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Departments of 1 Pharmacology and 2 Physiology and Biophysics, University of Nebraska Medical Center, Omaha, Nebraska 68198
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
FOOTNOTES
REFERENCES
ABSTRACT 
Toews, M. L., E. E. Ustinova, and H. D. Schultz.
Lysophosphatidic acid enhances contractility of isolated airway
smooth muscle. J. Appl. Physiol.
83(4): 1216-1222, 1997.
The effects of the simple phospholipid
mediator lysophosphatidic acid (LPA) on the contractile responsiveness
of isolated tracheal rings from rabbits and cats were assessed. In both
species, LPA increased the contractile response to the muscarinic
agonist methacholine, but LPA did not induce contraction on its own.
Conversely, LPA decreased the relaxation response to the
-adrenergic-agonist isoproterenol in both species. Concentrations of
LPA as low as 10
8 M were
effective, and the effects of LPA were rapidly reversed on washing.
Phosphatidic acid was much less effective, requiring higher
concentrations and producing only a minimal effect. Contractions induced by serotonin and by substance P also were enhanced by LPA, but
KCl-induced contractions were unaffected. LPA inhibited the
isoproterenol-induced relaxation of KCl-precontracted rings, similar to
its effects on methacholine-precontracted rings, and relaxation induced
by the direct adenylyl cyclase activator forskolin was inhibited in a
manner similar to that induced by isoproterenol. Epithelium removal did
not alter the contraction-enhancing effect of LPA. The ability of LPA
to both enhance contraction and inhibit relaxation of airway smooth
muscle suggests that LPA could contribute to airway hypercontractility
in asthma, airway inflammation, or other types of lung injury.
bronchoconstriction
INTRODUCTION LYSOPHOSPHATIDIC ACID (LPA) is a simple bioactive
lipid, the diverse physiological effects of which have come to be
appreciated only recently. Effects of LPA include mitogenesis in
fibroblasts and other cells; cell shape changes, including neurite
retraction in cultured neurons, glial cell rounding, and changes in
stress fibers, focal adhesion formation, and isometric contraction in fibroblasts; modulation of ion transport in epithelial cells; platelet
activation; and tumor cell invasion. LPA effects have been observed in
a wide variety of cell types, ranging from
Dictyostelium amoebas to
Xenopus oocytes to human neurons.
These effects have been summarized in recent review articles (12, 13).
LPA is released from activated platelets and is present at
relatively high concentrations in serum bound to albumin (4, 22).
Several recent studies have presented evidence that LPA or an LPA-like
compound is, in fact, the major factor responsible for several of the
effects of serum on cells of various types. Thus LPA has been suggested
to be the factor responsible for serum effects on stress fiber and
focal adhesion formation in fibroblasts (17), on
Xenopus oocyte chloride current
activation (22), and on sensitization of adenosine
3 LPA has also been shown to modulate contraction of various types of
smooth muscle. In fact, some of the earliest reports of physiological
effects of LPA were on regulation of blood pressure, with either
hypertension or hypotension observed depending on the species (24). A
more recent study documented the ability of LPA to alter
cerebrovascular reactivity in piglets and presented evidence for
increased production of LPA in a model of cerebral hemorrhage (21). LPA
has also been shown to stimulate contraction of gastrointestinal (25,
28) and uterine (26) smooth muscle.
During the course of our studies identifying LPA as the likely serum
factor responsible for sensitization of cAMP accumulation in glial
cells, our laboratory found that LPA could also induce sensitization of
cAMP accumulation in cultured human airway smooth muscle cells
(11). More recently, the complex effects of LPA on cAMP
and phosphoinositide metabolism in human airway smooth muscle cells
have been characterized in some detail (14). Our laboratory has also characterized the mitogenic effects of LPA in human
airway smooth muscle cells in culture (2). The present studies were designed to further investigate the various physiological effects mediated by the LPA signaling pathways present in airway smooth
muscle. In the present study we report the ability of LPA to potentiate
contraction and to inhibit relaxation of isolated tracheal smooth
muscle rings from both rabbits and cats. A preliminary report of some
of these findings has been published previously (23).
METHODS
,5-cyclic monophosphate (cAMP) accumulation (11) and
shape changes (10) in glial cells. The release of LPA from activated
platelets, together with its pronounced effects on fibroblast
proliferation, contraction, and fibronectin assembly, suggests a likely
role for LPA in wound repair (12, 13).
8 to
105 M). Sufficient time
(5-6 min) was allowed for the isometric tension to reach plateau
during each treatment. Isoproterenol was added in cumulative doses
(from 5 × 107 to
105 M) to the TSRs
precontracted with the highest dose of methacholine (105 M). After thorough
washout with fresh Krebs-Henseleit solution for 30 min, the TSRs were
incubated with LPA (106 M)
or vehicle (0.25% bovine serum albumin in Krebs-Henseleit solution) for 5 min, and the cumulative dose-response protocols to
methacholine and isoproterenol were repeated.
In the second experimental group of rabbit TSRs
(n = 20), changes in isometric tension
in response to methacholine
(106 M) were measured
before and after incubation of TSRs with increasing doses of LPA (from
109 to
105 M) or phosphatidic acid
(from 109 to
105 M).
In the third experimental group of rabbit TSRs
(n = 16), isometric tension was
measured in response to administration of
106 M methacholine and
105 M isoproterenol after 5 min incubation with vehicle, after 5 min incubation with
106 M LPA, and then 15 min
after thorough washout of the LPA to determine whether the effect of
the LPA was reversible.
In the fourth experimental group of rabbit TSRs, isometric tension was
measured in response to cumulative addition of KCl (10, 20, 40 and 50 mM). Prewarmed and gassed Krebs-Henseleit solution containing 100 mM
KCl was added to the bath to obtain the indicated final concentrations.
The tonicity of the buffer was not adjusted to compensate for the added
KCl. Isoproterenol (105 M,
n = 18) or forskolin
(106 M,
n = 8) was added to the TSRs
precontracted with the highest dose of KCl.
In the fifth experimental group, cumulative dose-response protocols to
methacholine and KCl were performed before and after incubation with
LPA (106 M) in rabbit TSRs
with intact epithelium (n = 8) or in
rabbit TSRs with epithelium removed (n = 8).
In the sixth experimental group of rabbit TSRs
(n = 10), the effect of LPA
(106 M) on the isometric
contraction caused by cumulative addition of serotonin (from
107 to
105 M) and substance P
(from 107 to
105 M) was determined.
For each of these series of experiments, appropriate time controls were
conducted, and the effects of all agonists were reproducible.
Data analysis.
Responses of TSRs to the various agents tested were expressed as the
change (
) in isometric tension (g). All data are presented as means ± SE. Differences among groups were determined by analysis of
variance for repeated measures, and differences between means were
isolated by the Bonferroni correction for multiple
t-tests. Student's paired and
unpaired t-tests were used for single
comparisons. Statistical significance was accepted at
P < 0.05.
RESULTS
6 M did not affect
baseline tension, which was 3.0 ± 0.2 g before and 2.9 ± 0.2 g
after incubation with LPA (n = 20, not
significant). LPA clearly potentiated contraction of the TSRs in
response to the lower doses of methacholine
(108 to
106 M), with increases
ranging from 27 ± 9 to 124 ± 34% greater than with
methacholine alone (n = 20, P < 0.05).
) in isometric tension of isolated rabbit TSRs induced by
cumulative addition of MCh were measured both before (control; open
bars) and after addition of
106 M LPA to bath (solid
bars). * P < 0.05 vs.
control.
LPA dose dependence and specificity of the enhancement of contraction. Figure 2 compares the effects of LPA and phosphatidic acid at doses from 10
9 to
105 M on the change in
isometric tension induced by administration of methacholine at
106 M. LPA caused a
dose-dependent increase in methacholine-induced contraction. The lowest
effective dose of LPA was
108 M. LPA alone, even at
the highest dose of 105 M,
had no significant effect on baseline tension. Administration of
phosphatidic acid had no significant effect on the methacholine-induced contraction. Changes in isometric tension in response to methacholine in rabbit TSRs incubated with phosphatidic acid were not significantly different from those in control TSRs and were significantly lower than
those in TSRs incubated with the same doses of LPA.
6 M MCh were measured in
absence (control) or presence of indicated concentrations of LPA (open
bars) or PA (hatched bars). * P < 0.05 vs. control. 
P < 0.05 for PA vs. same concentration of LPA.
Inhibition by LPA of isoproterenol-induced relaxation of rabbit TSRs. Figure 3 illustrates the ability of LPA to inhibit relaxation by isoproterenol of rabbit TSRs precontracted with methacholine at 10
5 M. The
lowest dose of isoproterenol tested (5 × 107 M) caused only a slight
relaxation that was not altered by LPA. Isoproterenol at
106 M caused a decrease in
tension of 0.31 ± 0.08 g, and this response was inhibited by 45%
(0.17 ± 0.06 g; n = 20, P < 0.05) when
106 M LPA was included.
Isoproterenol at 105 M
decreased isometric tension by 0.69 ± 0.11 g, and LPA at
106 M inhibited this
response by 29% (0.49 ± 0.08 g; n = 20, P < 0.05).
5 M
MCh were measured in response to indicated concentrations of isoproterenol in absence (control; open bars) or presence of
106 M LPA (solid bars).
* P < 0.05 vs. control.
Reversibility of the effects of LPA. Figure 4 demonstrates the changes in the isometric tension of rabbit TSRs in response to 10
6 M methacholine and
105 M isoproterenol before,
during, and after incubation of the TSRs with
106 M LPA. The effect of
LPA was completely reversible. By 15 min after the washout of LPA, both
the contractile response to methacholine and the relaxation response to
isoproterenol had returned to the control level.
6 M MCh and relaxations
induced by 105 M
isoproterenol were measured before exposure to LPA (open bars), during
incubation with 106 M LPA
(solid bars), and 15 min after washout of LPA (hatched bars).
* P < 0.05 vs. control.
Effects of LPA on responses to other contractile agonists. Figure 5A demonstrates dose-dependent contraction of the isolated rabbit TSRs elicited by cumulative administration of serotonin (10
7 to
105 M). Incubation of TSRs
with LPA (106 M) increased
the contraction of the TSRs in response to all doses of serotonin
tested. Figure 5B demonstrates
dose-dependent contraction of the isolated rabbit TSRs elicited by
cumulative administration of substance P
(107 to
105 M). LPA
(106 M) significantly
potentiated contraction of the TSRs in response to all doses of
substance P, with increases ranging from 730 ± 70% at the dose of
107 M to 59 ± 9% at
the dose of 105 M
(n = 8, P < 0.05).
6 M LPA (solid bars).
* P < 0.05 vs. control.
Effects of LPA on responses to KCl, isoproterenol, and forskolin. Figure 6 demonstrates dose-dependent contraction of the isolated rabbit TSRs elicited by cumulative administration of KCl (10 to 50 mM). Incubation of TSRs with LPA (10
6 M) did not affect
contraction of the TSRs in response to any of the doses of KCl.
Administration of isoproterenol
(105 M) to the TSRs
precontracted with 50 mM KCl induced relaxation; the decrease in
tension in response to isoproterenol before incubation with LPA was
1.04 ± 0.21 g, and this response was reduced to 0.63 ± 0.18 g
after incubation with LPA
(106 M), an inhibition of
39 ± 9% (n = 18, P < 0.05). Administration of
forskolin (106 M) to the
TSRs precontracted with 50 mM KCl caused a decrease in tension of 1.30 ± 0.19 g before incubation with LPA and of 0.71 ± 0.09 g
(n = 8, P < 0.05) after incubation with LPA
(106 M), an inhibition of
40 ± 7% (n = 8, P < 0.05).
6 M LPA (solid bars).
Effects of epithelium removal on responses to methacholine, KCl, and LPA. Figure 7 illustrates the effect of LPA (10
6 M) on the isometric
contraction of rabbit TSRs with intact or removed epithelium to
cumulative addition of methacholine
(A) or KCl
(B). Removal of epithelium did not
change the contractile responses of TSRs to either agonist. Incubation
with LPA similarly potentiated the contraction induced by methacholine
in TSRs with intact or without epithelium. LPA had no effect on the
contractile response to KCl in TSRs with intact or removed epithelium.
6 M LPA (circles) in TSRs
with intact epithelium [+epi (
); LPA+epi (
)] or with
epithelium removed [
epi (
); LPA epi
(
)]. * P < 0.05 for
+epi vs. LPA+epi. P < 0.05 for epi vs. LPA epi.
Effects of LPA on contraction and relaxation of cat TSRs. Figure 8 illustrates the effects of methacholine and LPA on contraction of isolated cat TSRs. Cumulative administration of methacholine elicited dose-dependent increases in isometric tension similar to those observed in rabbit TSRs. LPA alone at 10
6 M did not affect
baseline tension, which was 2.98 ± 0.25 g before and 2.97 ± 0.24 g after incubation with LPA (n = 16, not significant). LPA significantly enhanced contraction
of the TSRs, ranging from 51 ± 15 to 136 ± 44% in response to
all doses of methacholine tested (n = 16, P < 0.05).
6 M LPA
to bath (solid bars). * P < 0.05 vs. control.
Figure 9 illustrates the effects of isoproterenol and LPA on relaxation of cat TSRs. Cumulative administration of isoproterenol to cat TSRs precontracted with methacholine caused a dose-dependent relaxation, with marked relaxation at a concentration of isoproterenol of 5 × 10
7 M that was essentially
ineffective in rabbit TSRs (Fig. 3). Inclusion of LPA at
106 M significantly
attenuated the relaxation in response to 5 × 107 and
106 M isoproterenol by 61 ± 12 and 27 ± 8%, respectively
(n = 16, P < 0.05) but did not have a
statistically significant effect on the relaxation induced by
105 M isoproterenol.
5 M MCh were
measured in response to indicated concentrations of isoproterenol in
absence (control; open bars) or presence of
106 M LPA (solid bars).
* P < 0.05 vs. control.
DISCUSSION
The present study documents the ability of the simple phospholipid mediator LPA to both enhance contraction and inhibit relaxation of isolated tracheal smooth muscle rings from both rabbits and cats. Although effects of LPA on vascular, gastrointestinal, and uterine smooth muscle contraction and on blood pressure regulation have been reported previously (21, 24-26, 28), we believe this is the first report on the ability of LPA to modulate airway smooth muscle contraction.
LPA did not induce contraction on its own at any concentration.
However, a significant enhancement of methacholine-induced contraction
was observed with LPA concentrations as low as
108 M. The structurally
similar lipid phosphatidic acid was markedly less effective. Both the
enhancement of contraction and the inhibition of relaxation by LPA were
rapidly reversed on removal of LPA. The potency, specificity, and
reversibility of these effects on airway smooth muscle contraction and
relaxation are typical of those for a variety of other responses to LPA
in numerous cell types (12, 13). Considerable evidence indicates that
the effects of LPA are likely to be mediated by one or more members of
the G protein-coupled family of cell surface receptors (12, 13), and
two recent reports have described the cloning of LPA receptors from
Xenopus oocytes and from mammalian
brain (6, 7).
Potential mechanisms for the effects of LPA on airway smooth muscle contraction were investigated. LPA enhanced the contraction of rabbit TSRs not only to methacholine but also to serotonin and to substance P. These results suggest that LPA modulates a step in the contractile signaling pathway that is shared by all of these agents rather than acting on receptors for specific contractile agonists. However, LPA did not alter the contractions induced by KCl, which bypasses receptor-signaling pathways and leads directly to depolarization-induced Ca2+ release. This result suggests that LPA does not alter the Ca2+ sensitivity or responsiveness of the contractile machinery and again is consistent with LPA modulation of more upstream signaling pathways leading to Ca2+ mobilization and contraction. The contraction-enhancing effects of LPA are apparently mediated directly on the smooth muscle cells because removal of the epithelium did not alter either the contractions induced by methacholine or KCl or the enhancement of the methacholine contraction by LPA.
The mechanism by which LPA inhibits relaxation of rabbit TSRs was also
investigated. LPA was able to inhibit isoproterenol-induced relaxation
of TSRs contracted with KCl in a way similar to its inhibition of
isoproterenol-induced relaxation of TSRs contracted with methacholine.
Thus the inhibition of isoproterenol-induced relaxation by LPA is not
simply an artifact related to its ability to enhance agonist-induced
contraction because LPA did not enhance contraction induced by KCl as
it did for methacholine. LPA also inhibited the relaxation induced by
the direct adenylyl cyclase activator forskolin, indicating that the
mechanism of inhibition of relaxation is not unique to the
-adrenergic receptor signaling pathway but is probably common to all
activators of adenylyl cyclase.
LPA is known to activate a variety of signal transduction pathways in different cell types, including stimulation of phosphoinositide hydrolysis, inhibition of cAMP accumulation, and activation of tyrosine kinase-signaling cascades (12, 13). We have previously characterized some of the signal transduction pathways activated by LPA in cultured human airway smooth muscle cells (14). LPA stimulated phosphoinositide hydrolysis in these cells, and this seems a reasonable mechanism for the effects of LPA on contraction reported in this study. However, most agents that stimulate phosphoinositide hydrolysis in smooth muscle lead to contraction on their own. This is also true for LPA in previous studies in other types of smooth muscle (21, 24-26, 28). In contrast, LPA did not significantly affect tracheal smooth muscle contraction on its own but rather enhanced the responsiveness to methacholine and other contractile agonists.
The effects of LPA on the cAMP signaling pathway in the human airway
smooth muscle cells were complex (14). LPA inhibited cAMP accumulation
stimulated by the direct adenylyl cyclase activator forskolin, but it
enhanced cAMP accumulation stimulated by the -adrenergic
receptor agonist isoproterenol. Pretreatment of these cells with LPA
led to a "sensitization" of subsequent stimulation by both
forskolin and isoproterenol. The enhancement of
isoproterenol-stimulated cAMP accumulation by LPA would be predicted to
enhance isoproterenol-induced relaxation as well, but in the present
study an inhibition of relaxation was observed instead. The effects of
LPA on cAMP accumulation may be different in the isolated rabbit and
cat tracheal rings used in the present study than in the cultured human
airway smooth muscle cells used in our previous study
(14). Alternatively, the effects of LPA on contraction may
not be mediated by a direct effect on cAMP. Other possibilities include
LPA regulation of tyrosine kinase pathways or effects of G protein 
-
or 
-subunits on various membrane ion channels. It seems likely
that the effects of LPA on airway smooth muscle contractility may not
be mediated by a single signaling pathway but rather by complex
interactions among the multiple signaling pathways that can be
activated by LPA. Clearly, additional studies will be required to
understand the molecular basis for the observed effects of LPA on
tracheal smooth muscle contraction.
LPA also stimulates DNA synthesis and cell growth in human airway smooth muscle cells in culture and exhibits a profound synergism with epidermal growth factor for these effects (2). Several agents classically thought of as contractile stimuli, such as histamine, endothelin, and thrombin, have recently been shown to also promote airway smooth muscle cell growth (8, 15, 19). Conversely, some agents classically thought of as growth factors, such as epidermal growth factor, have been shown to also exert contractile effects on various types of smooth muscle (9), including tracheal smooth muscle (16). LPA can now be added to this list of agents inducing both responses. Previous studies have documented effects of LPA on both contraction (21, 24) and growth (27) of vascular smooth muscle. Our studies indicate that LPA also induces both effects in airway smooth muscle.
The physiological significance of LPA for lung function is a question of obvious interest. The best-characterized source of LPA is from activated platelets; thus LPA is present in serum but not in carefully isolated plasma (4, 22). Local concentrations of LPA would presumably be high at a site of tissue damage, where platelet activation would occur. LPA has also been shown to be released from fibroblasts stimulated with platelet-derived growth factor (5). To our knowledge, LPA has not been quantitated or documented to be present in the lung. However, increased concentrations of phospholipase A2 and of various lysophospholipids that could serve as precursors for LPA have been documented in bronchoalveolar lavage fluids from allergic subjects challenged with antigen (3). We believe that LPA is likely to be present in the lung and to be of physiological relevance there because we have observed multiple effects of LPA on several different types of lung cells. In addition to the effects on airway smooth muscle, LPA also stimulates fibronectin release from airway epithelial cells (18) and fibroblasts (T. Mio, M. L. Toews, D. J. Romberger, and S. I. Rennard, unpublished observations), promotes filopodia extension by airway epithelial cells (1), and enhances lung fibroblast-mediated collagen gel contraction (T. Mio, M. L. Toews, D. J. Romberger, and S. I. Rennard, unpublished observations).
These diverse effects of LPA suggest several possible roles for LPA in both normal and pathological lung function. Increased smooth muscle mass and enhanced contractility are both characteristic features of asthma and other obstructive pulmonary diseases (20, 29). Thus the ability of LPA to enhance both contraction and proliferation of airway smooth muscle cells suggests the possible involvement of LPA in the pathology of these diseases. It seems likely that the normal physiological function of LPA in the lung may be to promote tissue repair in response to injury or inflammation, as proposed previously for other tissues (12, 13). The effects of LPA on release of fibronectin, extension of filopodia, contraction of collagen gel matrixes, and promotion of cell growth are all consistent with a role in tissue repair in the lung. LPA could also play a role in lung fibrosis if these repair processes were not properly regulated.
In summary, the present study documents the ability of LPA to enhance contraction and inhibit relaxation of airway smooth muscle from two different species. These effects, together with additional responses documented in other studies, suggest that LPA may be an important regulator of lung cell function with both physiological and pathological significance. Further characterization of the receptors and signaling pathways by which LPA mediates these effects and of the factors controlling LPA release and metabolism in the lung may lead to novel approaches for the therapeutic modulation of lung cell function in various pulmonary diseases.
FOOTNOTES
Address for reprint requests: M. L. Toews, Dept. of Pharmacology, Univ. of Nebraska Medical Center, 600 S. 42nd St., Omaha, NE 68198-6260.
Received 8 July 1996; accepted in final form 17 June 1997.
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