Editorials
with fractalkine, and articles such as that of Balabanian and
colleagues provide an essential test of the durability of such
putative mechanisms in the context of disease.
TIMOTHY J. WILLIAMS, PH.D.
Division of Biomedical Sciences
Imperial College Faculty of Medicine
London, United Kingdom
References
1. Pan Y, Lloyd C, Zhou H, Dolich S, Deeds J, Gonzalo JA, Vath J, Gosse-
lin M, Ma J, Dussault B, et al. Neurotactin, a membrane-anchored che-
mokine upregulated in brain inflammation. Nature 1997;387:611617.
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Schall TJ. A new class of membrane-bound chemokine with a CX3C
motif. Nature 1997;385:640644.
3. Rossi D, Zlotnik A. The biology of chemokines and their receptors.
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4. Imai T, Hieshima K, Haskell C, Baba M, Nagira M, Nishimura M, Kak-
izaki M, Takagi S, Nomiyama H, Schall TJ, et al. Identification and
molecular characterization of fractalkine receptor CX-3CR1, which
mediates both leukocyte migration and adhesion. Cell 1997;91:521530.
5. Combadiere C, Salzwedel K, Smith ED, Tiffany HL, Berger EA, Mur-
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On Theophylline, Leukocytes, and Chicken Soup
Albrecht Karl Ludwig Martin Leonhard Kossel would have been
pleased and surprised to see a report on theophylline for the
treatment of chronic obstructive pulmonary disease (COPD)
published 114 years after his presentation at the Deutsche Che-
mische Gesellschaft in Berlin (1). This surprise arises because
Kossel witnessed the diverse use of the drug as a diuretic and an
antiangina and vasodilator agent, but it was not until 1922, five
years before Kossels death, that the bronchodilator effect was
described. What Kossel did not witness was the widespread use
of theophylline for asthma and COPD in the second half of the
20th century nor its steady decline in use after the introduction of
inhaled steroids and long-acting bronchodilators and the con-
stant concern over side-effects (2). At some point, it seemed that
the diversity of its actions proved also one of its biggest problems:
a substance that can do many things but nothing really well.
Over the years, 25,714 publications have appeared on theo-
phylline, including 1,833 clinical trials. Scientifically solid and long-
term trials are surprisingly rare, and the precise mechanism of ac-
tion is still a matter of debate. Nevertheless, it is newsworthy and
still exciting when new approaches are tested and presented (3, 4).
In this context, I have read with interest the article by Culpitt and
coworkers (5) in this issue of AJRCCM (pp. 13711376).
The study follows earlier reports that demonstrated anti-
inflammatory effects of low doses of theophylline in patients with
asthma. In the new study, 25 patients with a diagnosis of COPD
were included in a placebo-controlled, randomized, double-blind,
crossover trial. Patients were treated with theophylline for 4
weeks, resulting in a serum theophylline concentration between 9
and 11 mg/L. The endpoint was fortunately not the change in lung
function but rather the number of inflammatory cells in induced
sputum, particularly neutrophils, and the levels of the chemokine
interleukin-8, myeloperoxidase, and lactoferrin. The chemotactic
response to chemoattractants such as N-formyl-methionyl-leucyl-
phenylalanine was also assessed. The findings can be summarized
as showing a significant decrease in the absolute numbers of in-
1351
main in CX(3)C chemokine domain presentation. J Biol Chem 2000;
275:37813786.
7. Fong AM, Robinson LA, Steeber DA, Tedder TF, Yoshie O, Imai T,
Patel DD. Fractalkine and CX3CR1 mediate a novel mechanism of
leukocyte capture, firm adhesion, and activation under physiologic
flow. J Exp Med 1998;188:14131419.
8. Haskell CA, Cleary MD, Charo IF. Molecular uncoupling of fractalkine-
mediated cell adhesion and signal transduction: rapid flow arrest of
CX3CR1-expressing cells is independent of G-protein activation. J
Biol Chem 1999;274:1005310058.
9. Feng L, Chen S, Garcia GE, Xia Y, Siani MA, Botti P, Wilson CB, Har-
rison JK, Bacon KB. Prevention of crescentic glomerulonephritis by
immunoneutralization of the fractalkine receptor CX3CR1 rapid com-
munication. Kidney Int 1999;56:612620.
10. Balabanian K, Foussat A, Dorfmller P, Durand-Gasselin I, Capel F,
Bouchet-Delbos L, Portier A, Marfaing-Koka A, Krzysiek R, Riman-
iol A-C, et al. CX3C chemokine fractalkine in pulmonary arterial hy-
pertension. Am J Respir Crit Care Med 2002;165:14191425.
11. Garton KJ, Gough PJ, Blobel CP, Murphy G, Greaves DR, Dempsey PJ,
Raines EW. Tumor necrosis factor-alpha-converting enzyme (ADAM17)
mediates the cleavage and shedding of fractalkine (CX3CL1). J Biol
Chem 2001;276:3799338001.
12. Tsou CL, Haskell CA, Charo IF. Tumor necrosis factor-alpha-convert-
ing enzyme mediates the inducible cleavage of fractalkine. J Biol Chem
2001; 276:4462244626.
13. Lucas AD, Chadwick N, Warren BF, Jewell DP, Gordon S, Powrie F,
Greaves DR. The transmembrane form of the CX3CL1 chemokine
fractalkine is expressed predominantly by epithelial cells in vivo. Am J
Pathol 2001;158:855866.
DOI: 10.1164/rccm.2203020
flammatory cells in sputum and a significant decrease in sputum
neutrophils after theophylline. This decrease in cells was accom-
panied by a decrease in sputum interleukin-8 levels and a de-
creased chemotactic response of sputum neutrophils.
Why is the article so interesting? COPD is a common dis-
ease and is believed to result from an abnormal inflammatory
response where neutrophils play a significant role in long-term
progression and exacerbations. Existing medications, includ-
ing inhaled steroids, have not been conclusively shown to in-
terfere with this inflammatory response (6, 7). This leaves treat-
ing physicians only the choice of intense antismoking counseling
(we all know the problems), bronchodilator therapy, and the use
of steroids in those known to have frequent exacerbations (2).
Why is the article worth reading? It is an interesting approach,
a good study design, and it is typically written as if the conse-
quences for the long-term treatment of COPD were obvious.
Is this a definite report? COPD is a heterogeneous disor-
der, and the 11 active smokers among subjects probably con-
found data interpretation because smoking itself has chronic
and acute effects on neutrophils. Are data from these 25 pa-
tients sufficient to make any clinical claims? I doubt it. In
planning a solid clinical trial such as this one, estimates of sam-
ple size are a bit of a gamble because we do not know what
represents a clinically significant difference. What is the mean-
ing of 800,000 less neutrophils per milliliter of sputum, and
what is the relevance of 6% less neutrophils with a range of 52
to 94%? I do not know, and I do not believe that anyone does.
What is worthwhile in these types of studies is that they make
us think. For example, what is the mechanism of action? Is it
inhibition of phosphodiesterase that would ultimately result in
the elevation of cAMP in neutrophils? Then this effect might
also be achieved with  adrenoreceptor agonists and, probably
more interestingly, with novel selective phosphodiesterase 4
inhibitors, targeting the neutrophil more selectively, where
novel clinical data are now accumulating (8).
1352 AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE
I am sure this article will stimulate discussions, but it does not
provide us with the information we yet need. Rigid studies are
needed that are of the same scientific quality as the study by Cul-
pitt and coworkers in larger number of patients and definitely
over a longer period of time to provide solid advice to physicians
on the role of theophylline for COPD, as they undoubtedly will
not measure inflammatory markers in sputum. For longer term
studies in patients with COPD and significant comorbidity, com-
pliance and side-effects will be of great importance. In this con-
text, I was definitely surprised that 20% of subjects complained
of nausea with low-dose theophylline. We should remember that
chemotaxis of neutrophils to the very same stimulus N-formyl-
methionyl-leucyl-phenylalanine can be inhibited by other reme-
dies, including chicken soup (9), which undoubtedly has potential
for fewer adverse events, although in this case, long-term trials and
health economic assessments are also still outstanding.
The article of Culpitt and associates undoubtedly adds to the
current literature and addresses the urgent clinical question of
how to deal with inflammation in COPD. What the article cannot
do is provide evidence that low-dose theophylline is of any clini-
cal benefit for patients with COPD. The only way to prove that
this form of treatment is clinically superior to other remedies, in-
cluding chicken soup, is performing a long-term clinical trial with
theophylline in COPD, something Albrecht Kossel has not yet
witnessed in the 114 years since his Berlin presentation in 1888.
KLAUS F. RABE, M.D., PH.D.
Leiden University Medical Center
Leiden, The Netherlands
VOL 165 2002
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PJ. Effect of theophylline on induced sputum inflammatory indices and
neutrophil chemotaxis in chronic obstructive pulmonary disease. Am J
Respir Crit Care Med 2002;165:13711376.
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soup inhibits neutrophil chemotaxis in vitro. Chest 2000;118:11501157.
DOI: 10.1164/rccm.2203053