (2004) Clin. Neuropharmacol., 27 (6),
293-298.
[11] Zink, M.C.; Uhrlaub, J.; DeWitt, J.; Voelker, T.; Bullock, B.;
Mankowski, J.; Tarwater, P.; Clements, J. and Barber, S. (2005) J.
Am. Med. Assoc., 293 (16), 2003-2011.
[12] Ingbar, D.H. (1995) in Pulmonary and Critical Care Medicine, Vol.
1, (Bone, R.C.; Dantzker, D.R.; George, R.B.; Matthay, R.A. and
Reynolds, H.Y., Eds.) Mosby, St. Louis, MO, pp. A1-19.
[13] Valcke, Y.; Pauwels, R. and Van der Straeten, M. (1990) Eur.
Respir. J., 3 (6), 715-722.
[14] Gartmann, J. (1975) Chemotherapy, 21 (Suppl. 1), 19-26.
[15] Hartnett, B.J.S. and Marlin, G.E. (1976) Thorax, 31 (2), 144-148.
[16] Stockley, R.A. (1999) Am. J. Respir. Crit. Care Med., 160 (5 Pt 2),
S49-S52.
[17] Nguyen, M.; Arkell, J. and Jackson, C.J. (2000) J. Biol. Chem., 275
(13), 9095-9098.
[18] Wilhelm, S.M.; Collier, I.E.; Marmer, B.L.; Eisen, A.Z.; Grant,
G.A. and Goldberg, G.I. (1989) J. Biol. Chem., 264 (29), 17213-
17221.
[19] Ogata, Y.; Enghild, J.J. and Nagase, H. (1992) J. Biol. Chem., 267
(6), 3581-3584.
[20] Delclaux, C.; d’Ortho, M.P.; Delacourt, C.; Lebargy, F.; Brun-
Buisson, C.; Brochard, L.; Lemaire, F.; Lafuma, C. and Harf, A.
(1997) Lung Cell Mol. Physiol., 272 (3), L442-L451.
[21] Torii, K.; Iida, K.; Miyazaki, Y.; Saga, S.; Kondoh, Y.; Taniguchi,
H.; Taki, F.; Takagi, K.; Matsuyama, M. and Suzuki, R. (1997) Am.
J. Respir. Crit. Care Med., 155 (1), 43-46.
[22] Sagel, S.D.; Kapsner, R.K. and Osberg, I. (2005) Pediatr. Pul-
monol., 39 (3), 224-232.
[23] Ratjen, F.; Hartog, C.M.; Paul, K.; Wermelt, J. and Braun, J. (2002)
Thorax., 57 (11), 930-934.
[24] Hartog, C.M.; Wermelt, J.A.; Sommerfeld, C.O.; Eichler, W.;
Dalhoff, K. and Braun, J. (2003) Am. J. Respir. Crit. Care Med.,
167 (4), 593-598.
[25] Gonzales, A.A.; Segura, A.M.; Horiba, K.; Qian, S.; Yu, Z.X.;
Stetler-Stevenson, W.; Willerson, J.T.; McAllister, H.A. Jr. and
Ferrans, V.J. (2002) Hum. Pathol., 33 (12), 1158-1164.
[26] Garcia, R.A.; Pantazatos, D.P.; Gessner, C.R.; Go, K.V.; Woods,
V.L. Jr. and Villareal, F.J. (2005) Mol. Pharmacol., 67 (4), 1128-
1136.
[27] Lee, K.S.; Jin, S.M.; Kim, S.S. and Lee, Y.C. (2004) J. Allergy
Clin. Immunol., 113 (5), 902-909.
[28] Palei, A.C.T.; Zaneti R.A.G.; Fortuna, G.M.; Gerlach, R.F. and
Tanus-Santos, J.E. (2005) Angiology, 56 (5), 611-617.
[29] Van den Steen, P.E.; Dubois, B.; Nelissen I.; Rudd, P.M.; Dwek,
R.A. and Opdenakker, G. (2002) Crit. Rev. Biochem. Mol. Biol., 37
(6), 375-536.
[30] Battistini, B. (2003) Can. J. Physiol. Pharmacol., 81 (6), 555-569.
[31] Sepper, R.; Konttinen, Y.T.; Ding, Y.; Takagi, M. and Sorsa, T.
(1995) Chest, 107 (6), 1641-1647.
[32] Guignabert, C.; Taysse, L.; Calvet, J.-H.; Planus, E.; Delamanche,
S.; Galiacy, S. and d’Ortho, M.-P. (2005) Am. J. Physiol. Lung Cell
Mol. Physiol., 289 (1), L67-L74.
[33] Rappeneau, S.; Baeza-Squiban, A.; Marano, F. and Calvet, J.-H.
(2000) Toxicol. Sci., 58 (1), 153-160.
[34] Zeidler, P.; Hubbs, A.; Battlelli, L. and Castranova, V. (2004) J.
Toxicol. Environ. Health A, 67 (13), 1001-1026.
[35] Genovese, T.; Cuzzocrea, S.; Di Paola, R.; Failla, M.; Mazzon, E.;
Sortino, M.A.; Frasca, G.; Gili, E.; Crimi, N.; Caputi, A.P. and
Vancheri, C. (2005) Respir. Res., 6, 58-74.
[36] Hoyt, J.C.; Ballering, J.; Numanami, H.; Hayden, J.M. and Rob-
bins, R.A. (2006) J. Immunol., 176 (1), 567-572.
[37] D’Agostino, P.; La Rosa, M.; Barbera, C.; Arcoleo, F.; Di Bella,
G.; Milano, S. and Cillari, E. (1998) J. Infect. Dis., 177 (2), 489-
492.
[38] Shapiro, S.D.; Goldstein, N.M.; Houghton, A.M.; Kobayashi, D.K.;
Kelly, D. and Belaaouaj, A. (2003) Am. J. Pathol., 163 (6), 2329-
2335.
[39] Lee, C.T.; Fein, A.M.; Lippmann, M.; Holtzman, H.; Kimbel, P.
and Weinbaum, G. (1981) N. Eng. J. Med., 304 (4), 192-196.
[40] O’Connor, C.M.; Gaffney, K.; Keane, J.; Southey A.; Bryne, N.;
O’Mahoney, S. and Fitzgerald, M.X. (1993) Am. Rev. Respir. Dis.,
148 (6 Pt 1), 1665-1670.
[41] Birrer, P.; McElvaney, N.G.; Rudeberg, A.; Sommer, C.W.;
Liechti-Gallati, S.; Kraemer, R.; Hubbard, R. and Crystal, R.G.
(1994) Am. J. Respir. Crit. Care Med., 150 (1) 207-213.
[42] Mallya, S.K.; Hall, J.E.; Lee, H.M.; Roemer, E.J.; Simon, S.R. and
Golub, L.M. (1994) Ann. N.Y. Acad. Sci., 732, 303-314.
[43] Raza, M.; Ballering, J.G.; Hayden, J.M.; Robbins, R.A. and Hoyt,
J.C. (2006) Exp. Lung Res., 32 (1-2), 15-26.
[44] Golub, L.M.; McNamara, T.F.; D’Angelo, G.; Greenwald, R.A.
and Ramamurthy, N.S. (1987) J. Dent. Res., 66 (8), 1310-1314.
[45] Tolomeo, M.; Grimaudo, S.; Milano, S.; La Rosa, M.; Ferlazzo, V.;
Di Bella, G.; Barbera, C.; Simoni, D.; D’Agostino, P. and Cillari,
E. (2001) Br. J. Pharmacol., 133 (2), 306-314.
[46] Steinberg, J.; Halter, J.; Schiller, H.; Gatto, L.; Carney, D.; Lee, H.-
M.; Golub, L. and Nieman, G. (2005) Shock, 24 (4), 348-356.
[47] Carney, D.E.; McCann, U.G.; Schiller, H.J.; Gatto, L.A.; Steinberg, J.;
Picone, A.L. and Nieman, G.F. (2001) J. Surg. Res., 99 (2), 245-252.
[48] Liu, Y.; Ryan, M.E.; Lee, H.-M.; Simon, S.; Tortora, G.; Lauzon,
C.; Leung, M.K. and Golub, L.M. (2002) Antimicrob. Agents Che-
mother., 46 (5), 1447-1454.
[49] Liu, Y.; Tortora, G.; Ryan, M.E.; Lee, H.-M. and Golub, L.M.
(2002) Antimicrob. Agents Chemother., 46 (5), 1455-1461.

Received: 31 October, 2006 Accepted: 13 December, 2006