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Departments of 1 Medicine and 2 Pathology, Vanderbilt University Medical Center, Nashville, Tennessee 37232
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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PGE2 is an important cyclooxygenase product
that modulates airway inflammatory and smooth muscle responses. Signal
transduction is mediated by four EP receptor subtypes that cause
distinct effects on cell metabolism. To determine the role of
EP2 receptor activation, we produced a mouse lacking the
EP2 receptor by targeted gene disruption. The effect of
aerosolized PGE2 and other agonists was measured using
barometric plethysmography and by measurements of lung resistance in
mechanically ventilated mice. Inhalation of PGE2 inhibited
methacholine responses in wild-type but not in mice lacking the
EP2 receptor
[EP2(
/)]. After airway
constriction was induced by methacholine aerosol, PGE2
reduced the airway constriction enhanced pause in wild-type mice (from
0.88 ± 0.15 to 0.55 ± 0.06) but increased it in
EP2(/) mice (from 0.73 ± 0.08 to 1.27 ± 0.19). Similar results were obtained in mechanically ventilated mice.
These data indicate that the EP2 receptor mediates the
bronchodilation effect of PGE2.
pharmacology; airway reactivity; methacholine; knockout mice
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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PROSTAGLANDIN E2 (PGE2) is an endogenous lipid autacoid derived from the action of the cyclooxygenase enzymes on free arachidonic acid and subsequent isomerization of the endoperoxide product by PGE2 isomerase. PGE2 is produced by a variety of cells, including airway smooth muscle, epithelial cells, alveolar macrophages, and pulmonary endothelial cells (12, 23). In addition to many immunomodulatory effects, PGE2 also has effects on airway smooth muscle and nerves, which allow it to modulate airway caliber (4, 16, 22).
PGE2 mediates its action via G protein-coupled receptors to alter cyclic nucleotide levels in cells or stimulate phosphatidylinositol, thereby causing effects such as airway smooth muscle relaxation or uterine muscle contraction. Four types of cell surface receptors have been identified for which PGE2 is the cognate ligand. These EP receptors modulate a variety of effects. EP1 receptors binding PGE2 signal via G proteins to activate phospholipase C, generate phosphatidylinositol, mobilize calcium, and cause a chloride current (for review see Ref. 2). In contrast, EP2 and EP4 receptors characteristically relax smooth muscle by signaling through a Gs protein to increase intracellular cAMP levels. The EP3 receptor consists of a number of splice variants displaying various degrees of constitutive activity (6). EP3 signals through activation of a Gi protein to inhibit cAMP generation.
In vitro PGE2 causes relaxation of airway smooth muscle and also has effects on airway cholinergic nerve activity (8, 20). For example, PGE2 released from epithelial cells inhibits vagal cholinergic efferent transmission via a prejunctional mechanism (11). Human subjects inhaling PGE2 may show airway constriction or bronchodilation, which may in part be dependent on the timing of measurements after PGE2 administration (10, 19, 21). The relaxation of airway smooth muscle is thought to result from activation of EP2 and, possibly, EP4 receptors. To examine the role of EP2 receptors in mediating the many effects of PGE2, we used homologous recombination to construct a mouse lacking the EP2 receptor (7). We found that bronchodilation of mouse airways by PGE2 is dependent on signaling through the EP2 receptor.
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METHODS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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The disruption of the EP2 receptor in the mouse is described elsewhere (7). Briefly, the mice appear to have a normal phenotype but are less fertile, develop a greater degree of hypertension when fed a high-salt diet, and do not respond to infused PGE2 with hypotension.
F2 C57/B6X129 mice homozygous for the targeted deletion of
the EP2 receptor gene and littermate controls underwent
measurements of a dimensionless index thought to represent airflow
obstruction (enhanced pause; Penh) by barometric plethysmography (Buxco
Electronics, Troy, NY) (5). A nebulizer (Pari II, Pari Respirator
Equipment, Richmond, VA) was used to expose mice to aerosols of various
concentrations of agonists. Methacholine (Sigma Chemical, St. Louis,
MO) dose-response curves were determined by measuring Penh in response
to aerosols of methacholine at concentrations of 12.5, 25, and 50 mg/ml
for 2 min at 2-min intervals. Dose-response curves were constructed after inhalation of placebo, the muscarinic antagonist ipratropium bromide (200 µg/ml; Roxane Laboratories, Columbus, OH), or
PGE2 (100 µg/ml; Cayman Chemical, Ann Arbor, MI). To
investigate the action of PGE2 on constricted airways, we
produced airflow obstruction in mice with aerosols of methacholine (100 mg/ml for 4 min) followed by 2 min of PGE2 (100 µg/ml) or
placebo (10% ethanol). The response over time in Penh was determined
immediately after the 2-min aerosol. The effect of isoproterenol (1 mg/ml; Sigma Chemical), a nonspecific 
-adrenergic agonist, was also determined.
To confirm the effects of PGE2 on airway mechanics, we measured lung resistance (RL) in anesthetized, tracheotomized, ventilated animals, as previously described (9, 15). Aerosols of saline, methacholine, or PGE2 were delivered to the inspiratory port of a Harvard ventilator. Increases in RL were measured at baseline, immediately after cessation of a 2-min methacholine aerosol (100 mg/ml), and during aerosols of PGE2.
Statistics. Comparisons within groups were done using a paired t-test. Comparisons between groups of animals were done using an unpaired t-test. When the data were found to be nonnormal in distribution, a corresponding nonparametric t-test was applied. Significance was accepted at P < 0.05. Values are means ± SE.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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There was no significant difference between the baseline measurements
of Penh in wild-type and EP2(/) mice.
Inhalation of PGE2 (100 µg/ml for 2 min) significantly
increased Penh in wild-type and EP2(/) mice
(Fig. 1). Serially increasing doses of
aerosolized methacholine caused a dose-dependent increase in Penh in
wild-type and knockout mice (Fig. 2).
Although the EP2(/) mice had greater Penh
measurements after methacholine than did the wild-type mice, this was
not true of the larger group of mice studied after inhalation of 100 mg/ml of methacholine (see below). Prior inhalation of PGE2
(100 µg/ml for 2 min) significantly reduced the response to inhaled
methacholine in the wild-type, but not the knockout, mice (Fig. 2). The
muscarinic antagonist ipratropium bromide prevented methacholine-induced changes in Penh in both groups of animals (Fig.
3).
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Methacholine aerosols (100 mg/ml for 4 min) induced transient increases
in Penh in wild-type and EP2(/) mice that
were not statistically different. Compared with placebo at the same
time point, PGE2 (100 µg/ml for 2 min) reduced the
airflow obstruction induced in wild-type mice by methacholine aerosols
(Fig. 4). In marked contrast, inhalation of
PGE2 failed to reduce methacholine Penh and was instead
associated with a significant increase in this value in the
EP2(/) mice. The nonspecific -agonist
isoproterenol reduced the methacholine changes in Penh in both groups
of mice (Fig. 5).
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In anesthetized and mechanically ventilated animals, aerosols of
methacholine were used to provoke increased RL, and the
effect of aerosols of PGE2 on the induced constriction was
determined. The baseline RL was similar in the two groups
[1.28 ± 0.06 and 1.29 ± 0.05 ml · min · cmH2O
1
in wild-type and EP2(/) mice,
respectively]. In wild-type mice, inhaled PGE2 caused
a significant reduction in RL; in contrast, inhaled
PGE2 caused no significant change in RL in the
EP2(/) mice (Fig.
6).
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There was no difference in the bronchoalveolar lavage cell counts or
differentials between the two groups of animals (n = 4).
Histological examination of the lungs of wild-type and
EP2(/) mice did not reveal any evidence of
differences in morphology between the two groups.
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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PGE2 has complex effects on mammalian airway smooth muscle tone and on airflow. In humans, PGE2 provokes cough and bronchoconstriction in some individuals, and in others it produces bronchodilation (10). PGE2 is active on sensory nerve terminals, smooth muscle, mucous glands, and a variety of inflammatory cells. Part of the complex effects of PGE2 may result from the variety of cells affected, but further complexity is introduced by the presence of a variety of receptor subtypes for PGE2 that have different signaling characteristics. Thus the EP1 receptor is thought to mediate constriction, and the EP2 receptor is thought to mediate relaxation (13). Depending on the repertoire of receptor subtypes expressed in a given cell, binding of PGE2 could have opposing effects (1).
Pharmacological probes for the various EP receptor subtypes have allowed considerable progress to be made in determining their function. The development of techniques for targeted gene disruption in the mouse and refinement of techniques for measurement of airway mechanics have allowed precisely defined experiments to be undertaken. We constructed a mouse lacking the EP2 receptor subtype to explore the mechanism of PGE2 signaling via this receptor. Because PGE2 is an important autacoid in the lung, we sought to define the mechanism of PGE2 action in wild-type and in littermate mice lacking the EP2 receptor.
We used the technique of barometric plethysmography to measure airway responses. The technique measures box pressure difference between the animal chamber and a chamber vented to the atmosphere (5). From the box pressure, a variable, Penh or enhanced pause, is calculated. The value of Penh changes with alterations in breathing pattern, compression volume, and expiratory flow. Because several of these are linked to bronchoconstriction, the measurement of Penh often tracks with measures of airflow obstruction. We utilized this technique because it allows serial measurements in the same animals over time. We used conventional measures of RL to confirm the more important of our findings in anesthetized mechanically ventilated animals.
Inhaled PGE2 increased Penh slightly in wild-type and
EP2(/) mice. This increase may have been
related to stimulation of sensory nerve fibers provoking reflex
bronchoconstriction. Neurally mediated bronchoconstriction has been
demonstrated in an isolated canine tracheal segment when
PGE2 was delivered to the lower airway (17). In humans,
aerosols of PGE2 provoke cough and substernal discomfort
and alterations in the sense of dyspnea, suggesting direct activation
of sensory nerves (3). Because Penh is measured in conscious animals,
airway sensory receptors responding to EP2 stimulation
could alter breathing pattern and Penh. The increase in Penh in
wild-type mice and in mice lacking the EP2 receptor suggests that if activation of sensory nerves is responsible, it must
be mediated at least in part by another EP receptor such as
EP1 or EP3.
Inhaled PGE2 in wild-type mice consistently decreased measures of airflow obstruction, Penh or RL, when the animals had been preconstricted with methacholine. Similarly, PGE2 aerosols prevented the increase in Penh caused by inhaled methacholine. In humans, PGE2 has variable effects on histamine- or methacholine-induced bronchoconstriction (10, 14, 21). The difference could lie in the timing of measurements, difference in regulation of smooth muscle tone by nerves in humans and mice, or different complements of EP receptor subtypes expressed in human and mouse airway.
In marked contrast to the bronchodilating properties of
PGE2 in wild-type mice, EP2(/)
mice manifested bronchoconstriction or no change after
PGE2. This provides evidence that the EP2
receptor is the principal receptor responsible for airway smooth muscle relaxation in the mouse. The response of both groups of mice to the
-adrenergic agent isoproterenol was similar, thereby documenting that the mice had similar capacities for smooth muscle relaxation. The
baseline measurement of Penh was the same in both groups of mice, as
was the response to inhaled methacholine. This would suggest that tonic
modulation of airway tone via the EP2 receptor in mice does
not occur. We conclude that signaling via the EP2 receptor
in the mouse is responsible for the bronchodilatory effects of
PGE2.
The increase in Penh in preconstricted EP2(/)
mice given aerosols of PGE2 might result from further
bronchoconstriction resulting from unopposed signaling via the
EP1 or EP3 receptor. In guinea pig, the
EP1 receptor appears to mediate bronchial smooth muscle
contraction (13). However, when PGE2 is given
alone to mice, the increase in Penh was small. Thus there must be some interaction between constriction with methacholine and the effects of
PGE2, which differ in the EP2(/)
and wild-type mice. In the anesthetized, mechanically ventilated mouse,
the increase after PGE2 aerosols in mice preconstricted
with methacholine was not present, suggesting that anesthesia was
preventing a neural response to PGE2 that was responsible
for the increase in Penh in the awake EP2(/)
animals. Barbiturate anesthesia, as used in our experiments on
mechanically ventilated mice, has the potential to suppress neural
responses (18). We suggest that in the wild-type mice the smooth
muscle-relaxing effects of signaling through the EP2 receptor dominate, resulting in a drop in Penh and RL. In
the EP2(/) animals, a neurally mediated
increase in Penh, caused by signaling via EP1,
EP3, or EP4 receptors unopposed by
EP2 receptor activation, results in an increase in Penh.
We conclude that the EP2 receptor in murine airways transduces airway dilatation and can prevent and reverse muscarinic airway narrowing. When the EP2 receptor is absent, resting airway mechanics are not affected, but in the conscious animal with airway narrowing induced by methacholine, the lack of EP2 signaling results in further airway narrowing mediated by neural mechanisms.
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ACKNOWLEDGEMENTS |
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This study was supported in part by National Institute of General Medical Sciences Grant GM-15431.
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FOOTNOTES |
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The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.
Address for reprint requests and other correspondence: J. R. Sheller, T 1217 MCN, Vanderbilt University Medical Center, Nashville, TN 37232-2650 (E-mail: James.Sheller{at}MCMail.Vanderbilt.edu).
Received 27 August 1999; accepted in final form 19 January 2000.
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REFERENCES |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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1.
Ashby, B.
Co-expression of PG receptors with opposite effects: a model for homeostatic control of autocrine and paracrine signaling.
Biochem Pharmacol
55:
239-246,
1998[ISI][Medline].
2.
Breyer, MB,
Zhang Y,
Guan YF,
Hao CM,
Hebert RL,
and
Breyer RM.
Regulation of renal function by prostaglandin E receptors.
Kidney Int
67:
S88-S94,
1998.
3.
Choudry, NB,
Fuller RW,
and
Pride NB.
Sensitivity of the human cough reflex: effect of inflammatory mediators prostaglandin E2, bradykinin, and histamine.
Am Rev Respir Dis
140:
137-141,
1989[ISI][Medline].
4.
Cocks, TM,
Fong B,
Chow JM,
Anderson GP,
Frauman AG,
Goldie RG,
Henry PJ,
Carr MJ,
Hamilton JR,
and
Moffatt JD.
A protective role for protease-activated receptors in the airways.
Nature
398:
156-160,
1999[Medline].
5.
Hamelmann, E,
Schwarze J,
Takeda K,
Oshiba A,
Larsen GL,
Irvin CG,
and
Gelfand EW.
Noninvasive measurement of airway responsiveness in allergic mice using barometric plethysmography.
Am J Respir Crit Care Med
156:
766-775,
1997
6.
Jin, J,
Mao GF,
and
Ashby B.
Constitutive activity of human prostaglandin E receptor EP3 isoforms.
Br J Pharmacol
121:
317-323,
1997[ISI][Medline].
7.
Kennedy, CR,
Zhang Y,
Brandon S,
Guan Y,
Coffee K,
Funk CD,
Magnuson MA,
Oates JA,
Breyer MD,
and
Breyer RM.
Salt-sensitive hypertension and reduced fertility in mice lacking the prostaglandin EP2 receptor.
Nat Med
5:
217-220,
1999[ISI][Medline].
8.
Madison, JM,
Jones CA,
Sankary RM,
and
Brown JK.
Differential effects of prostaglandin E2 on contractions of airway smooth muscle.
J Appl Physiol
66:
1397-1407,
1989
9.
Martin, TR,
Gerard NP,
Galli SJ,
and
Drazen JM.
Pulmonary responses to bronchoconstrictor agonists in the mouse.
J Appl Physiol
64:
2318-2323,
1988
10.
Mathe, AA,
and
Hedqvist P.
Effect of prostaglandins F2
and E2 on airway conductance in healthy subjects and asthmatic patients.
Am Rev Respir Dis
111:
313-320,
1975[ISI][Medline].
11.
Matsumoto, K,
Aizawa H,
Takata S,
Hoto H,
Inoue H,
and
Hara N.
Cultured epithelial cells release cyclooxygenase-dependent and cyclooxygenase-independent factors that inhibit cholinergic contraction of canine airway smooth muscles.
Respiration
63:
205-212,
1996[ISI][Medline].
12.
Meyrick, B,
Hoover R,
Jones MR,
Berry LC, Jr,
and
Brigham KL.
In vitro effects of endotoxin on bovine and sheep lung microvascular and pulmonary artery endothelial cells.
J Cell Physiol
138:
165-174,
1989[ISI][Medline].
13.
Ndukwu, IM,
White SR,
Leff AR,
and
Mitchell RW.
EP1 receptor blockade attenuates both spontaneous tone and PGE2-elicited contraction in guinea pig trachealis.
Am J Physiol Lung Cell Mol Physiol
273:
L626-L633,
1997
14.
Pavord, ID,
Wisniewski A,
Mathur R,
Wahedna I,
Knox AJ,
and
Tattersfield E.
Effect of inhaled prostaglandin E2 on bronchial activity to sodium metabisulphite and methacholine in patients with asthma.
Thorax
46:
633-637,
1991
15.
Peebles, RS,
Sheller JR,
Johnston J,
Mitchell DA,
and
Graham BG.
Respiratory syncytial virus prolongs methacholine-induced airway hyperresponsiveness in ovalbumin-sensitized mice.
J Med Virol
57:
186-192,
1999[ISI][Medline].
16.
Portanova, JP,
Zhang Y,
Andersen GD,
Hauser SD,
Masferrer JL,
Seibert K,
Gregory SA,
and
Isakson PC.
Selective neutralization of prostaglandin E2 blocks inflammation, hyperalgesia, and interleukin 6 production in vivo.
J Exp Med
184:
883-891,
1996
17.
Roberts, AM,
Schultz HD,
Green JF,
Armstrong DJ,
Kaufman MP,
Coleridge HM,
and
Coleridge JC.
Reflex tracheal contraction evoked in dogs by bronchodilator prostaglandin E2 and I2.
J Appl Physiol
58:
1823-1831,
1985
18.
Skoogh, BE,
Holtzman MJ,
Sheller JR,
and
Nadel JA.
Barbiturates depress vagal motor pathway to ferret trachea at ganglia.
J Appl Physiol
53:
253-257,
1982
19.
Smith, AP,
Cuthbert MF,
and
Dunlop LS.
Effects of inhaled prostaglandins E1, E2 and F2 on the airway resistance of healthy and asthmatic man.
Clin Sci Mol Med
48:
421-430,
1975[ISI][Medline].
20.
Sweatman, WJ,
and
Collier HO.
Effects of prostaglandins on human bronchial muscle.
Nature
217:
69-72,
1968[Medline].
21.
Walters, EH,
Bevan C,
Parrish RW,
Davies BH,
and
Smith AP.
Time-dependent effect of prostaglandin E2 inhalation on airway responses to bronchoconstrictor agents in normal subjects.
Thorax
37:
438-442,
1982
22.
Walters, EH,
O'Byrne PM,
Fabbri LM,
Graf PD,
Holtzman MJ,
and
Nadel JA.
Control of neurotransmission by prostaglandins in canine trachealis smooth muscle.
J Appl Physiol
57:
129-134,
1984
23.
Widdicombe, JH,
Ueki IF,
Emery D,
Margolskee D,
Yergey J,
and
Nadel JA.
Release of cyclooxygenase products from primary cultures of tracheal epithelia of dog and human.
Am J Physiol Lung Cell Mol Physiol
257:
L361-L365,
1989
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) and after
(
) treatment with PGE2 (100 µg/ml for 2 min) in
wild-type (A) and EP2(
