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ABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION
Research and Development Center (H.N., K.K., M.T., H.O., S.T., C.K., M.N., T.A., H.A.), Fuso Pharmaceutical Industries Ltd., Osaka, Japan; and Division of Physiology and Pathophysiology (A.K.), School of Pharmaceutical Sciences, Kinki University, Higashi-Osaka, Japan
Received June 1, 2004; accepted August 26, 2004.
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Abstract |
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; Hollenberg and Compton, 2002; Kawabata, 2002). Four distinct subtypes of PARs have been cloned. Thrombin activates PAR-1, PAR-3, and PAR-4, whereas PAR-2 is activated by trypsin, mast cell tryptase, and coagulation factors VIIa and Xa (Molino et al., 1997; Camerer et al., 2000; Kawabata, 2002; Ossovskaya and Bunnett, 2004). Interestingly, with the exception of PAR-3, synthetic peptides based on the receptor-activating sequence of the tethered ligand, known as PAR-activating peptides (PAR-APs), are capable of activating the receptors by a mechanism independent of proteolysis (Vu et al., 1991; Nystedt et al., 1994; Xu et al., 1998; Macfarlane et al., 2001; Hollenberg and Compton, 2002; Kawabata, 2002). The endogenous agonist enzymes for PARs may activate multiple PARs. In contrast, many of PAR-APs specifically activate one type of PARs. Due to the complication of multiple PAR activation by endogenous agonists, the PAR-APs are more useful than the proteases themselves in the study on physiological roles of PARs in vivo and in vitro.
PAR-2 is involved in a variety of biological events in the cardiovascular, respiratory, alimentary, and central nervous systems. For instance, PAR-2 is expressed in sensory neurons and involved in neurogenic inflammation (Steinhoff et al., 2000) and nociception (Kawabata et al., 2001a, 2002a; Vergnolle et al., 2001). In contrast, the PAR-2 agonist given in vivo induces cytoprotective mucus secretion in the gastric mucosa by stimulating sensory neurons (Kawabata et al., 2001b). PAR-2 thus plays a dual role, being protective following its mild activation but proinflammatory/nociceptive when activated excessively (Kawabata et al., 2001a,b). PAR-2 is abundantly expressed in the parotid, sublingual, and submaxillary glands and the pancreas (Bohm et al., 1996; Nguyen et al., 1999; Kawabata et al., 2000b). PAR-2-APs, administered systemically to mice or rats, trigger prompt salivation in vivo (Kawabata et al., 2000b, 2001c). In the in vitro study, PAR-2-APs and the endogenous PAR-2 activator trypsin induced the secretion of amylase and mucin from isolated rat parotid gland and sublingual glands, respectively (Kawabata et al., 2000a,b). In addition, PAR-2-APs administered systemically cause a prompt increase followed by a transient decrease in secretion of pancreatic juice and subsequently produce a persistent increased juice secretion in anesthetized rats (Kawabata et al., 2000b). The PAR-2-APs facilitate secretion of amylase in isolated pancreatic acinar fragments in vitro (Bohm et al., 1996) and also in conscious mice (Kawabata et al., 2002b). PAR-2 agonists produce transient activation of dog pancreatic duct epithelial cell ion channels (Nguyen et al., 1999). Those findings strongly suggest that PAR-2 plays a general or key role in regulation of digestive exocrine secretion.
The stimulatory actions of PAR-2 agonists in salivary and pancreatic exocrine secretion suggest that upon activation, PAR-2 might promote clearance of toxins and debris in these glandular tissues, particularly during inflammation. Given the extensive roles for PAR-2 in glandular exocrine secretion, it is also likely that PAR-2 might stimulate tear secretion and promote clearance of toxic substances or organisms from the eyes. In Sjögren's syndrome, exocrine secretion is damaged extensively in a variety of glandular tissues including salivary and lacrimal glands. Muscarinic agonists are often used to treat dry mouth and eyes in Sjögren's syndrome. PAR-2 agonists may also be available for the same purpose if they are capable of triggering tear secretion in addition to salivation. The present study thus examined if PAR-2-related peptides could modulate tear secretion in rats in vivo. Here we show for the first time to our knowledge that PAR-2-APs, including SLIGRL-NH2 and SLIGKV-NH2, strongly trigger tear secretion in rats, whereas a PAR-2-inactive partially reversed peptide, LSIGRL-NH2, but not other PAR-2-inactive peptides, LRGILS-NH2, LSIGKV-NH2, or VLGILS-NH2, also causes tear secretion in rats. We then characterized and identified the distinct mechanisms underlying the evoked tear secretion.
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Materials and Methods |
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In Vivo Salivation Bioassay in Rats. The salivation bioassay was performed essentially according to the previously described method (Takeda and Krause, 1989). In brief, rats were anesthetized with i.p. sodium pentobarbital (50 mg/kg) and tracheotomized. A piece of cotton was placed in their mouths and replaced repeatedly with new ones every 1 min. The increase in the weight of the cotton was defined as the amount of secreted saliva for each interval.
In Vivo Tear Secretion Bioassay in Rats. The tear secretion bioassay was performed in pentobarbital-anesthetized rats essentially according to the previously described method with minor modifications (Iga et al., 1998). Briefly, Schirmer strips that are clinically used to measure the amount of tear secreted were inserted into the inner aspect of bilateral eyelids in the rats and replaced with new strips every 2 min. The length of the part soaked with tear in the strip paper was determined as a parameter of the amount of the secreted tear for 2 min.
In Vivo Desensitization Experiments. SLIGRL-NH2 or LSIGRL-NH2 at 5 µmol/kg, a maximal dose, in combination with amastatin at 2.5 µmol/kg was first administered i.v. to the anesthetized rat. Ten minutes after the first injection, the second challenge with i.v. SLIGRL-NH2 or LSIGRL-NH2 at 2.5 µmol/kg was performed in the rat.
Inhibition Experiments. The rats received i.p. atropine at 1 mg/kg and i.v. hexamethonium at 30 mg/kg, 20 and 3 min before i.v. administration of PAR-2-related peptides, respectively. Mast cell depletion was achieved by eight repeated i.p. injections of compound 48/80 twice daily in the morning and evening, starting with an evening dose. The dose of compound 48/80 was 0.6 mg/kg for the first six administrations and 1.2 mg/kg for the last two administrations. Indomethacin at 10 mg/kg was administered i.p. 30 min before i.v. challenge with the SLIGRL-NH2 at 5 µmol/kg.
Detection of mRNA for PAR-2 in Rat Lacrimal Gland by a Reverse Transcriptase-PCR. Isolation of total RNA from lacrimal gland was accomplished using TRIzol Reagent (Invitrogen, Carlsbad, CA). Messenger RNA was reverse-transcribed and amplified using a RNA LA PCR kit (AMV) Version 1.1 (Takara Shuzo Co, Ltd., Kyoto, Japan). The PCR primers for amplification of PAR-2 sequences were 5'-CAACAGTAAAGGGAGAAGTCT-3' and 5'-GGGCAGCACGTCGTGACAGGT-3', leading to amplification of 601-bp fragments. The primers targeted to glyceraldehyde 3-phosphate dehydrogenase were 5'-ACCACAGTCCATGCCATCAC-3' and 5'-TCCACCACCCTGTTGCTGTA-3', yielding amplification of 452-bp fragments. Amplification was allowed to proceed for 30 cycles beginning with a 30-s denaturation period at 94°C followed by a 30-s reannealing time at 60°C and a primer extension period of 1 min at 72°C. The PCR products were separated by 2% agarose gel electrophoresis and visualized by the ethidium bromide staining procedure.
Chemicals. All peptides were prepared by a standard solid-phase synthesis procedure. The concentration, purity, and composition of the peptides were determined by high-performance liquid chromatography, mass spectrometry, and quantitative amino acid analysis. Hexamethonium chloride dihydrate and indomethacin were purchased from Wako Pure Chemicals Industries, Ltd. (Osaka, Japan), and atropine sulfate salt and amastatin were obtained from Sigma-Aldrich (St. Louis, MO) and Peptide Institute, Inc. (Osaka, Japan), respectively. Indomethacin was dissolved in 4% sodium bicarbonate. All other chemicals including peptides were dissolved in saline. Control animals received administration of each vehicle.
Statistical Analysis. Data are represented as means with S.E.M., and statistical significance was analyzed by Tukey's test for multiple comparisons and set at a P < 0.05 level.
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Results |
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). The effects of SLIGRL-NH2 and LSIGRL-NH2 on tear secretion were dose-dependent in dose ranges of 1 to 5 and 1 to 2.5 µmol/kg, respectively (Fig. 1, D and E). SLIGKV-NH2, a human PAR-2-derived PAR-2-AP, given at 5 µmol/kg in the same manner, induced relatively small but significant secretions of tear (Fig. 1F). Most interestingly, neither LSIGKV-NH2, a partially reversed peptide, nor VKGILS-NH2, a reversed peptide, caused tear secretion (Fig. 1F). Namely, among PAR-2-inactive control peptides tested, only LSIGRL-NH2 had an effect as a secretagogue for tear.
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In Vivo Desensitization Experiments to Discriminate the Mechanisms for Tear Secretion Caused by SLIGRL-NH2 and LSIGRL-NH2 in Rats. After the first dose of SLIGRL-NH2 at 5 µmol/kg, the second dose of SLIGRL-NH2 at 2.5 µmol/kg produced no significant tear secretion (Fig. 2, A and C). On the other hand, preadministration of SLIGRL-NH2 tended to only partially inhibit the peak-time tear secretion caused by subsequent administration of LSIGRL-NH2 at 2.5 µmol/kg (Fig. 2B), although an apparently clearer tendency toward inhibition was observed when shown as total secretion for 6 min (Fig. 2D). Preadministration of LSIGRL-NH2 at 5 µmol/kg blocked the tear secretion caused by subsequent administration of LSIGRL-NH2 at 2.5 µmol/kg (Fig. 3, A and C). In contrast, preadministration of LSIGRL-NH2 did not affect the tear secretion caused by SLIGRL-NH2 at 2.5 µmol/kg (Fig. 3, B and D).
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Effects of Muscarinic and Ganglionic (Nicotinic) Antagonists on the SLIGRL-NH2- and LSIGRL-NH2-Triggered Tear Secretion in Rats. To evaluate the involvement of the parasympathetic nervous system in the tear secretion caused by SLIGRL-NH2 and LSIGRL-NH2, we performed inhibition experiments using the muscarinic antagonist atropine and the ganglionic (nicotinic) antagonist hexamethonium. Although the tear secretion caused by SLIGRL-NH2 or SLIGKV-NH2 at 5 µmol/kg was resistant to i.p. atropine at 1 mg/kg (Fig. 4, A and B), the LSIGRL-NH2-evoked tear secretion was abolished by atropine at the same dose (Fig. 4C). Furthermore, the effect of LSIGRL-NH2 but not SLIGRL-NH2 was also completely inhibited by pretreatment with i.v. hexamethonium at 30 mg/kg (Fig. 4, D and E).
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Effect of Mast Cell Depletion or Indomethacin on the SLIGRL-NH2- and LSIGRL-NH2-Triggered Tear Secretion in Rats. LSIGRL-NH2 is known as a potent stimulator for mast cell degranulation in vitro (Nishikawa et al., 2000), and SLIGRL-NH2 is also capable of causing mast cell degranulation in vivo (Kawabata et al., 1998). In this context, we examined the effect of mast cell depletion by repeated treatment with compound 48/80 and found that both SLIGRL-NH2 and LSIGRL-NH2 at 5 µmol/kg induced tear secretion, even in mast cell-depleted rats (Fig. 5, A and B). Although endogenous prostanoids mediate some of actions of PAR-2 agonists in certain tissues/cells (Macfarlane et al., 2001; Ossovskaya and Bunnett, 2004), pretreatment with indomethacin at 10 mg/kg did not significantly inhibit the tear secretion caused by SLIGRL-NH2 at 5 µmol/kg in the present study. The amount of tear secreted was 34.5 ± 5.4, 35.8 ± 7.4, 122.2 ± 9.0, and 100.7 ± 10.3 mm/6 min (n = 5-6) in groups treated with vehicle plus vehicle, indomethacin plus vehicle, vehicle plus SLIGRL-NH2, and indomethacin plus SLIGRL-NH2, respectively.
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Activity of IGRL-NH2, a Short Peptide Based on the Possible Core Structure of LSIGRL-NH2, as a Secretagogue for Tear in Rats. Since LSIGRL-NH2 but not LSIGKV-NH2 was active as a secretagogue in the present tear secretion assay, the last two-amino acid sequence "RL" of LSIGRL-NH2 is considered important for the activity. To identify the core structure critical for the atropine-sensitive activity of LSIGRL-NH2 as a secretagogue for tear, we synthesized a shorter peptide, IGRL-NH2, which lacks the N-terminal two-amino acid sequence "LS" of LSIGRL-NH2. IGRL-NH2, administered i.v. at 5 µmol/kg in combination with amastatin, evoked tear secretion, the magnitude being similar to that caused by the same dose of LSIGRL-NH2 (Fig. 6; see also Figs. 1, 4, and 5), and the IGRL-NH2-induced tear secretion was abolished by atropine (Fig. 6). Thus, "IGRL" is the critical core structure of LSIGRL-NH2.
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Discussion |
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TopAbstractMaterials and MethodsResultsDiscussionReferences |
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, 2002b, 2004; Kawabata, 2002). However, our data also reveal that LSIGRL-NH2, a PAR-2-inactive partially reversed peptide based on SLIGRL-NH2, also has an effect as a secretagogue for tear. The in vivo desensitization study suggests that the mechanisms for the tear secretion caused by PAR-2-APs and LSIGRL-NH2 are considered to be largely different, and the inhibition study indicates that the effect of LSIGRL-NH2 but not PAR-2-APs involves activation of the parasympathetic postganglionic neurons. It is also suggested that the tear secretion following PAR-2-APs and/or LSIGRL-NH2 is independent of mast cell degranulation or prostanoid formation. Finally, our data demonstrate that IGRL is a core structure of LSIGRL-NH2 as a secretagogue for tear.
Upon activation, PAR-2 is known to trigger or enhance the secretion of saliva, pancreatic juice (Nguyen et al., 1999; Kawabata et al., 2000b, 2002b), and gastric mucus and pepsinogen (Kawabata et al., 2001b; Kawao et al., 2002) but suppress gastric acid secretion (Nishikawa et al., 2002) in the gastrointestinal tract. The present data add to the list of a variety of regulatory roles played by PAR-2 in glandular secretion its novel function as a secretagogue for tear secretion, although it has yet to be confirmed ultimately by experiments using PAR-2-knockout mice. Considering the role of PAR-2 in salivation, PAR-2 agonists, preferably nonpeptide compounds if any, might be clinically applicable as therapeutic drugs for treatment of certain clinical symptoms such as dry eyes and dry mouth, e.g., Sjögren's syndrome.
It is worth noting that SLIGRL-NH2 tended to partially suppress the tear secretion caused by subsequent administration of LSIGRL-NH2 in the desensitization experiments, whereas LSIGRL-NH2 had no effect on the secretion caused by subsequent SLIGRL-NH2. LSIGRL-NH2 is inactive with PAR-2, as evidenced by the salivation assay in this present investigation (see Fig. 1C) and previous studies (Kawabata et al., 2000b, 2004). Considering that SLIGRL-NH2 contains IGRL, the core structure of LSIGRL-NH2, SLIGRL-NH2 might activate and desensitize to a certain extent the unidentified "target molecule" that LSIGRL-NH2 would stimulate to cause tear secretion. However, this hypothesis is apparently inconsistent with the findings that preadministration of LSIGRL-NH2 had no effect on the tear secretion caused by subsequent SLIGRL-NH2. It is likely that the PAR-2-mediated pathway activated by SLIGRL-NH2 might compensate the PAR-2-independent component that is blocked by desensitization with LSIGRL-NH2. As tear secretion is strongly controlled by the parasympathetic nervous systems, it is critical to examine involvement of muscarinic or ganglionic (nicotinic) neurotransmission in the evoked tear secretion. Therefore, it is very interesting that the effect of LSIGRL-NH2 or IGRL-NH2 but not SLIGRL-NH2 was clearly inhibited by pretreatment with atropine or hexamethonium. The slight attenuation of SLIGRL-NH2-evoked tear secretion by atropine (see Fig. 4A) might imply contribution of some neuronal component that does not involve PAR-2, being consistent with the above-mentioned finding that SLIGRL-NH2 reduced the effect of subsequent LSIGRL-NH2 in desensitization experiments. Since LSIGRL-NH2 and IGRL-NH2 had a similar potency as a tear secretagogue, the N-terminal dipeptide structure "SL" in SLIGRL-NH2 might suppress or partially mask the neurally mediated tear secretion via non-PAR-2 mechanisms caused by the C-terminal tetrapeptide structure IGRL-NH2 in SLIGRL-NH2. The relatively low activity of SLIGKV-NH2 as a secretagogue for tear, compared with SLIGRL-NH2, when administered in combination with amastatin, is not attributable to the lack of its action on the PAR-2-independent pathway that can be activated by LSIGRL-NH2 or possibly moderately by SLIGRL-NH2. The low activity of SLIGKV-NH2 relative to SLIGRL-NH2 in tear secretion may simply reflect the lower agonistic activity on PAR-2 and the lower stability to amastatin-resistant metabolic enzymes in vivo because the potency of the former peptide relative to the latter in the in vivo salivation assay is 0.25 and 0.08 in the absence and presence of amastatin, respectively (Kawabata et al., 2004). Although histamine secreted by mast cells on degranulation could indirectly cause tear secretion by stimulating sensory neurons, the effect of SLIGRL-NH2 or LSIGRL-NH2 as a tear secretagogue does not appear to involve such a mechanism, as evidenced by the experiments using compound 48/80.
It remains unclear whether PAR-2-triggered tear secretion is physiologically relevant since exact endogenous activators of PAR-2 in the lacrimal glands have been unidentified. PAR-2 may not play a physiological role in the lacrimal glands under normal conditions but becomes activated under pathological conditions including inflammation. Tryptase, known as an endogenous PAR-2 activator, can be released from mast cells upon degranulation during inflammation, and coagulation factors VIIa and Xa, possible PAR-2 agonists, may become accessible to PAR-2 when vascular permeability is elevated during inflammation. These endogenous PAR-2-activating enzymes might activate PAR-2 during inflammation in the lacrimal glands and cause tear secretion, promoting clearance of toxins and debris. Furthermore, there are also exogenous PAR-2 activators such as mite allergens (Sun et al., 2001) and cockroach proteases (Page et al., 2003); thus, PAR-2 might function to clear environmental substances or organisms from the eyes.
Our inhibition study clearly shows that the target molecule for LSIGRL-NH2 (and also IGRL-NH2) would be present on preganglionic neurons in the parasympathetic nervous system, although the possibility could not be ruled out that LSIGRL-NH2 might directly stimulate postganglionic nicotinic receptors. However, exact identity of the molecule or `receptor' activated by LSIGRL-NH2 has yet to be clarified. The hypothetical scheme interpreting the distinct mechanisms for the tear secretion caused by LSIGRL-NH2/IGRL-NH2 and PAR-2-APs is shown in Fig. 7. In conclusion, the present study provides evidence that SLIGRL-NH2 and SLIGKV-NH2 PAR-2-APs cause tear secretion most probably via PAR-2, and that LSIGRL-NH2/IGRL-NH2, PAR-2-inactive peptides, trigger tear secretion by stimulating parasympathetic nerves via an unidentified target molecule.
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Footnotes |
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ABBREVIATIONS: PAR-2, protease-activated receptor-2; PAR-2-AP, protease-activated receptor-2-activating peptide; PCR, polymerase chain reaction.
Address correspondence to: Dr. Atsufumi Kawabata, Division of Physiology and Pathophysiology, School of Pharmaceutical Sciences, Kinki University, 3-4-1 Kowakae, Higashi-Osaka 577-8502, Japan. E-mail: kawabata{at}phar.kindai.ac.jp
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