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in smoke inhalation lung injury
1 Pulmonary and Critical Care Unit, Department of Medicine, Massachusetts General Hospital, Shriners Burns Institute, and Harvard Medical School, Boston, Massachusetts 02114; and 2 Growth Biology Laboratory, Livestock and Poultry Institute, United States Department of Agriculture, Beltsville, Maryland 20705
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
ACKNOWLEDGEMENTS
FOOTNOTES
REFERENCES
ABSTRACT 
Hales, Charles A., T. H. Elsasser, Peter Ocampo, and Olga
Efimova. TNF-
in smoke inhalation lung injury.
J. Appl. Physiol. 82(5):
1433-1437, 1997.
Adult respiratory distress syndrome is a major
cause of morbidity in fire victims. Tumor necrosis factor- (TNF-)
is edematogenic and has been associated with the etiology of other
forms of adult respiratory distress syndrome. In the sheep lymph
fistula model, we measured TNF- after 48 (n = 7) or 128 (n = 3) breaths of cotton smoke and
compared this with sham controls (n = 5) or controls in which left atrial pressure was elevated to 20 mmHg
(n = 5) to increase lymph flow in the absence of inflammation. Smoke induced a rise in lymph flow and pulmonary arterial pressure with either no fall in lymph-to-plasma protein ratio (128 breaths) or a modest fall in lymph-to-plasma protein
ratio (48 breaths), consistent with a change in microvascular permeability as well as a rise in microvascular pressure.
Lymph concentration of TNF- fell in both groups, although lymph flux (concentration × flow) transiently rose in both. In neither case did TNF- flux exceed that induced by left atrial pressure elevation. TNF- was detectable in only one out of five sheep in alveolar lavage. Thus, by utilizing a sensitive and specific radioimmunoassay, we were unable to demonstrate a role for TNF- in smoke-induced microvascular lung injury in sheep.
lung lymph; acute lung injury; sheep; tumor necrosis
factor- INTRODUCTION RESPIRATORY COMPLICATIONS are the major cause of
morbidity and mortality in victims of fires who reach the hospital
(18). Smoke inhalation alone can cause lung injury, or the combination of smoke injury with body surface burn can markedly increase
respiratory complications compared with burn alone (23). Smoke
inhalation causes increased microvascular permeability with pulmonary
edema acute in some circumstances, or in others the appearance of
microvascular injury is delayed, appearing as adult respiratory
distress syndrome (ARDS) 48-96 h after the fire (4, 6,
11). The delay in presentation of the microvascular injury
is at least in part related to the dose of smoke because larger doses
produce more acute injury (4, 12). We have developed the hypothesis
that smoke injury to the microvessels, whether acute or delayed, is
through a series of secondary messengers of inflammation released by
smoke from alveolar macrophages or other lung tissue. We have shown
that eicosanoids are one of these mediators of acute edema because they
are released into lung lymph and alveolar secretions for 3-4 h
after smoke exposure. Blockade of the production of
lipoxygenase and cyclooxygenase products by the combined inhibitor
BW-755C can diminish, although not eliminate, the ensuing acute
pulmonary edema even when given 15 min after smoke exposure (5,
9). We, therefore, wondered whether other mediators might
be involved, in particular tumor necrosis factor- MATERIALS AND METHODS 
(TNF-) because
it is released by alveolar macrophages and is known to be edematogenic
(2, 7). TNF- levels in bronchoalveolar lavage fluid of ARDS patients have been shown to be elevated (8, 17), especially on
day 1, and alveolar macrophages of
ARDS patients show increased expression of the mRNA for TNF- (24).
TNF- has been shown to increase phospholipase
A2
(PLA2) release from cells (21),
and we have shown that alveolar lavage levels of
PLA2 correlate with the extent of
ARDS (11). In addition, Ogura et al. (16) have shown that pentoxifylline, which among other effects inhibits alveolar macrophage production of TNF-, lessens hypoxemia, pulmonary hypertension, and
pulmonary edema after smoke exposure. We, therefore,
assessed lymph accumulation of TNF- over the first hours after
exposure of sheep to smoke from burning cotton. When a moderate dose of cotton smoke (48 breaths) failed to produce the appearance of TNF-
in the increased lymph flow, we subsequently added a large dose (128 breaths) to determine whether that would produce detectable TNF-.
20
cmH2O pressure applied. A
Swan-Ganz pulmonary arterial catheter (model 93A-13 H-7F, American
Edwards Laboratories, Santa Ana, CA) was inserted via an internal
jugular vein and positioned in the pulmonary artery on the basis of
continuous monitoring of the waveforms. Femoral arterial, pulmonary
arterial, intermittent pulmonary capillary wedge, and tracheal
pressures were monitored with transducers (model P23XL,
Spectramed, Oxnard, CA) mounted at the midthoracic level; waveforms and
trends were continuously recorded (model 3400, Gould, Cleveland, OH).
Cardiac output was determined in duplicate by using thermal dilution
and a cardiac output computer (COM-1, American Edwards
Laboratories). Airway pressure was continuously monitored by a
gas-filled transducer attached to a side port of the connector between
the ventilator and the endotracheal tube. Sheep were kept at 38°C
via a heating pad under the animal. In five sheep, a left thoracotomy
was also performed, and a saline-filled Foley catheter was inserted
into the left atrium and secured in place with a purse-string
suture. The balloon was inflated to raise atrial pressure and hence
pulmonary venous pressure as required.
80°C for later TNF-
assay. Bronchoalveolar lavage specimens were likewise spun
at 2,300 rpm at 4°C, and the supernatant was saved at
80°C for TNF- assay.
Experimental procedures.
The animals [control, n = 5; 48 breaths smoke, n = 7; 128 breaths
smoke, n =3;
Escherichia coli endotoxin (lot
055:B565 1873; DIFCO Laboratories, Detroit, MI),
n = 1; left atrial pressure elevation,
n = 5] were allowed 1 h to
stabilize on the anesthetic, during which time baseline measurements of
the particular parameters were taken every 30 min. Smoke
or E. coli endotoxin (bolus of 2 µg/kg over 20 min) was administered, and the physiological response was followed without major intervention for the subsequent 3 h. Lymph
flow, cardiac output, and blood samples were measured at 30-min
intervals. The animals were heparinized (10,000 U iv) and killed with
an intravenous KCl overdose while deeply anesthetized. The lungs were
quickly excised, examined grossly, and trimmed for gravimetric analysis
as previously described (4, 5).
In five separate sheep, mini-bronchoalveolar lavage with 10 ml of
saline was done at 2 h after 128 breaths of cotton smoke exposure on
the left lung and at 4 h after smoke on the right lung via a wedged
polyethylene tube (0.66-mm ID, Intramedic) via the technique of Suter
et al. (22).
TNF- assay.
The concentration of TNF- in sheep plasma lymph and lavage fluid was
measured by a radioimmunoassay specific for sheep and cattle (10).
Antiserum (r314) was developed in rabbits immunized with recombinant
bovine TNF- (rbTNF-; Ciba Geigy, St. Aubin, Switzerland).
rbTNF- was used to construct the assay standard curve and was
iodinated by using iodogen to obtain an assay tracer (125I-labeled rbTNF-; sp act 84 µCi/µg). Assay tracer was purified by elution of Sephadex G-75 to
obtain monomeric radioiodinated rbTNF-. The following
assay characteristics were obtained: slope of the standard curve (log
TNF- vs. logit binding), 2.33; slope of bovine internal
standard (increasing plasma volumes), 2.31; slope of ovine
internal standard, 2.18; percent tracer binding at working
antibody dilution, 34%; recovery of added unlabeled rbTNF-,
>95%; intra-assay coefficient of variability, 9%; interassay coefficient of variation, 13%; and minimal detectability, 0.028 ng/tube.
Smoke generation and administration.
Smoke was generated with a modified bee smoker (The Bee Keeper, Woburn,
MA), as originally described by Walker et al. (25) and subsequently
modified by Kimura et al. (12). Ten pure cotton pledgits (14 g) were
packed into the chamber and ignited instantly with a blowtorch. The
smoker was attached to the sheep's endotracheal tube while 16 breaths
of cooled smoke (<40°C) were delivered. The sheep was then
returned to the ventilator while the smoker was recharged and refired.
A total of 48 breaths with a tidal volume of 15 ml/kg was delivered to
each sheep. Smoke particle size was determined with an Anderson Sampler
(Atlanta, GA). Smoke delivery time ranged from 19 to 22 min.
Statistics.
All values were calculated as means ± SE. Data were compared by
analysis of variance for repeated measures within groups, with
P < 0.05 regarded as a significant
difference, by use of the StatView 512+ statistical program
(Brainpower, Calabasas, CA). A Fisher protected least-significant
difference test was used for posteriori contrasts. If a value was
significantly different from control, then that value was compared by a
factorial analysis of variance against other groups at the same time.
All groups at baseline were also tested against each other by a
factorial analysis of variance to be certain control values were
similar.
RESULTS
), cardiac output (CO; 
), and pulmonary vascular resistance (PVR;
) before and for 4 h after 48 breaths of cotton smoke given just
before time 0 to 7 sheep.
B: same values in 3 sheep given 128 breaths of cotton smoke. * P < 0.05 from control.
+ P < 0.05 from control for both CO and PVR.
) or 128 (
) breaths of cotton
smoke or left atrial pressure elevation to 20 mmHg (;
n = 5 sheep) or
Escherichia coli bolus (
;
n = 1 sheep) given just before
time 0. All points are
P < 0.05 from control after smoke and left atrial atrial pressure elevation.
) or 128 () breaths of cotton smoke or left atrial pressure elevation to 20 mmHg (; n = 5 sheep) or
E. coli bolus (;
n = 1 sheep) given just before
time 0.
* P < 0.05 from control.
) or 128 () breaths of cotton smoke or left
atrial pressure elevation to 20 mmHg (;
n = 5 sheep) or E. coli bolus (, n = 1 sheep) given just before time 0.
* P < 0.05 from control.
TNF-
concentration was initially 233 pg/ml in lung lymph and fell
significantly by 120 min (Fig. 5), although
total lymph flux of TNF- rose transiently at 30 min (Fig.
6).
(TNF-)
before and after 48 () or 128 (
) breaths of cotton smoke or left
atrial pressure elevation to 20 mmHg (;
n = 5 sheep) or E.
coli bolus (;
n = 1 sheep) given just
before time 0. All values after 48 or
128 breaths of smoke or after left atrial pressure elevation were less
than control (P < 0.05).
before and
after 48 () or 128 (open cross) breaths of cotton smoke or left atrial pressure elevation to 20 mmHg (;
n = 5 sheep) or E. coli bolus (;
n = 1 sheep) given just
before time 0.
* P < 0.05 from control.
To an additional three sheep we administered 128 breaths of cotton smoke. Pulmonary arterial pressure rose from 11 to 14 mmHg (Fig. 1B). Cardiac output and pulmonary capillary wedge pressure were unchanged, so there was a modest rise in pulmonary vascular resistance as was seen with 48 breaths of smoke. Lymph flow rose (Fig. 2) as did lymph protein flux (Fig. 4). In contrast to data obtained with 48 breaths of smoke, lymph-to-plasma protein ratio with 128 breaths did not decrease (Fig. 3). Lung lymph TNF-
concentration decreased (Fig. 5) after the
larger dose of smoke, although as with the smaller dose of smoke the
lung lymph flux of TNF- rose (Fig. 6). The peak rise in flux was not
significantly higher with 128 breaths compared with 48 breaths of
smoke.
Left atrial pressure elevation.
In five sheep we raised the left atrial pressure from 5 ± 1 to 23 ± 2 mmHg and kept it above 20 mmHg for 4 h. Lymph flow doubled (Fig. 2). Lymph protein flux rose (Fig. 4), although lymph protein concentration fell (Fig. 3), as is classic for high-pressure effects on
lung lymph. TNF- concentration fell, although not significantly (Fig. 5), and, as with smoke, lung lymph flux of TNF- transiently increased (Fig. 6).
Bronchoalveolar lavage fluid.
No TNF- was detectable in the lavage fluid when it was undiluted or
after concentration by freeze-drying and reconstitution in one-fifth
volume.
Endotoxin.
In one sheep, 2 µg/kg of endotoxin as an intravenous bolus over 20 min raised pulmonary arterial pressure acutely from 15 to 37 mmHg, but
then it remained at 24-25 mmHg for 3 h. Lymph flow rose from 3 to
12-14 ml/0.5 h (Fig. 2). Lymph-to-plasma protein ratio fell (Fig.
3), and total lymph protein flux rose (Fig. 4). TNF- rose as an
absolute concentration from 380 to 1,970 pg/ml by 2 h (Fig. 5), and
TNF- lymph flux rose from 1,060 to 23,700 pg/0.5 h (Fig. 6).
DISCUSSION
Inhalation of 48 or 128 breaths of smoke from burning cotton caused an increase in lung lymph flow (Fig. 2). After 48 breaths of smoke, lymph flow tripled but lymph-to-plasma protein concentration fell (Fig. 3), suggesting high microvascular pressure as being at least a large part of the cause for increased flow, consistent with the 6-mmHg rise in pulmonary arterial pressure (Fig. 1A). Compared with a much greater rise in microvascular pressure caused by inflation of a left atrial balloon (Fig. 3), the fall in lymph-to-plasma protein concentration was less (P < 0.05), suggesting 48 breaths of smoke may also have increased microvascular permeability. After 128 breaths of cotton smoke, the pulmonary arterial pressure rose 3 mmHg (Fig. 1B) and lung lymph flow more than quadrupled (Fig. 2). However, in contrast to 48 breaths of smoke, the lymph-to-plasma protein concentration no longer fell (Fig. 3), clearly consistent with a change in vascular permeability influencing the increase in lung lymph flow in addition to a pulmonary vascular pressure rise (1).
TNF- was detectable in the lung lymph of sheep and rose as a flux
(lymph flow × TNF concentration) after inhalation of 48 and 128 breaths of cotton smoke, although the absolute concentration of TNF-
decreased (Figs. 5 and 6). The peak increase in flux of TNF- after
smoke was numerically greater with 128 than 48 breaths but not
statistically so.
We were concerned that the TNF- flux increase could have been a
purely passive phenomenon on the basis of washout of lung interstitial
space with increased lymph flow. Therefore, we increased lung lymph
flow with pressure elevation in the pulmonary vessels by raising left
atrial pressure to 20 mmHg (Fig. 2). This produced a doubling of lymph
flow, an insignificant fall in the concentration of lung lymph TNF-
(Fig. 5), and a transient increase in the TNF- flux (Fig. 6), which
followed a pattern very similar to the lymph flow of protein (Fig. 4)
in this group.
We also administered E. coli endotoxin
intravenously to one sheep as a positive control and found a marked
increase in lung lymph concentration and flux of TNF- (Figs. 5 and
6). Thus our methods were capable of detecting TNF- as previously
shown as occurring in chronic endotoxin infusion in sheep (15, 19). Other studies have shown that TNF- levels peak in the circulation at
2-3 h after endotoxin challenge (15, 19), and thus we should have
covered the time span when TNF- levels should have risen after smoke
injury if they were going to rise.
Although TNF- has been found in bronchoalveolar lavage in patients
with ARDS and perhaps in serum of high-risk patients for ARDS, we did
not find it in sheep with ARDS after smoke inhalation injury (8). A
previous study in humans that attempted to correlate the presence of
circulating levels of TNF- and other cytokines with the presumed
cause of ARDS had only small numbers and no cases of smoke-induced ARDS
(14). Our present results may be unique to sheep and not
apply to humans. This is unlikely true, though, because TNF- goes up
in humans and sheep after endotoxin administration (15,
19). More likely, our results highlight the fact that
ARDS is a syndrome that lumps together diverse pathophysiological pathways to cause the injury. Smoke-induced acute lung injury may not
involve TNF-, at least not acutely, whereas endotoxin-induced acute
lung injury does involve TNF-. It is, however, possible that
domestic livestock have evolved compensatory mechanisms to lessen the
severity of pathophysiological response to lung toxicants on the basis
of environmental quality. We have also not excluded a role for TNF-
in the delayed-onset ARDS lung injury at 48-96 h after smoke
inhalation.
It is likely then that improved lung function after pentoxifylline
treatment of smoke exposed sheep is due to one of pentoxifylline's multiple effects other than on alveolar macrophage production of
TNF- (3, 16). Pentoxifylline has been shown to alter red cell
deformity as well as neutrophil function independent of the presence of
TNF- (13).
In summary, TNF- flux increased acutely in lung lymph after smoke
inhalation injury but not beyond that which would be seen with a
passive increase in lung lymph flow, as is seen after elevation of
pulmonary microvascular pressure. Thus, in contrast to other forms of
acute lung injury such as that after endotoxin infusion, we were not
able to demonstrate the presence of TNF- after smoke-induced acute
lung injury. Further studies are warranted to establish whether a local
TNF- response at the cellular level is present with smoke but is not
readily evident with TNF- measurement of plasma or lymph.
ACKNOWLEDGEMENTS
This work was supported by National Heart, Lung, and Blood Institute Grant HL-36829.
FOOTNOTES
Address for reprint requests: C. A. Hales, Pulmonary/Critical Care Unit, Massachusetts General Hospital, Boston, MA 02114.
Received 9 October 1996; accepted in final form 20 December 1996.
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Increasing duration of smoke exposure induces more severe lung injury in sheep.
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