1 Division of Pulmonary and Critical Care Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin 53226; 2 Department of Physiology, Michigan State University, East Lansing, Michigan 48824; and 3 Department of Pathology, Northwestern University, Chicago, Illinois 60085
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ABSTRACT |
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Norepinephrine (NE) induces apoptosis in cardiac
myocytes, and autocrine production of angiotensin (ANG) II is required
for apoptosis of alveolar epithelial cells (AECs) (Wang R,
Zagariya A, Ang E, Ibarra-Sunga O, and Uhal BD. Am J Physiol
Lung Cell Mol Physiol 277: L1245-L1250, 1999; Wang R, Alam G,
Zagariya A, Gidea C, Pinillos H, Lalude O, Choudhary G, and Uhal BD.
J Cell Physiol 185: 253-259, 2000). On this basis,
we hypothesized that NE might induce apoptosis of AECs in a
manner inhibitable by ANG system antagonists. Purified NE induced
apoptosis in the human A549 AEC-derived cell line or in primary
cultures of rat AECs, with EC50 values of 200 and 20 nM,
respectively. Neither the -agonist phenylephrine nor the
-agonist
isoproterenol could mimic NE when tested alone but when applied
together could induce apoptosis with potency equal to NE.
Apoptosis and net cell loss (47-59% in 40 h) in
response to NE was completely abrogated by the ANG-converting enzyme
inhibitor lisinopril or the ANG II receptor antagonist saralasin, each
at concentrations capable of blocking Fas- or tumor necrosis
factor-
-induced apoptosis. These data suggest that NE
induces apoptosis of human and rat AECs through a mechanism involving the combination of
- and
-adrenoceptor activation followed by autocrine generation of ANG II.
catecholamine; angiotensin II; lung injury; pulmonary edema; type II pneumocyte
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INTRODUCTION |
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PULMONARY ALVEOLAR EPITHELIAL CELLS (AECs) have varied and important roles in lung homeostasis, one of which is the replacement of epithelial cells lost to lung injury (21). Repair of the alveolar epithelium is accomplished by the regulated proliferation and differentiation of type II AECs (37). Incomplete or delayed alveolar repair leads to acceleration of collagen deposition and lung fibroblast proliferation in animal models (41, 48). For these reasons, type II pneumocytes are thought to be crucially important in the pathogenesis of lung fibrosis (34, 48).
Apoptosis of unneeded cells during lung development or during resolution of lung injury is a normal physiological process, but inappropriate stimulation or delay of apoptosis may play a role in the pathogenesis of lung disease (9). For example, the repair process after acute lung injury requires elimination of excess mesenchymal and inflammatory cells from the alveolar space and wall. Failure to clear these cells by apoptosis could accelerate the progression to fibrosis or delay its resolution (7, 9, 29). As examples of excessive apoptosis, acute fulminant hepatitis and death occurred after intraperitoneal injection of a Fas-activating antibody into adult mice (26). Moreover, intratracheal instillation of the same antibody into normal mice caused epithelial cell apoptosis followed by lung fibrosis (12), consistent with the notion that the loss of epithelial integrity is a key event in fibrogenesis.
The influence of circulating catecholamines on the proliferation or
death of AECs is largely unknown. Although high serum levels of
norepinephrine (NE) have some beneficial effects in the lung, such as
the stimulation of lung liquid clearance (28), high
sympathetic drive may also cause pulmonary edema (28). In
heart failure, apoptosis of cardiac myocytes in response to NE
is believed to be an important component of the progression of cardiac
fibrosis (6, 14, 18). Moreover, cardiomyocyte apoptosis in response to NE is mediated by -adrenergic
receptors and is inhibited by the
-adrenergic antagonist propranolol.
For these reasons, we hypothesized that NE might induce
apoptosis of AECs as it does in cardiac myocytes. Moreover, on
the basis of recent work in which Wang and colleagues found a
requirement for autocrine production of angiotensin (ANG) II in the
signaling of AEC apoptosis in response to Fas (44)
or tumor necrosis factor (TNF)- (42), we further
theorized that AEC apoptosis in response to NE might also
involve autocrine generation of ANG II. We report here that NE induces
apoptosis in cultured AECs by a mechanism that involves the
combination of
- and
-adrenoceptors as well as autocrine ANG II production.
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METHODS |
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Reagents and materials. Norepinephrine (NE), isoproterenol (Iso), phenylephrine (PE), propranolol, prazosin, atenolol, lisinopril, and saralasin were obtained from Sigma (St. Louis, MO). Fluorescein-conjugated annexin V was obtained from PharMingen (San Diego, CA). Z-Val-Ala-Asp-fluoromethylketone (ZVAD-fmk) was obtained from Kamiya Biomedical (Seattle, WA).
Cell culture. The human lung adenocarcinoma cell line A549 was obtained from the American Type Culture Collection and cultured in Ham's F-12 medium supplemented with 10% fetal bovine serum. Primary AECs were isolated from adult male Wistar rats as described earlier (38, 40). The primary cells were studied on day 2 of culture, a time at which they are type II cell-like by accepted morphological and biochemical criteria (38). All primary cell preparations were of >90% purity as assessed by acridine orange staining as previously described (40). All cells were seeded on 12-mm sterile coverslips in 24-well chambers at subconfluent densities of 80-90% in serum-free Ham's F-12 medium. Test reagents were diluted with Ham's F-12 medium. The cells were exposed to propranolol, ZVAD-fmk, and antagonists of the renin-ANG system 30 min before exposure for 20 h to NE, Iso, or PE.
Quantitation of apoptosis and cell loss. Detection of apoptotic cells with propidium iodide was conducted as described earlier (39, 42) after digestion of ethanol-fixed cells with DNase-free RNase in PBS containing 5 µg/ml of propidium iodide. In these assays, detached cells were retained by centrifugation of the 24-well culture vessels during fixation with 70% ethanol. Cells with discrete nuclear fragments containing condensed chromatin were scored as apoptotic. As in earlier publications (42, 44), the induction of apoptosis was verified by annexin V binding and abrogation of nuclear fragmentation by caspase inhibition with ZVAD-fmk.
In Figs. 1, 3, and 4, nuclear fragmentation data are expressed as the percentage of positive cells relative to the control (untreated) group, which was set to 100% in each assay. This manner of expression reflects the fact that the nuclear fragmentation assay, although specific for apoptosis (42, 45), detects only the very late and rapid stage of karyorrhesis and thus underestimates the true apoptotic index by three- to fourfold (see Fig. 2 for comparison to the annexin V binding assay). The actual numbers of cells displaying nuclear fragments are provided in Figs. 2-4.
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RESULTS |
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Purified NE induced apoptosis of cultured human (A549) and
rat AECs in a concentration-dependent manner (Fig.
1). In both cell culture models, the
induction of apoptosis was maximal at 1 µM NE, but the
primary rat AECs were more sensitive (EC50 = 20 nM)
than the A549 cell line (EC50 = 200 nM). The
-adrenergic antagonist propranolol (10 µM) completely blocked the
apoptosis induced by 1 µM NE. At the maximally stimulatory
dose of NE (1 µM), the percentage of primary rat AECs undergoing
apoptosis at any given time was at least 30% as detected by
annexin V binding (Fig. 2), a fraction
sufficient to result in a net cell loss of 50% or more in 40 h
(see below).
The apoptotic effect of 1 µM NE on primary rat AECs could not be
reproduced by stimulation of -adrenergic receptors alone with an
equivalent dose of Iso (1 µM; Fig.
3A) nor by stimulation of
-adrenergic receptors alone with PE. In contrast, NE applied at the
same doses as PE (0.01 and 0.1 µM; compare Figs. 1 and 3) was
sufficient to cause a significant induction of apoptosis. However, when the cultured AECs were challenged with Iso and PE together (Fig. 3), the stimulation of apoptosis was equal to
that induced by NE at the same total agonist concentration (actually 1.1 µM total agonist). These data suggest that the proapoptotic effect of NE on AECs is mediated through the combined activation of
- and
-adrenoceptors simultaneously. Consistent with that interpretation, the apoptotic effect of 1 µM NE could be
abrogated (Fig. 3A) by either the
1-antagonist prazosin (10 µM) or the
1-antagonist atenolol (1 µM). Qualitatively similar
results were obtained for the cell line A549 (Fig. 3B).
Apoptosis of A549 cells in response to NE was also abrogated by
the broad-spectrum caspase inhibitor ZVAD-fmk, the ANG-converting enzyme (ACE) inhibitor lisinopril or the ANG receptor antagonist saralasin (Fig. 4A).
Essentially identical results were obtained for primary rat AECs (Fig.
4B). These data are consistent with recent work from this
laboratory indicating a requirement for autocrine production of ANG II
for the execution of apoptosis in AECs in response to Fas
ligand (39) or TNF- (37).
The induction of apoptosis by NE at 1 µM was sufficient to
result in a net cell loss of 49 and 56% of A549 cells (Fig.
5A) and primary rat AECs (Fig.
5B), respectively, each over 40 h of incubation. The
method used for cell counting (see METHODS) ensured that
cell loss due to detachment did not confound the assay; in any case, no
significant differences in the number of detached versus adherent cells
were noted under any treatment condition (data not shown). The
combination of PE and Iso was equally as potent as 1 µM NE in
promoting the cell loss as it was in inducing apoptosis (Fig.
3). Moreover, the net cell loss induced by NE over 40 h could be
completely blocked by the same antagonists of the renin-ANG system that
blocked nuclear fragmentation, i.e., lisinopril or saralasin. This was
the case in either A549 cells (Fig. 5A) or primary rat AECs
(Fig. 5B). The net cell loss also was abrogated by the
-antagonist propranolol (10 µM) or by the caspase inhibitor
ZVAD-fmk (Fig. 5B). The latter result confirms that the net
cell loss was due to apoptosis (24).
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DISCUSSION |
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Type II AECs have roles in antioxidant defense, immunomodulation,
surfactant synthesis, and injury repair (37). These cells are believed to be a critical player in the pathogenesis of pulmonary fibrosis (34). It is also known that apoptosis is
an important regulator of AEC population size (37) and is
a prominent feature of the fibrotic lung in vivo (2).
Catecholamine-induced apoptosis has been studied in cardiac
myocytes (6), brown adipose tissue (17),
Cajal-Retzius cells (25), pheochromocytoma cells
(4), glioma cells (5), lymphocytes
(15), and hepatocytes (49). Increased levels
of serum NE in congestive heart failure are believed to be cardiotoxic
in circumstances involving relative hypoxia, calcium overload,
elevation of cAMP, activation of - or
-adrenergic receptor, and
the formation of oxidative catecholamine metabolites (19, 27,
30). A recent study by Communal et al. (6) showed that NE (10 µM) induced apoptosis in rat ventricular myocytes by activation of the
-adrenergic pathway, which is speculated to
contribute to myocardial fibrosis and heart failure.
In the same study, the effect of NE was mimicked by Iso but was blocked
by propranolol, findings that suggested that NE-induced apoptosis of cardiac myocytes is mediated primarily by
-adrenoceptors. In contrast, the blockade of NE-induced
apoptosis of AECs by the
1-antagonist prazosin
or the
1-antagonist atenolol (Fig. 3) together with the
ability of PE and Iso to induce apoptosis when applied jointly
but not separately supports the contention that both
- and
-receptor activation are required simultaneously for NE-induced
apoptosis of AECs. Moreover, the ability of atenolol to block the
apoptotic response to NE suggests the involvement of
1-receptors; this, in turn, sheds light on the failure
of Iso to elicit a response when applied alone. The mechanistic basis for this cell type-specific difference in apoptosis signaling is an interesting topic for future inquiry.
Here we also showed that ACE inhibition or ANG II receptor antagonism
can completely abrogate NE-induced apoptosis as it does for AEC
apoptosis in response to Fas activation (8, 39,
44), TNF- (42), or the pneumotoxic benzofuran
antiarrythmic agent amiodarone (3). Taken together, these
data support the hypothesis that autocrine production of ANG II by AECs
and its binding to ANG II receptors may be a common event required for
the execution of apoptosis regardless of the initiating
stimulus. Data from other cell types suggest that possible candidates
for a signal transduction mechanism common to NE, Fas, and TNF-
might include p53, p21 (WAF1), and/or associated DNA damage (16,
20, 23, 24). Although the molecular linkage between
proapoptotic stimuli and autocrine production of ANG II by AECs is
not yet known, preliminary results suggest that the linkage does not
include autocrine synthesis of Fas ligand or TNF-
; neutralizing
antibodies capable of blocking Fas- or TNF-induced apoptosis in
AECs had no effect on NE-induced apoptosis (data not shown).
Regardless, a role for catecholamines in acute respiratory distress
syndrome (ARDS) has been suggested by a variety of studies. NE is
increased greatly in the serum in endotoxin-induced experimental ARDS
and in models of neurogenic edema (13, 35). In
experimental neurogenic edema induced by bicuculline injection
(35), plasma NE rose from a basal level of ~100 pg/ml to
well over 30,000 pg/ml (~0.15 µM), well within the range necessary
for maximal induction of apoptosis in primary cultures of AECs
(Fig. 1, right). The high serum level of NE is thought to be
meaningful as an indicator for the early diagnosis of ARDS (11,
13). It is believed that in rats with septic shock, endogenous
release of catecholamines stimulates lung epithelial clearance of
liquid through a -adrenoceptor-mediated stimulation of active sodium
transport (28). Similarly, the effect of catecholamines to
increase edema clearance was also observed in guinea pigs at birth
(10). The findings that the moderately
-selective
agonists Iso and terbutaline could mimic the effect of endogenous
catecholamines (32) have led to the suggestion that
increased lung edema clearance is mediated by
2-receptors. However, the selectivity of these agonists
for the
2-receptor is not absolute, and recent work
(31) has shown that the
1-selective agonist
denopamine can promote edema clearance at the same doses
(10
6 to 10
3 M). These concentrations are an
order of magnitude higher than those required by NE for induction of
AEC apoptosis (see Fig. 1).
In addition to their positive effect, adrenergic agonists have also
been suggested to play a negative role in lung injury. In animal
models, high-dose epinephrine injections (30 µg/kg) may cause
pulmonary edema and death (33). A recent study
(1) examining the effect of catecholamines on
endotoxin-induced lung injury revealed that administration of the
1-adrenergic agonist PE before endotoxin significantly
increased the expression of TNF-
and macrophage inflammatory
protein-2 mRNAs by lung neutrophils compared with endotoxin alone. In
contrast,
2-adrenergic stimulation prevented
endotoxin-induced increases in lung myeloperoxidase and lung neutrophil
cytokine mRNA levels (1).
An inhibitory effect of ACE inhibitors on lung fibrogenesis has been documented (22, 46, 47). A more recent study (43) in which the fibrogenic effect of intratracheal administration of bleomycin was blocked with equal potency by the ACE inhibitor captopril or the caspase inhibitor ZVAD-fmk supports the contention that at least part of the antifibrotic effect of captopril was due to its ability to block bleomycin-induced apoptosis of AECs. By the same rationale, it will be interesting to determine whether acute lung injury might be induced in experimental animals by intratracheal instillation of NE in a manner inhibitable by antagonists of the renin-ANG system.
In summary, NE caused dose-dependent apoptosis of human and rat
AECs that is mediated by a combined effect of - and
-adrenoceptors and, indirectly, ANG receptor activation. NE-induced
apoptosis of AECs was abrogated by antagonists of the renin-ANG
system, suggesting that autocrine production of ANG II is required for AEC apoptosis in response to NE. These findings are consistent with recent demonstrations (42, 44) of a
requirement for ANG II generation for the execution of
apoptosis in response to Fas or TNF-
. They also raise the
possibility that apoptosis of AECs may be a contributing factor
in the pathogenesis of acute lung injuries such as ARDS and neurogenic
edema in which circulating NE is known to be greatly elevated. The
relevance of these findings to lung injury mechanisms in vivo is
currently being evaluated.
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ACKNOWLEDGEMENTS |
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This work was supported by National Heart, Lung, and Blood Institute Grant HL-45136 (to B. D. Uhal) and by the Research Foundation, Michigan State University (East Lansing, MI).
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FOOTNOTES |
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Address for reprint requests and other correspondence: B. D. Uhal, Dept. of Physiology, Michigan State Univ., 310 Giltner Hall, East Lansing, MI 48824 (E-mail: uhal{at}msu.edu).
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. Section 1734 solely to indicate this fact.
Received 27 December 2000; accepted in final form 11 April 2001.
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