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Cardiovascular Research Institute, University of California, San Francisco, CA 94143
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Abstract |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionDisclosuresReferences |
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To probe the potential roles of PARs in lung, we instilled PAR-APs into the airspaces of the lungs in anesthetized, ventilated, and spontaneously breathing mice. PAR2-dependent effects of PAR2-AP on airway pressure, lung vascular, and epithelial permeability to protein, extravascular lung water, arterial blood gases, and leukocyte infiltration were measured. Pharmacologic ablation of sensory neurons and neuropeptide antagonists was used to determine the mechanisms of PAR2-mediated lung pathophysiology.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionDisclosuresReferences |
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Mice (C57BL/6J; 8 wk old) were purchased from The Jackson Laboratory. Generation of mice deficient in PAR2 has been described elsewhere (11). All procedures were approved by the Animal Committee of University of California.
Chemicals and reagents
The PAR-APs, including TFLLRN-NH2 (PAR1-AP), SLIGRL-NH2 (PAR2-AP), AYPGKF-NH2 (PAR4-AP), and control SLIGRL peptide (LSIGRL) were synthesized as carboxyl amides and purified by reverse-phase HPLC (AnaSpec). The PAR-APs and LSIGRL were dissolved in HEPES-buffered Hanks’ at concentration of 50 mM. Capsaicin, myeloperoxidase (MPO), malondialdehyde (MDA), CGRP8–37 (calcitonin gene-related peptide receptor antagonist), and other reagents were purchased from Sigma-Aldrich. Spantide III (a NK1 receptor antagonist, sequence: H-D-Lys(nicotinoyl)-Pro-b-(3-pyridyl)-Ala-Pro-3,4-dichloro-D-Phe-Asn-D-Trp-Phe-b-(3-pyridyl)-D-Ala-Leu-Nle-NH2) and GR87389 (a NK2 receptor antagonist, sequence: Boc-Ala-Ala-D-Trp-Phe-D-Pro-Pro-Nle-NH2) were purchased from Bachem. The neuropeptide antagonists were dissolved in 0.9% saline.
Delivery of PAR-APs to the airspaces
To deliver PAR-APs during ventilation, a lateral vent was made in a tracheal cannula at the proximal end of the carina and connected with a PE 10 by superglue. An insulin syringe containing 25 µl of PAR-APs (50 mM), 25 µl of LSIGRL (50 mM), or Hanks’ was connected with PE-10 and was injected in 1 min, followed by 25 µl of air. To prevent reflux of the instillate, mice were placed in a supine position on a board with an angle of 45°. In nonventilated mice, anesthesia was induced with ketamine (90 mg/kg) and xylazine (10 mg/kg). The mouse was suspended with incisors attached to a 
60° wood support by 3/0 suture. A cold-light source (Dolan-Jenner Industries) with two 25-inch flexible fiber-optic arms allowed transillumination to visualize glottis and vocal cords to deliver 25 µl of PAR-APs (50 mM), 25 µl of LSIGRL (50 mM), or Hanks’ into the airspaces (22). The investigator was blinded to the genotype of the mice and the instillate.
Measurement of airway pressure and arterial blood gases
Mice were anesthetized by ketamine (90 mg/kg) and xylazine (10 mg/kg) given i.p. A tracheotomy was done with implantation of a tracheal cannula, a PE-90, with a lateral vent connected with PE 10 to deliver the PAR-APs. Pancronium (0.5 mg/kg) was injected i.p. to prevent spontaneous breath during mechanical ventilation. Mice were ventilated with 30% O2 at 130 breaths/min and 7 ml/kg tidal volume, using a rodent respirator (MINI vent, type 845; March-Hugstetten). Body temperature was maintained at 37°C with a heating lamp and monitored by a rectal thermometer (Fisher Scientific). The right jugular vein was catheterized for administration of radioactive label (0.05 µCi of 125I-labeled albumin (125I-albumin; Merck Frosst Labs) or vehicle. Airway pressure was recorded by Biopac system (BIOPAC Systems) through a lateral passage connected with the tracheal cannula (PE-90). The airway peak pressure and plateau pressure at 30 min (after subtracting the baseline) were used to compare the effects of the different PAR-APs. Blood samples were withdrawn from the carotid arterial catheter at the end of the experiment and measured by a blood gas analyzer (Diamond Diagnostics).
Excess lung water (ELW) and lung extravascular plasma equivalent (EPE)
The lungs were removed, counted in the gamma counter (Packard Instrument), weighed, and homogenized (after addition of 1 ml of distilled water). The blood was collected through right ventricle puncture. The homogenate was weighed, and a portion was centrifuged (12,000 rpm, 8 min) for assay of hemoglobin concentration in the supernatant. Another portion of homogenate, supernatant, and blood was weighed and then desiccated in an oven (60°C for 24 h) for gravimetric determination of extravascular lung water. The lung wet-to-dry weight ratio (lung W/D ratio) was calculated by standard formula (23, 24). ELW was calculated by: (lung W/D ratioexperimentalx lung dry weightexperimental – lung W/D rationormalx lung dry weightnormal) x 1000 (µl). Lung EPE (index of lung vascular permeability to protein) were calculated as the counts of 125I-albumin in the lung tissue divided by the counts of 125I-albumin in the plasma (23, 24).
MPO and MDA in plasma
The activity of myeloperoxidase and the levels of malondialdehyde were measured by standard methods (25, 26).
Bronchoalveolar lavage (BAL)
We used the methods as previously described (27). The white blood cells were counted by a counter (Beckman Coulter). Blood cell smear was made using cytospin (Thermo Shandon). The slides were visualized using Wright-Giemsa staining (Fisher Scientific). Neutrophils and macrophages were identified by a certified laboratory technologist in a blinded fashion. Protein concentration in the BAL was determined by a Bio-Rad protein assay (Bio-Rad). MIP-2 (analog of IL-8) in the BAL was measured by ELISA (R&D Systems). For measurement of substance P in the BAL, mice were euthanized at 30 min and the lungs were lavaged with 0.4 ml of chilled PBS (containing 500 kallikrein inhibitor U/ml aprotonin). Substance P levels in the BAL were assessed by ELISA (R&D Systems).
Histology
After euthanasia by inhalation of halothane, the chest and abdomen were rapidly opened and the base of the heart was clamped to prevent escape of the pulmonary blood volume. The thoracic organs were removed en bloc, and 10% Formalin was instilled through the trachea at a pressure of 25 cm H2O. After 72-h fixation, lungs were embedded in paraffin, and 5-µm sections were cut and stained with H&E. Using light microscopy (x400), a counting grid (1 mm2 of the magnified field) was used as a field for neutrophil counting. A sequestered neutrophil was defined as a neutrophil within a pulmonary capillary. An emigrated neutrophil was defined as a neutrophil within the extravascular (interstitial and alveolar) compartments. On each slide, we randomly selected three to four counting fields and calculated the mean value (28, 29). The investigator who reviewed the pathology was blinded to the experimental groups.
Ablation of capsaicin-sensitive neurons
For ablation of the C-fiber sensory neurons, under halothane anesthesia, individual mice received three consecutive doses of capsaicin (25, 50, and 50 mg/kg, s.c.) dissolved in vehicle (10% ethanol, 10% Tween 80, sterile physiological saline) over 32 h (at 0, 6, and 32 h, respectively; total dose 125 mg/kg) or an equivalent volume of vehicle. Mice were studied 10 days after the last injection (5).
Blockade of receptors of neuropeptides
Spantide III (NK1 receptor antagonist; 2 mg/kg) (30), GR87389 (NK2 receptor antagonist; 2 mg/kg) (31), or CGRP8–37 (CGRP
1 receptor antagonist; 10 µg/kg) (5) was given i.p. 2530 min before PAR2 stimulation to block the effects of neuropeptides. The respective control received the same amount of vehicle (0.9% saline).
Statistical analysis
Statistics were done by SPSS software. An unpaired t test was used unless there were multiple comparisons, in which case we used ANOVA (significance level set at p 
0.05). The results are presented as mean ± SD.
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Results |
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PAR2-AP instilled into the airspaces increased peak and plateau airway pressure compared with Hanks’ control and control peptide (Fig. 1). PAR2-AP also increased ELW and lung vascular permeability to protein at 30 min in a receptor-dependent manner (Fig. 2, A and B). PAR2-AP also induced respiratory acidosis, hypoxemia, and hypercapnia (Table I). The effect of PAR2 activation on airway pressure and ELW was dose dependent (Fig. 2, C and D). Airspace PAR1-AP and PAR4-AP did not significantly affect any of these parameters.
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Plasma MPO activity (an index of neutrophil degranulation) and MDA concentration (an indicator of lipid peroxidation) were significantly increased in wild-type mice that received the PAR2-AP compared with wild-type mice instilled with Hanks’, control peptide, or PAR2 knockout mice instilled with PAR2-AP (Fig. 2, E and F). Airspace PAR1- and PAR4-APs did not affect these parameters.
Effect of PAR2-AP on composition of BAL fluid
To study later effects of PAR2-AP on lung inflammation, mice were instilled with Hanks’, LSIGRL, or PAR2-AP, and the protein content, leukocyte numbers, and MIP-2 levels in the BAL were examined at 4 h. The protein concentration and leukocyte numbers in the BAL were increased compared with controls (Fig. 3, A and B). Neutrophils were increased 12-fold in the PAR2-AP-instilled group compared with control peptide (Fig. 3C) and macrophages were slightly increased (Fig. 3D). PAR2 activation caused an 8-fold increase of MIP-2 levels (Fig. 3E). To study neuropeptide release after airspace exposure of PAR2-AP, the lungs were lavaged at 30 min. PAR2 activation caused a 5-fold increase in substance P levels in the BAL compared with the control peptide (Fig. 3F).
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To examine histological changes induced by PAR2-AP, mice were instilled with Hanks’, LSIGRL, or PAR2-AP and euthanized at 30 min and 4 h. At 30 min, the alveolar septa were wider (more edema) and more neutrophils were sequestered in the pulmonary microcirculation in the PAR2-AP group (Fig. 3, G and I). At 4 h, more emigrated neutrophils were present in the PAR2-AP group (Fig. 3, H and J).
Effect of the C-fiber neurotoxin capsaicin on the lung responses to PAR2-AP
To determine whether airway responses to PAR2 activation were mediated by neuropeptides, we pretreated mice with capsaicin to ablate C-fibers before instillation of Hanks’ or PAR2-AP. Mice used to study immediate (30 min) and later (4 h) responses were ventilated. The elevated peak pressure and plateau airway pressures at 30 min induced by PAR2 activation in sensory neuron-ablated mice were reduced compared with intact control mice (Fig. 4, A and B). The increase in ELW and EPE in the capsaicin group was also decreased compared with control group at both 30 min (Fig. 4, C and D) and 4 h (Fig. 4, E and F) after PAR2-AP instillation.
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To determine which neuropeptides contribute to airway constriction and lung injury, we pretreated mice with neuropeptide receptor antagonists or corresponding vehicle before instillation of PAR2-AP or Hanks’. NK2 receptor blockade (GR87389) reduced the increases in peak and plateau airway pressure compared with the vehicle, whereas NK1 (Spantide III) and CGRP receptor blockade did not affect airway pressures (Fig. 5, A and B). Both NK1 (Spantide III) and NK2 receptor blockade (GR87389) reduced the elevation in lung water and protein permeability, while CGRP receptor blockade (CGRP8–37) had no effect (Fig. 5, A and B).
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To further test whether PAR2-AP-induced lung inflammation and protein permeability were dependent on the NK1 and the NK2 receptor, we instilled PAR2-AP into lungs of mice pretreated with neuropeptide antagonists of NK1 and NK2 receptors (Spantide III + GR87389) or capsaicin and performed BAL at 4 h. The PAR2-AP-induced increases in protein concentration, number of neutrophils, and MIP-2 level in the BAL were blunted in mice pretreated with Spantide III plus GR87389 (NK1 + NK2 receptor blockade) or with capsaicin compared with vehicle-pretreated mice (Fig. 6, A–C). In addition, histological examination of lungs collected 4 h after PAR2-AP instillation revealed that the increase in marginated and emigrated neutrophils as well as protein-rich fluid in the airspaces was blunted in the capsaicin group compared with control (Fig. 6, D–G).
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Discussion |
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Several of our observations are consistent with previous reports. The observation that instillation of PAR2-AP into the airway doubled the peak airway pressure and increased plateau pressure in wild-type but not PAR2 knockout mice is consistent with reports that PAR2 promotes hyperreactivity in allergic inflammation of the airway in mice (8), that PAR2-AP can increase the contractile response of isolated bronchi from guinea pigs to histamine (32), and that PAR2-AP can induce contraction of human airways and potentiate contractions to histamine (13, 14). Our observation that PAR2-AP can trigger leukocyte infiltration into lung is consistent with reports that PAR2-AP can promote leukocyte rolling and arrest on mesenteric (10) and cremasteric vessels (11) and neurogenic inflammation in rat paw (5). The lack of response in the control peptide group and in the PAR2 knockout mice in these studies supports the conclusion that most of proinflammatory responses to PAR2-AP are indeed PAR2 mediated.
The magnitude of PAR2-AP-induced responses in the lung was impressive. In addition to doubling airway pressure, PAR2-AP 5-fold increased substance P level in the BAL and nearly doubled the ELW in only 30 min, and by 4 h increased protein concentration in BAL by 50%, MIP-2 levels by 8-fold, and the number of neutrophils by 12-fold. Plasma MDA levels were increased 4-fold. These changes were functionally significant because they were associated with hypoxemia, hypercapnia, and acidosis. Thus, PAR2 activation in the lung can significantly impair ventilation and gas exchange.
In principle, the various inflammatory responses caused by PAR2-AP may be mediated by PAR2 expressed on any of a number of different cell types. Airway epithelial cells would be the first cells to encounter acting peptide after intratracheal administration, and PAR2 expression is increased in the airway epithelium of patients with allergic asthma (33). Activation of PAR2 has been reported to cause bronchorelaxation ex vivo in a manner that depends upon the presence of airway epithelium, perhaps through epithelial production of PGE2 (12). We measured PGE2 in the BAL 30 min after Hanks’, PAR2-AP, and LSIGRL instillation in this study; PAR2-AP triggered only a modest increase in the level of PGE2 (530 ± 10 pg/ml, n = 6) relative to Hanks’ (490 ± 40 pg/ml, n = 10) and LSIGRL (467 ± 71 pg/ml, n = 6). Thus, at least in our acute in vivo studies, the PG response was small and the effects of PAR2 activation on airway pressures suggest bronchoconstriction was predominant response.
PAR2 is also expressed on mouse microvascular endothelial cells (34), and PAR2 may be expressed by and contribute to a variety of functions in human neutrophils (35, 36). Thus, a direct effect of PAR2-AP on neutrophils might contribute to increased MPO activity and MDA levels in plasma, and perhaps additional responses in the lung in these studies. Intriguingly, however, capsaicin pretreatment of mice markedly reduced the ability of PAR2-AP to trigger increases in airway pressure, lung water and lung vascular permeability, protein content, MIP-2 production, and the number of neutrophils in the airspaces and interstitium. Antagonists of neuropeptide function also prevented these responses to PAR2-AP, and PAR2-AP triggered neuropeptide release as indicated by increased substance P levels in BAL. Overall, our results suggest that PAR2-AP-induced inflammatory responses in the lung are substantially dependent upon neurogenic mechanisms. Of note, however, inhibition of PAR2-AP-induced increases in airway pressure by capsaicin and neuropeptide antagonists was less complete than inhibition of other indices of inflammation (Figs. 4 and 6), suggesting that a neuropeptide-independent component, perhaps mediated by the airway epithelium, contributes to the former response.
Neurogenic mechanisms have been implicated in lung inflammation, and PAR2 has been implicated in neurogenic inflammation in other tissues. Airways are innervated by bronchopulmonary capsaicin-sensitive C-fiber afferents that are carried by the vagus nerve (37), and some spinal DRG neurons (38). Sensory DRG neurons coexpress substance P, CGRP, and PAR2 (5, 21), and neuropeptides in the airways can induce airway constriction (through NK2 receptor) and peripheral lung vascular leakage (NK1 receptor). Neuropeptides have been reported to contribute to lung inflammation associated with hepatic ischemia/reperfusion (39), and NK1 receptor activation can promote neutrophil recruitment to alveoli (38).
Based on the known effects of activating PAR1 on endothelial cells, we had expected that PAR peptides might act on endothelial cells directly to initiate edema formation and perhaps recruitment of neutrophils. Our results suggest that activation of PAR1 alone is not sufficient to trigger lung inflammation, at least under the conditions used in our studies. By contrast, these results suggest that activation of PAR2 alone is sufficient, and the neurogenic mechanism involved is consistent with a recent report that, unlike PAR1-AP, PAR2-AP is unable to directly enhance endothelial permeability in culture (40).
Epithelial and endothelial cells are both candidate targets of neurokinins released upon activation of PAR2 in the lung (17, 41, 42). Also, the alveolar macrophage is a potential effector cell. Alveolar macrophages are a source of proinflammatory cytokines in acute lung injury (43), and isolated mouse alveolar macrophages do express the NK1 receptor (44). Interaction of alveolar macrophages with NK1 released from subepithelial sensory neurons stretched by high tidal volume ventilation may help propagate lung inflammation (44). Thus, it is possible that the action of neuropeptides upon alveolar macrophages contributes in part to PAR2-AP-induced lung inflammation.
Taken together, our results indicate that PAR2 activation in lung can cause airway constriction, lung inflammation, and pulmonary edema, and that these responses are dependent upon, and perhaps mediated by, neuropeptides. PAR2 can be activated by a variety of extracellular proteases with trypsin-like specificity, including coagulation proteases (34, 45), tryptase (46), membrane-tethered serine protease-1 (47), and allergens (e.g., dust mite and cockroach proteases) (48). Which if any of these proteases activates PAR2 in vivo and the relative importance of PAR2 activation among potentially redundant signaling pathways that orchestrate inflammatory responses in the lung remain to be explored.
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Acknowledgments |
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Disclosures |
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Footnotes |
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1 This study was supported by National Heart, Lung, and Blood Institute Grants HL-51854 and HL-51856 (to M.A.M.). This work was also supported by National Institutes of Health Grants HL44907, HL59202, HL65185, and HL65590 (to S.R.C.). J.R.H. was supported by a C.J. Martin Fellowship (166904) from the National Health and Medical Research Council of Australia. 
2 Address correspondence and reprint requests to Dr. Michael A. Matthay, Cardiovascular Research Institute, University of California San Francisco, Health Science West 825, 505 Parnassus Avenue, San Francisco, CA 94143-0130. E-mail address: mmatt{at}itsa.ucsf.edu
3 Abbreviations used in this paper: PAR, protease-activated receptor; BAL, bronchoalveolar lavage; DRG, dorsal root ganglia; ELW, excess lung water; EPE, extravascular plasma equivalent; 125I-albumin, 125I-labeled albumin; MDA, malondialdehyde; MPO, myeloperoxidase; PAR-AP, PAR-activating peptide; W/D, wet-to-dry weight.
Received for publication January 20, 2005. Accepted for publication June 1, 2005.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionDisclosuresReferences |
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formation and neutrophil sequestration into the murine lungs. J. Immunol. 161: 474-480. release from the pulmonary macrophage in lung ischemia-reperfusion injury. J. Thorac. Cardiovasc. Surg. 127: 1502-1508. 
: possible relevance to human fibrotic disorders. Proc. Natl. Acad. Sci. USA 99: 15072-15077. This article has been cited by other articles:
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  Q. Gu and L.-Y. Lee Effect of protease-activated receptor 2 activation on single TRPV1 channel activities in rat vagal pulmonary sensory neurons Exp Physiol, August 1, 2009; 94(8): 928 - 936. [Abstract] [Full Text] [PDF]
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X. Su, M. Johansen, M. R. Looney, E. J. Brown, and M. A. Matthay CD47 Deficiency Protects Mice from Lipopolysaccharide-Induced Acute Lung Injury and Escherichia coli Pneumonia J. Immunol., May 15, 2008; 180(10): 6947 - 6953. [Abstract] [Full Text] [PDF]
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S. M. Saleh, T. S. Mann, T. Peters, R. J. Betts, and P. J. Henry Influence of Dexamethasone on Protease-Activated Receptor 2-Mediated Responses in the Airways J. Pharmacol. Exp. Ther., February 1, 2008; 324(2): 622 - 630. [Abstract] [Full Text] [PDF]
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 D. A. Vesey, W. A. Kruger, P. Poronnik, G. C. Gobe, and D. W. Johnson Proinflammatory and proliferative responses of human proximal tubule cells to PAR-2 activation Am J Physiol Renal Physiol, November 1, 2007; 293(5): F1441 - F1449. [Abstract] [Full Text] [PDF]
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C. Ebeling, T. Lam, J. R. Gordon, M. D. Hollenberg, and H. Vliagoftis Proteinase-Activated Receptor-2 Promotes Allergic Sensitization to an Inhaled Antigen through a TNF-Mediated Pathway J. Immunol., September 1, 2007; 179(5): 2910 - 2917. [Abstract] [Full Text] [PDF]
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 X. Su, J. W. Lee, Z. A. Matthay, G. Mednick, T. Uchida, X. Fang, N. Gupta, and M. A. Matthay Activation of the {alpha}7 nAChR Reduces Acid-Induced Acute Lung Injury in Mice and Rats Am. J. Respir. Cell Mol. Biol., August 1, 2007; 37(2): 186 - 192. [Abstract] [Full Text] [PDF]
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 J. Sevastos, S. E. Kennedy, D. R. Davis, M. Sam, P. W. Peake, J. A. Charlesworth, N. Mackman, and J. H. Erlich Tissue factor deficiency and PAR-1 deficiency are protective against renal ischemia reperfusion injury Blood, January 15, 2007; 109(2): 577 - 583. [Abstract] [Full Text] [PDF]
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M. C. Winter, S. S. Shasby, D. R. Ries, and D. M. Shasby PAR2 activation interrupts E-cadherin adhesion and compromises the airway epithelial barrier: protective effect of beta-agonists Am J Physiol Lung Cell Mol Physiol, October 1, 2006; 291(4): L628 - L635. [Abstract] [Full Text] [PDF]
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E. Camerer, I. Cornelissen, H. Kataoka, D. N. Duong, Y.-W. Zheng, and S. R. Coughlin Roles of protease-activated receptors in a mouse model of endotoxemia Blood, May 15, 2006; 107(10): 3912 - 3921. [Abstract] [Full Text] [PDF]
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 F. Noorbakhsh, S. Tsutsui, N. Vergnolle, L. A. Boven, N. Shariat, M. Vodjgani, K. G. Warren, P. Andrade-Gordon, M. D. Hollenberg, and C. Power Proteinase-activated receptor 2 modulates neuroinflammation in experimental autoimmune encephalomyelitis and multiple sclerosis J. Exp. Med., February 21, 2006; 203(2): 425 - 435. [Abstract] [Full Text] [PDF]
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