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448
Current Respiratory Medicine Reviews, 2012, 8, 448-453
The Effects of Erythropoietin on the Respiratory Function: Measurements
of Respiratory Mechanics in the Rat
Alessandro Rubini1, Gerado Bosco1, Andrea Par magnani1, Daniele del Monte2 and Vincenzo Catena2
1
Department of Biological Sciences, Section Physiology, University of Padova, Italy
2
Department of Emergency and Intensive Care, ULSS 2, Feltre (BL), Italy
Abstract: Data reported in the literature indicate that erythropoietin (EPO) influences mammals respiratory function, for
example stimulating pulmonary ventilation.
Direct experimentations about possible effects of EPO on respiratory mechanics are lacking. In the present report, the endinflation occlusion method was applied in control and EPO-treated anaesthetised and positive-pressure ventilated rats to
assess respiratory mechanics. The method involves a sudden flow arrest after a constant flow inflation, and allows to
measure the ohmic airway resistance and the respiratory system elastance.
A significant decrement of the ohmic airway resistance after 20 and 30 minutes from i.p. EPO administration was
observed in experimental animals, which was not seen in control animals. The elastic characteristics of the respiratory
system did not change over time in both groups.
Hypothesis about the mechanism(s) explaining the results and potential applications to humans are addressed. In
particular, further data were obtained by performing additional experiments suggesting that the observed airway resistance
decrement may be related to an EPO-induced increased nitric oxide production, a rather well known bronchodilator agent.
Literature and present results indicate that the spontaneous increments of plasmatic EPO concentrations, such as those
happening in hypoxia and/or blood loss, may be associated with airway resistance decrement. It is suggested that
erythropoietin, beside the well known effect on haematopoiesis, may activate complex physiological responses including
haematological, circulatory and respiratory adaptations to hypoxia in mammals.
Keywords: Airway resistance, end-inflation occlusion method, erythropoietin, hypoxia, rat, respiratory mechanics.
1. INTRODUCTION
Erythropoietin (EPO) is known to stimulate
differentiation and growth of erythroid precursor, but
recently some non-haematopoietic effects have also been
reported. As indicated by the expression of EPO and its
receptors in normal healthy human lung tissues [1], those
effects may include influences on the respiratory system
functions. If verified, these influences could suggest that
EPO-mediated responses to hypoxia and/or blood loss
represent a complex scenario of physiological mechanisms
of adaptation, including not only haematological but also
circulatory and respiratory responses. However, few data are
available regarding this subject.
2. REPORTED EFFECTS OF EPO ON RESPIRATORY
FUNCTION
It has been reported that EPO can increase pulmonary
ventilation by increasing both breathing rate and tidal
volume in patients with renal failure [2], and a similar effect
has also been detected in anaesthetised rats after
intracisternal administration [3].
*Address correspondence to this author at the Department of Biological
Sciences, Section Physiology, University of Padova, Via Marzolo, 3, 35100
Padova, Italy; Tel: ++390498275310; Fax: ++390498275301;
E-mail: [email protected]
1875-6387/12 $58.00+.00
Moreover, EPO probably has some effect on airway
resistance: it has been reported to cause inhibition of
carbachol-induced bronchoconstriction in mice [4], and to
induce increments in forced vital capacity and in peak
expiratory flow rate in humans [2].
Similar effects may also ensue because of beneficial
effects of EPO on inflamed lung tissues [5, 6], counteracting,
for example, the increment in airway resistance caused by
inflammatory cytokines such as IL-6 [7].
In addition, EPO affects vascular smooth muscle tone
causing relaxation [8, 9], suggesting a possible similar effect
on airway smooth muscle tone too. The relaxing activity has
been, in fact, related to increased nitric oxide (NO)
production [10-12], a well known bronchodilator [13-16].
Studies investigating the possible direct EPO’s effects on
respiratory mechanics parameters and airway resistance in
healthy mammals are lacking in the literature. However, the
effects of EPO administration on respiratory system
mechanics were recently assessed in rats using the endinflation occlusion method [17]. This made it possible to
investigate both the ohmic, Newtonian airway resistance, as
predicted by Poiseuille's law, and respiratory system
elastance [18-20]. Purpose of the study was to elucidate if
variations in EPO blood concentration occurring in
spontaneous conditions, such as blood loss or hypoxia, may
affect respiratory system mechanics parameters.
© 2012 Bentham Science Publishers
Erythropoietin and Respiratory Mechanics
3. DESCRIPTION OF EPO’S EFFECTS
RESPIRATORY MECHANICS: METHODS.
Current Respiratory Medicine Reviews, 2012, Vol. 8, No. 6
ON
Animals
These experiments were performed on 20 albino rats of
both sexes (mean weight 307 ± 23 g., 10 males). To
investigate the effects of EPO on respiratory mechanics eight
animals were used, and six additional rats with similar
characteristics were studied as control animals. Six others
rats served for the experiments testing the hypothesis that
EPO administration may increase NO production (see
below).
The experimental protocol was approved by the local
Ethical Committee (CEASA, University of Padova, ref. N°
48/2011).
The housing and the management of the experimental
animals were in keeping with the Italian law on animal
experimentation (L. 116/92) and with the European Council
(EC) provision 86/609/EEC.
Experimental Procedure
Rata were anaesthetized (50 mg /100 gr ip chloralose)
and laid on a heated operating table. Following
tracheostomy, a polyethylene tracheal cannula (2mm ID, 5
cm long) was inserted and secured in place.
ECG was derived from limb probes. After the start of
positive pressure ventilation, the animals was paralyzed (cisatracurium 1 mg/100 gr ip).
Positive pressure ventilation used 10 ml/Kg tidal volume
and a 60/min breathing frequency (PEEP 3 cmH2O) (Rodent
Ventilator 7025, Basile, Italy), and these parameters were
maintained constantly throughout the experiment.
449
For each rat, measurements by the end-inflation
occlusion method were performed at different times (10, 20,
and 30 minutes) after the ip injection of 1000 U Kg-1 rat
recombinant EPO (SIGMA, St. Louis, Missouri, USA)
dissolved in 100 μl PBS.
Literature indicates that the adopted mechanical
ventilation parameters are not injurious to the respiratory
system [7, 16]. Nevertheless, additional six (a number
considered sufficient for this purpose) control animals were
studied to verify if the variations observed in the
experimental group (see below) could be due to a timedependent effect. The control rats received 100 μl PBS ip
and respiratory mechanics were studied according to the
same procedure described for the experimental rats receiving
EPO.
Data Calculation
On magnified recordings (Fig. 1), the static elastic
pressure of the respiratory system achieved after the
inflations (Pel,rs), and the resistive pressure drop due to the
flow interruption (Pmin,rs), were measured. Pmin,rs was
identified as the pressure drop between Pdyn, max, the
maximum value of the tracheal pressure at the end of the
inflations, and the pressure value immediately after the flow
was arrested (P1, see Fig. 1). In the magnified pressure
tracings, P1 separated the sudden Newtonian pressure drop
due to airflow frictional forces in the airway (Pmin,rs) from
the subsequent slower, nearly exponential, pressure decay
which is due to the respiratory system visco-elastic
characteristics, i.e. stress relaxation [19, 20, 23, 24].
According to the literature [19, 20, 23, 24], the overall
pressure decay, including Pmin,rs and the subsequent viscoelastic component, was termed Pmax,rs (Fig. 1).
After 5 minutes, mechanical ventilation and PEEP were
discontinued and the end-inflation occlusion method applied
to measure respiratory system mechanics [18-20], as follows.
A constant flow pump (SP 2000 Series Syringe Pump
sp210iw, World Precision Instruments, USA) delivered an
inflation volume (VT) of 3 ml according to a square wave
flow (F) of 4 ml/sec through the tracheal cannula. The time
taken for the arrest of inflation flow was approximately 30
msec. The pump settings were carefully checked during
separate measurements performed before the experiments.
According to the literature, to avoid significant blood gas
changes the time the mechanical ventilation was suspended
during the constant-flow inflations was kept very short (less
than 30 sec.) [21].
The pressure in the tracheal cannula was laterally
monitored (142 pc 01d, Honeywell, USA) and recorded
(1326 Econo Recorder, Biorad, Italy). In the ventilatory
circuit abrupt changes in the diameters of tubing were not
present, so that errors in flow resistance measurements, such
as those previously described [22], were avoided. The
frequency-response characteristics of the transducer and of
the pressure measuring circuit were checked by sinusoidal
forcing. The frequency response was found to be flat up to
20 Hz which, according with literature data [23, 24], allowed
to avoid significant mechanical artefacts in pressure signal
recording.
Fig. (1). An example of lateral tracheal pressure tracing on flow
interruption. The pressures used for the definition of respiratory
system mechanics are reported: the maximal pressure at end
inflation (Pdyn max), the pressure immediatly after airflow
interruption (P1), the static elastic pressure of the respiratory
system after inflation (Pel,rs), the nearly instantaneous pressure
drop due to the ohmic respiratory system resistance (Pmin,rs) and
the total pressure drop including the effects of the visco-elastic
characteristics of the respiratory system’ tissues, i.e. stress
relaxation (Pmax,rs).
To limit the effect of visco-elastic pressure components
was in Pmin,rs, P1 values were determined by extrapolating
450 Current Respiratory Medicine Reviews, 2012, Vol. 8, No. 6
Rubini et al.
the pressure tracings to the instant the flow stopped, as
previously described in the literature [25].
Est,rs
The data obtained from 3 to 5 inflations for each rat were
used in the calculation of the respiratory system static
elastance (Est,rs = Pel,rs/VT) and of the ohmic inspiratory
resistance to airflow offered by frictional forces in the
airways (Rmin,rs =Pmin,rs/F).
100
75
Est,rs %
The value of the equipment resistance (Req), which
included the tracheal cannula and a standard three-way
stopcock, was separately measured. Measurements were
performed at the same flow rate of 4 ml/sec which was used
in the experiments. Req resulted 0.0575 cmH2O ml-1 s-1 and
was subtracted from the results, which thus represent
intrinsic values.
125
50
25
0
0
20
30
TIME (min)
Statistics
The mean values of respiratory system mechanics
parameters before and following EPO were statistically
compared (ANOVA). Data are here reported as mean values
± SE (n=8).
4. DESCRIPTION OF EPO’S EFFECTS
RESPIRATORY MECHANICS: RESULTS
ON
The mean values of respiratory mechanics parameters
before EPO administration resulted as follows: Rmin,rs =
0.14±0.02 cmH2O ml-1 sec-1, Est,rs= 1.95±0.07 cmH2O ml-1.
The time-related percentage variations following EPO and
PBS intraperitoneal administration in the experimental and
control rats are outlined in Figs. (2, 3). No significant timerelated changes were detected in the control animals after ip
injections of PBS, while in the experimental rats significant
decrements in Rmin,rs were observed after EPO. Est,rs mean
values did not change significantly neither in the control nor
in the experimental animals. Heart rate values did not vary
significantly during the experiments (Table 1).
Rmin,rs
125
*p<0.05
100
Rmin,rs %
10
75
*
*
50
25
0
0
10
20
30
TIME (min)
Fig. (2). The acute effects of erythropoietin on airway resistance.
The percentage changes of Rmin,rs (mean values ±SE) at different
times after i.p. injections (time = 0). Data are reported for
experimental (1000U Kg-1 rat recombinant erythropoietin, n=8,
white columns) and control rats (n=6, hatched columns). Statistical
significance of the changes is reported.
Fig. (3). The acute effects of erythropoietin on respiratory system
elastance. The percentage changes of Est,rs (mean values ±SE) at
different times after i.p. injections (time = 0). No significant change
was detected in control (n=6, hatched columns) nor in experimental
rats (1000U Kg-1 rat recombinant erythropoietin, n=8, white
columns).
5. DESCRIPTION OF EPO’S EFFECTS ON RESPIRATORY MECHANICS: DISCUSSION
Experimental Procedure
The end-inflation occlusion method has been widely
applied before to study respiratory mechanics both in
experimental animals [7, 16, 24] and in humans [19, 20, 23].
Theoretically, the inflation flow should stop
instantaneously, but this is impossible to be obtained in real
systems. A correction for this technical limitation has been
proposed in which the pressure recordings are extrapolated
to the time that is requested to completely arrest the
inspiratory flow [25], thereby rendering the error practically
neglibible [7, 16, 24]. The same was applied in the study
here described. It is not possible to exclude that any stress
relaxation pressure decays do take place during inflation,
thus influencing the value of the observed Pmin,rs. However,
any stress-relaxation effect should be negligible because the
duration of inflation was very short compared with the
stress-relaxation phenomena timing (Fig. 1).
The mechanical ventilation modalities applied in these
experiments were the same as those reported to have not any
injurious effect on respiratory system mechanics in the
literature [7, 16]. “Non injurious” ventilation lasting till one
hour has in fact been shown to exert no deleterious effect on
respiratory system mechanics parameters [7, 16]. Thus, as
also confirmed by data obtained in control rats, results here
described were not affected by the injurious effects that
mechanical ventilation per se might exert when applied for
longer time.
Significant changes of mean heart rate values during the
experimental time were not observed, suggesting that the
rats’ conditions during the experiments were generally stable
(Table 1).
Intraperitoneal EPO injection is a largely applied
procedure [26-28], and the dosage utilized was rather similar
Erythropoietin and Respiratory Mechanics
to that previously adopted for other rat experimentations [2628]. According to the literature [29], this dosage is expected
to increase EPO concentration in the extracellular fluids by a
factor of approximately 40 with respect to basal
concentrations. Thus, the experimental injections were
expected to induce an increment in plasma EPO of a similar
magnitude compared to that documented in spontaneous
pathological conditions such as hypoxia [30] and/or blood
loss [31].
Table 1.
Time (min) 0 10 20 30
Heart rate (b min-1) 338±16 333±23 322±22 316±19
Mean values (±SE, n=8) of heart rate during the experiments.
Data are reported at different times following i.p. 1000U Kg-1 rat
recombinant erythropoietin injection, which was given at time=0. Mean
values do not differ significantly.
The mean values for respiratory system mechanics
parameters that were observed are comprised in the range of
those previously reported in rats by various researchers
working in different laboratories [7, 16, 24, 32, 33].
The Effects of EPO on Respiratory Mechanics
The main finding is the demonstration that EPO
significantly affects the inspiratory resistive pressure
dissipation, thus Rmin,rs.
This result confirms previously reported indirect
indications showing that EPO can inhibit the carbacholinduced bronchoconstriction in mice [4], and that can
increase forced vital capacity and peak expiratory flow rate
mean values in humans [2].
The EPO-induced decrement in airway resistance could
be due to a relaxing effect on airway smooth muscle tone. In
fact, EPO has been reported to cause smooth muscle
relaxation mediated by increased NO production in the
vascular walls [10-12], and NO is a well known
bronchodilator [13-16]. NO production in the rats was not
directly investigated, but the above reported suggestion that
the EPO-related decrement in airway resistance may be
related to incremented NO production was tested by
measuring respiratory mechanics in six additional rats. It was
found that the rats did not show any significant variations in
Rmin in the time of observation when, following EPO, a
NO-synthase inhibitor (L-Name) was given ip. Thus, the
effects of EPO on Rmin,rs were cancelled when nitric oxide
synthesis was inhibited, confirming that nitric oxide
synthesis contributes to the EPO’s mechanism of action.
In addition, NO is known to act as potent vasodilatory
agent on the systemic circulation, and peripheral arterial
vasodilation is associated with a decrement in blood lung
volume. Thus, an increment in NO production because of
EPO administration is expected to induce a decrement in
Rmin,rs also as a result of the reduced lung blood volume
[31].
According to the literature, EPO could induce
bronchodilatation also because it has been reported in the rat
to potentiate endothelium-derived hyperpolarizing factor
Current Respiratory Medicine Reviews, 2012, Vol. 8, No. 6
451
(EDHF) activity [9], which causes airway smooth muscle
relaxation [34, 35].
Finally, at least another mechanism could be involved in
reducing airway resistance: in fact, EPO activates MAP
kinases [36] which reduce airway mucous production [37].
Present data indicate that EPO has not significant effects
on respiratory system elasticity. This finding suggest that
EPO does not exert any significant effect on the anatomical
structures respiratory system elasticity depends on, namely
collagen and elastin in the alveolar wall, and on alveolar
surfactant. In the recent literature, an EPO-induced inhibition
of collagen deposition and fibrosis in rat models of kidney
ischemia-reperfusion injury [38] and experimental diabetesinduced cardiac function impairment [39] has been indeed
described, but these were long-term effects only, which were
moreover observed in anatomical structures different from
the respiratory system.
Presently described results may help to clarify the
mechanism(s) underlying the decrement in airway resistance
observed in mammals exposed to chronic hypoxia [40]
and/or to hemorrhagic shock [41]. In both conditions, in fact,
an increased EPO synthesis is expected, which could
contribute, at least in part, to the observed reduction in
airway resistance. As a confirmation, beneficial effects of
erythropoietin on airway histology in a murine model of
chronic asthma have been recently reported [42].
Further studies are needed to investigate the possible
effects of long term exposure to EPO on respiratory
mechanics. In this regard, it is known that haematocrit
increments start several hours after EPO administration [43],
so that any related effect should be delayed in time and not
influencing present data.
Although a direct experimental demonstration of EPO
activities in human respiratory system mechanics is lacking,
various effects on the respiratory system of man have been
reported, including a stimulating effect on pulmonary
ventilation [2, 44] and an improvement in forced vital
capacity and peak expiratory flow rate [2]. Thus, it seems
highly probable that the decrement in airway resistance
described in the rat may hold for humans too.
As a consequence, the here described findings may be
interpreted suggesting that EPO effects are involved in a
complex physiological response to hypoxia in mammals,
including not only the well known increment in haematocrit,
but also a) an increase in pulmonary ventilation [2, 3, 44],
contributing to further counteract arterial hypoxia; b) a
vasodilatation in peripheral blood vessels, increasing tissue
oxygen delivery, which has been suggested to be of clinical
relevance in humans [10-12]; c) the presently reported
decrement in inspiratory pressure dissipation, which may
support the increased pulmonary ventilation, counteracting
deleterious increments in energy dissipation during
breathing.
CONCLUSION
At least during a rather short time of observation, EPO
has been shown to cause acutely a decrement in the ohmic
airway resistance, leaving unaltered respiratory system
elastance.
452 Current Respiratory Medicine Reviews, 2012, Vol. 8, No. 6
These data for the first time directly describe the acute
influences of EPO on respiratory mechanics parameters in
mammals. They may be interpreted by suggesting that the
spontaneously occurring increments in plasma EPO levels in
mammals in conditions of hypoxia and/or blood loss, induce
a modulation of the inspiratory pressure dissipation
counteracting the increment in the mechanical work of
breathing needed to allow the increased pulmonary
ventilation [2, 3].
Although present data refer to the rat, some reports in the
literature suggest that the respiratory effects of EPO may
take place in humans also [2, 44]. Thus, EPO appear to act
on various physiological regulatory mechanisms, including
circulatory and respiratory responses, acting together to
improve the adaptation to arterial hypoxia in mammals.
Considering the very high profile use of “doping” in
certain sports, the results here described suggest also that
some athletes may find apparent advantages when using
EPO or similar drugs in their respiratory function. Beside the
well known advantage due to the increment in haematocrit,
also circulatory and respiratory effects of EPO should be
considered. In particular, the here described reduction in
airway resistance could permit a reduction of the inspiratory
work of breathing for any given alveolar ventilation or, even
more significantly, an increment of alveolar ventilation for a
given inspiratory muscle effort. Most of all the latter effect
could be effective in increasing exercise performance.
CONFLICT OF INTEREST
The authors confirm that this article content has no
conflicts of interest.
ACKNOWLEDGEMENTS
Rubini et al.
[10]
[11]
[12]
[13]
[14]
[15]
[16]
[17]
[18]
[19]
[20]
[21]
[22]
[23]
Declared none.
[24]
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Revised: November 22, 2012
453
Accepted: November 25, 2012