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Experimental Physiology 92.4 pp 749-755
DOI: 10.1113/expphysiol.2006.036673
© The Physiological Society 2007
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Respiratory

Behaviours of pulmonary sensory receptors during development of acute lung injury in the rabbit

 Shuxin Lin1, Jerome Walker1,2, Ling Xu3, David Gozal4 and Jerry Yu1

Departments of 1 Medicine4 Pediatrics, University of Louisville, Louisville, KY 40292, USA 2 Department of Respiratory Therapy, Bellarmine University, Louisville, KY 40205, USA 3Department of Mathematics and Statistics, James Madison University, Harrisonburg, VA 22807, USA


   Abstract
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 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
We tested the hypothesis that oleic acid-induced acute lung injury activates pulmonary nociceptors, that is, C fibre receptors (CFRs) and high-threshold A{delta} fibre receptors (HTARs). Single-unit activity was recorded in the cervical vagus nerve and assessed before and after injecting oleic acid (75 µl kg–1 I.V.) into anaesthetized, open-chest, mechanically ventilated rabbits. Unit activities increased within seconds and peaked within a few minutes (from 0.3 ± 0.1 to 1.4 ± 0.9 impulses s–1 for CFRs and from 0.5 ± 0.1 to 1.7 ± 0.3 impulses s–1 for HTARs, both n = 8 and P < 0.05). These activities were sustained while pulmonary oedema developed and dynamic lung compliance decreased over the 90 min observation period. Activities in slowly adapting receptors and rapidly adapting receptors were also increased; however, their responsiveness to airway pressure stimulation decreased progressively. We conclude that pulmonary nociceptors are stimulated during acute lung injury. The dual nociceptor system, consisting of both non-myelinated CFRs and myelinated HTARs, may play an important role in the pathophysiological process of acute lung injury-induced respiratory responses.

(Received 21 November 2006; accepted after revision 13 March 2007; first published online 28 March 2007)
Corresponding author J. Yu: Pulmonary Division, Department of Medicine, University of Louisville, ACB-3, 530 South Jackson Street, Louisville, KY 40292, USA. Email: j0yu0001{at}louisville.edu


   Introduction
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 Introduction
Methods
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 Discussion
 References
 
Multiple factors, including infection, trauma, shock and aspiration, contribute to acute lung injury (ALI) and potential development of acute respiratory distress syndrome (ARDS). Pathophysiologically, ARDS presents as diffuse injury to the lung parenchyma. Pulmonary capillary permeability increases, leading to low-pressure pulmonary oedema and intrapulmonary shunting. Clinically, the patient will manifest progressive dyspnoea, acute onset of bilateral infiltrates on chest radiograph, refractory hypoxaemia and decreased lung compliance. Despite recent advances, fundamental characterization of ALI/ARDS remains incomplete and elusive (Matthay & Zimmerman, 2005), and mortality rates of ARDS remain as high as 40% (Bernard et al. 1994). In animal studies, intravenous injection of oleic acid (OA) successfully induces ALI in the rat (Davidson et al. 2000; McGuigan et al. 2003), guinea-pig (Ishitsuka et al. 2004), rabbit (Furue et al. 1999; Kuwabara et al. 2001) and dog (Tachmes et al. 1991; Martynowicz et al. 1999; Hubloue et al. 2003), presenting pathological processes commonly seen in ARDS (Schuster, 1994).

In the lung there are four types of sensors: slowly adapting receptors (SARs), rapidly adapting receptors (RARs), high-threshold A{delta} fibre receptors (HTARs) and C fibre receptors (CFRs). The first two are mechanosensitive and the last two are chemosensitive, behaving like nociceptors in other tissues (Coleridge & Coleridge, 1986; Lee & Pisarri, 2001; Widdicombe, 2003; Yu, 2005; Canning et al. 2006). Activation of pulmonary nociceptors may cause adverse effects, making patient management more difficult (Yu, 2002a). Pulmonary nociceptors are expected to be activated during ARDS; however, few studies have directly examined their activity in this condition. In the present study, we tested the hypothesis that pulmonary nociceptors participate in the pathophysiology of ALI and ARDS, and systematically examined the four types of airway sensors in the OA-induced ARDS rabbit model.


   Methods
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 Introduction
 Methods
Results
 Discussion
 References
 
Experiments were performed in 45 male New Zealand White rabbits weighing 2.20 ± 0.12 kg. All protocols conformed to the ethical requirements as stipulated by the Internal Animal Use and Care Committee of the University of Louisville. Rabbits were premedicated with ketamine hydrochloride (50 mg kg–1, I.M.) and xylazine (5 mg kg–1, I.M.), and then intravenously anaesthetized with a mixture of 10% urethane and 1% {alpha}-chloralose (5 ml kg–1). Both femoral arteries were cannulated for blood gas sampling and measuring blood pressure through a strain gauge pressure transducer.

Tracheotomy was performed and the rabbits were mechanically ventilated (22 cycles min–1; tidal volume 8 ml kg–1) with 3 cmH2O of positive end-expiratory pressure (PEEP). Airway pressure was measured at the opening of the endotracheal tube by a pressure transducer (model P23, Statham). Oleic acid was administered intravenously (75 µl kg–1). At the end of the 90 min experiment, the rabbits were euthanized with 5 ml of saturated KCI intravenously, the lungs were removed, weighed and then dried to constant weight at 80°C for 24 h in an oven. The ratio of the lung wet-to-dry weights was calculated to estimate lung tissue oedema. In another group, at the end of the experiment, we injected 5 ml of normal saline into each lung, and bronchoalveolar lavage (BAL) fluid was harvested and stored at –20°C. The total protein concentration in BAL fluid was determined by the Bradford method (Bradford, 1976).

Afferent activity was recorded as previously described (Coleridge & Coleridge, 1977; Pisarri et al. 1986; Kappagoda et al. 1987). Slowly adapting receptors and RARs were identified by their adaptation index (< 30% for SARs and > 70% for RARs). Their activities during constant pressure inflation were counted and averaged over a 4 s period. A{delta} Fibre receptors were identified by their discharge pattern (Zhang et al. 2006). They do not behave like SARs or RARs, but more like CFRs, with a conduction velocity usually from 4 to 15 m s–1 (Yu, 2002b). C Fibre receptors were identified according to their discharge pattern and conduction velocity (< 1.5 m s–1). After identifying a particular unit, experimental manoeuvres consisted of: (1) removal of PEEP by opening the end-expiratory line to atmosphere; (2) clamping the expiratory line of the ventilator for two consecutive cycles to apply 10, 20 and 30 cmH2O pressure to produce lung inflation; (3) applying a negative pressure (–7 cmH2O) to the expiratory line; and (4) altering tidal volumes to 10, 20 and 30 ml.

A statistical program (GB-Stat v9.0 Dynamic Microsystems, Inc., Silver Spring, MD, USA) was used to perform the data analysis. Group data are expressed as means ± S.E.M. Group comparisons involved the use of repeated measures analysis of variance (ANOVA), followed by Bonferroni post hoc analysis of simultaneous confidence intervals, or paired Student's t test. A value of P < 0.05 was considered to be statistically significant.


   Results
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 Introduction
 Methods
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Discussion
 References
 
Blood gases changed significantly after OA injection, with arterial partial pressure of O2 (Formula ) declining substantially within 10 min. Carbon dioxide retention and acidosis were also apparent. The Formula , arterial partial pressure of CO2 (Formula ) and pH during the initial control period and at 10, 30, 60 and 90 min after intravenous injection of OA are shown in Table 1.

After OA injection, lung mechanics changed over time. Airway pressures began to increase at about 2 min (118 ± 19 s), ranging from 46 to 264 s. They rose by 2 cmH2O at about 5 min (298 ± 44 s), ranging from 141 to 470 s. The increase was significant at 10 min and sustained until the end of the experiment at 90 min (Table 2), with an increasing trend, although not statistically significant. In the meantime, the animal developed pulmonary oedema, evidenced by appearance of frothy pinkish fluid in the tracheal tube. This occurred as early as 30 min. At the end of a 90 min observation period, damage to the lung was apparent. Frothy, pink fluid exuded from the tracheal tube, and the lungs became congested and dark red instead of their normal light pink colour. Patchy consolidation of the lung parenchyma was also apparent. The lungs became wet and heavy (Table 3). The wet/dry ratio increased significantly from 5.27 ± 0.36 in control animals (n = 8) to 6.67 ± 0.51 in OA-treated animals (n = 18; P < 0.01). The total protein content in the BAL fluid increased approximately threefold from 4.9 ± 0.6 to 14.9 ± 0.7 mg ml–1 (P < 0.01).

Airway nociceptors, HTARs and CFRs (n = 8 of each type), behaved similarly (Figs 1 and 2). Under resting conditions, they discharged sporadically at a very low frequency (0.5 ± 0.1 and 0.3 ± 0.1 impulses s–1 for HTARs and CFRs, respectively) with no clear relation to cyclic changes in lung mechanics. During lung inflation at 20 cmH2O, HTARs and CFRs discharged with peak frequency at 13.8 ± 1.9 and 13.7 ± 1.8 impulses s–1, respectively. The nociceptors were stimulated within a few seconds after OA injection, peaking within the first few minutes. This increased activity was maintained throughout the 90 min experimental period (Fig. 3A and B for HTARs and CFRs, respectively).

Slowly adapting receptors and RARs had adaptation indexes of 15.5 ± 2.1 and 78.8 ± 3.5%, respectively. All eight RARs tested were stimulated by lung deflation. At baseline, the SARs discharged at 14.7 ± 2.7 impulses s–1 and the RARs at 5.1 ± 1.5 impulses s–1. These mechanoreceptors were very sensitive to lung inflation. For example, at 20 cmH2O, SARs and RARs fired with a peak frequency of 151.4 ± 19.9 and 73.3 ± 13.6 impulses s–1, respectively. Activity of SARs was increased several minutes after intravenous injection of OA. This increase was accompanied by an increase in airway pressure swings of approximately 50% at 10 min (Table 2). However, SAR activity decreased in response to constant pressure inflation, becoming apparent at 30 min and progressing thereafter (Fig. 4). The SAR response curve in response to airway pressure stimulation shifted to the right and downwards (Fig. 5). This effect continued as pulmonary oedema progressed. Rapidly adapting receptors had a similar response pattern to the SARs, with the response curve shifted to the right and downwards over time (Fig. 5).


   Discussion
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 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
Lung injury is of clinical importance. It may alter ventilation through multiple pathways, including peripheral chemoreceptors (Jacono et al. 2006). Obviously, airway sensors are important in this regard. In the present study, we reproduced the OA-induced ARDS model in the rabbit and examined different types of airway sensors during development of ARDS. Oleic acid is a fatty acid that causes endothelial and epithelial damage, increasing vascular permeability, oedema, bleeding and intravascular clotting (Goff et al. 1997; McGuigan et al. 2003). Oleic acid also can destroy alveolar surfactant, producing atelectasis (Hall et al. 1990) and decreasing lung compliance (Davidson et al. 2000; Hubloue et al. 2003). After injection into the venous system, OA causes vigorous neurally and humorally mediated pulmonary vasoconstriction and fat embolism, resulting in dysfunction of the pulmonary microcirculation (Goff et al. 1997). In the present study, OA significantly increased the BAL fluid protein content and wet/dry lung weight ratio, indicating increased permeability of the pulmonary capillary–alveolar membrane. The magnitude of these changes is consistent with a previous report in the rabbit in which 100 µl kg–1 of OA caused a 3.3-fold increase in protein content and increased wet/dry lung weight from 4.77 to 6.49 (Furue et al. 1999).

Our data show that both HTARs and CFRs were stimulated early during development of OA-induced ARDS. While some of the underlying mechanisms are known, we believe that activation of the pulmonary nociceptors must be multifactorial. C Fibre receptors discharge irregularly at low frequency (Pisarri et al. 1986) and are activated during pulmonary congestion or oedema by increased extravascular fluid (Paintal, 1973). Nociceptor activation cannot be explained by oedema alone because the activation occurs within several seconds, while pulmonary oedema develops gradually. If the oedema or water flux is the only stimulus, then the increased activity should follow the time course of oedema development. In this brief period of time, increase in lung extravascular fluid would be only in its initial phase and interstitial oedema would be minimal. Thus, non-lung water factors must be involved in stimulating these nociceptors. During OA-induced ALI, different endogenous mediators, especially cyclo-oxygenase metabolites, can be released to stimulate nociceptors (Tachmes et al. 1991; Karla et al. 1992; Ishitsuka et al. 2004; Lai et al. 2005).

In the present study, SAR activity increased within minutes after injection of OA. This increased activity did not result from increased SAR sensitivity but rather from changes in lung mechanics, such as increased airway pressure. In fact, SAR responsiveness (response at a given strength of stimulus) to mechanical stimulation decreased as evidenced by a downwards shift of the SAR stimulation response curve with time. It is possible that swelling of the pulmonary interstitium during pulmonary oedema may uncouple the sensory device of the SAR from its environment, making it less sensitive to mechanical stimuli. If so, we should expect to see the slope of the response flatten as a result of a change in sensitivity. Our data, however, show a shift of the response curve to the right and downwards, with minimal decreases in the slope (Fig. 5). Thus, the uncoupling theory is unlikely. Alternatively, SAR activity would decrease because water in the airway impedes pressure to distend the bronchioles downstream. Indeed, OA-induced lung oedema developed rapidly, with pink, foamy fluid often appearing in the trachea within 60 min after OA injection. As oedema fluid filled the alveoli and airways, the effects of inflation pressures to distend the lung fell and so did the activity of stretch-sensitive SARs.

Furthermore, the SAR is known to sense the tension in the airway wall (Yu, 2005). According to the Laplace equation, P, the distention pressure, is directly proportional to T/r, where T is wall tension and r is the airway radius. According to this equation, when lung compliance falls at a given value of P, the airway will distend to a lesser extent, resulting in a smaller r. Thus, the value of T decreases, which will decrease the stimulus to SARs. Conversely, as lung compliance decreases, the value of r will remain the same at a given lung volume; however, the value of P will increase, as will T, which will stimulate SARs. While the exact mechanisms are unknown, it seems that multiple factors may contribute to the change in SAR behaviour.

Our findings may explain previous conflicting reports on SAR activity in response to pulmonary oedema or congestion. For example, SARs were claimed not to be sensitive to extravascular fluid changes (Hargreaves et al. 1991). Elsewhere, SARs were active throughout the respiratory cycle or only during the expiratory phase (Costantin, 1959) and remained unchanged during pulmonary congestion (Roberts et al. 1986). Such diverse results indicate that multiple factors may be operative in SAR responses to lung injury, with sensory unit activity depending on the balance between stimulation strength and sensor response. During the development of ARDS, stimulation of SARs increased, but their responsiveness progressively decreased. Thus, SAR activity could be increased, unchanged or decreased, depending on when and how the activity is assessed.

In general, the behaviour of RARs during development of ARDS is similar to that of SARs. This is not particularly surprising because both RARs and SARs are mechanoreceptors and may even share the same afferents (Yu, 2005). Rapidly adapting receptors in the rat are generally not sensitive to chemical stimulation, except for a small subgroup with very low discharge frequency, which behave as CFRs (Ho et al. 2001). These RARs could be those corresponding to our HTARs (Yu, 2002b).

In conclusion, intravenous injection of OA in the rabbit induces ARDS and stimulates airway nociceptors (HTARs and CFRs) within several seconds. Nociceptor activity reaches its peak within a minute or so and persists thereafter. The activity of mechanosensors also increases owing to changes in lung mechanics; however, their responsiveness to mechanical stimulation decreases as ARDS develops. The HTAR and CFR may act in concert, generating dual information to modify the body's response.


Figure 1
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  		Figure 1.  A high-threshold A{delta} receptor (HTAR), located in the left lower lobe, recorded from the left cervical vagus nerve in an anaesthetized, open-chest, mechanically ventilated rabbit
Traces are: IMP, impulses (sensory activity); and Paw, airway pressure recorded from the tracheal tube opening. A–E are the receptor responses to removal of PEEP (A), to lung inflation at constant pressures of 10 (B), 20 (C) and 30 cmH2O (D), and to lung deflation at –7 cmH2O (E). F shows afferent stimulation by injecting oleic acid (75 µl kg–1) into the femoral vein. The arrow denotes injecting time. G is a continuance of F and there is a 16 min interval between G and H. This receptor has very low background activity (0.1 impulses s–1) and does not respond to lung deflation, either by PEEP removal (A) or by negative pressure (E). It has very high threshold to lung inflation (about 20 cmH2O) with a conduction velocity of 4 m s–1. Thus, it is an HTAR.

 

Figure 2
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  		Figure 2.  A C fibre receptor recorded from the left cervical vagus nerve
Please see Fig. 1 legend for abbreviations. A shows CFR stimulation by injection of oleic acid (75 µl kg–1) into the femoral vein. The arrow denotes the start of the injection, and the receptor was activated 28 s thereafter. B is the trace 3 min after the end of A. C and D are receptor activity in response to lung inflation to 20 and 30 cmH2O, respectively. E and F are repeats of lung inflation at 20 and 30 cmH2O, respectively, 1 h after the OA injection. The conduction velocity of the afferent is 0.7 m s–1.

 

Figure 3
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  		Figure 3.  Grouped data of HTAR (A) and CFR responses (B) to oleic acid
The sensors activated after intravenous injection of OA at 1 min, reaching peak activity within the first few minutes. Receptor activity remained at a high level until the end of the observation at 90 min. Data are expressed as means ± S.E.M. All data points (n = 8) were different from the control values (0 min) by at least P < 0.05.

 

Figure 4
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  		Figure 4.  Illustration of single unit activity in a SAR during the progression of OA-induced ARDS: control (A), and 10 (B), 30 (C) and 60 min after OA injection (D)
Please see the Fig. 1 legend for abbreviations. IMP/s is SAR activity expressed as impulses per second, which was counted every 0.1 s. Note that the unit activity during each ventilatory cycle increased after OA injection, accompanied by an increased swing in airway pressure (7, 15, 21 and 23 cmH2O for A, B, C and D, respectively). Concurrently, the SAR activity during constant airway pressure inflation decreased progressively as pulmonary oedema developed (136, 118, 104 and 80 impulses s–1 for A, B, C and D, respectively). This suggests that the increased activity is caused by changes in lung mechanics even though the receptor responsiveness decreases.

 

Figure 5
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  		Figure 5.  Effect of oleic acid on mechanosensor responses (SARs and RARs) to constant airway pressure inflation (10, 20 and 30 cmH2O)
Mechanosensor activity increases as airway pressure increases. This relationship is preserved after OA-induced lung injury. However, the SARs (n = 12) and RARs (n = 9) became less responsive to the airway pressure as evidenced by the downwards shift of the stimulation–response curve. Values are: C, control; 10, 30, 60 and 90 min after OA injection.

 

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  		Table 1.  Haemodynamics and blood gases before and after oleic acid
 

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  		Table 2.  Effects of oleic acid on airway pressure and activities in airway mechanoreceptors
 

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  		Table 3.  Effect of oleic acid on lung weights
 

   References
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 Introduction
 Methods
 Results
 Discussion
 References
 
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   Acknowledgements
 
This work is supported by NIH (HL-58727).

Author's present address
S. Lin: Department of Pathophysiology, The Fourth Military Medical University, Xi'an, China.




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