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Histopathology of Vascular Injury in Sprague-Dawley Rats Treated with Phosphodiesterase IV Inhibitor SCH 351591 or SCH 534385
1 Division of Applied Pharmacology Research (HFD-910), Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, Maryland, USA Correspondence: Jun Zhang, M.D., M.S., Division of Applied Pharmacology Research, Center for Drug Evaluation and Research, Food and Drug Administration (HFD-910), 10903 New Hampshire Ave., Silver Spring, MD 20993-0002, USA; e-mail:jun.zhang{at}fda.hhs.gov.
Histopathological and immunohistochemical studies were conducted to characterize vascular injuries in rats treated with phosphodiesterase (PDE) IV inhibitors SCH 351591 or SCH 534385. Sprague-Dawley rats were administered PDE IV inhibitors by gavage at a range of doses and times. The two PDE IV inhibitors induced comparable levels of vascular injury, primarily in the mesentery and to a lesser extent in the pancreas, kidney, liver, small intestine, and stomach. Mesenteric vascular changes occurred as early as one hour, progressively developed over twenty-four to forty-eight hours, peaked at seventy-two hours, and gradually subsided from seven to nine days. The typical morphology of the vascular toxicity consisted of hemorrhage and necrosis of arterioles and arteries, microvascular injury, fibrin deposition, and perivascular inflammation of a variety of blood vessels. The incidence and severity of mesenteric vascular injury increased in a time- and dose-dependent manner in SCH 351591- or SCH 534385-treated rats. Mesenteric vascular injury was frequently associated with activation of mast cells (MC), endothelial cells (EC), and macrophages (MØ). Immunohistochemical studies showed increases in CD63 immunoreactivity of mesenteric MC and in nitrotyrosine immunoreactivity of mesenteric EC and MØ. The present study also provides a morphological and cellular basis for evaluating candidate biomarkers of drug-induced vascular injury.
Key Words: activation and degranulation of mast cell • activation of endothelial cell and macrophage • apoptosis of endothelial and smooth muscle cells • arterial hemorrhage and necrosis • nitrotyrosine • peroxynitrite Abbreviations: bFGF, basic fibroblast growth factor • EC, endothelial cell • iNOS, inducible nitric oxide synthase • MØ, macrophage • MC, mast cells • mkd, mg/kg/day • NO, nitric oxide • PDE, phosphodiesterase • PTAH, phosphotungstic acid hematoxylin stain • SMC, vascular smooth muscle cell
Phosphodiesterase (PDE) IV inhibitors have been investigated as possible anti-inflammatory and anti-asthma drugs (Souness et al. 2000; Torphy and Undem 1991). However, the side effects of these drugs on the central nervous, gastrointestinal, and vascular systems (Losco et al. 2004; Lyoumi et al. 1998; Robertson et al. 2001; Slim et al. 2002, 2003) have posed an obstacle to drug development. A major obstacle is that it is not known if preclinical drug-induced vascular injury (DIVI) is relevant to clinical applications. DIVI has become a major discussion point for the FDA and for pharmaceutical companies. The mechanisms by which PDE IV inhibitors induce vascular injury may be multifaceted. An increase in intracellular cAMP (Larson et al. 1996) and nitrative stress (Slim et al. 2003) were proposed to contribute to DIVI. Physical stress secondary to local vasodilation may be a significant factor leading to injury (Daguès, Pawlowski, Sobry et al. 2007; Kerns et al. 2005). A significant inflammatory component to DIVI has also been observed in multiple studies (Slim et al. 2002, 2003; Dietsch et al. 2006; Mecklenburg et al. 2006; Daguès, Pawlowski, Sobry et al. 2007). A study on PDE III-inhibitor–induced vascular injury revealed that inducible nitric oxide synthase (iNOS) and nitrotyrosine were locally produced by mast cells (MC) and endothelial cells (EC) (Zhang et al. 2006). Peroxynitrite formation was correlated with proinflammatory changes and the later development of necrotic and apoptotic cell death of mesenteric blood vessels (Zhang et al. 2006). Recently, a comprehensive review of nitric oxide (NO) and peroxynitrite in cardiovascular disease has suggested that peroxynitrite formation may contribute to the development of early vascular injury, followed by the formation of other reactive nitrogen species derived from the reaction of nitrite with proteins such as myeloperoxidase in inflammatory cells, secondarily contributing to nitrosative stress (Pacher et al. 2007). Evidence is growing that peroxynitrite formation is a common final pathway in drug-dependent toxicity (Denicola and Radi 2005). Biomarkers for detecting DIVI remain to be discovered and characterized. Although metabonomic profiling of urine has been demonstrated to be useful in the assessment of PDE IV-inhibitor–induced vascular injury in rats (Robertson et al. 2001; Slim et al. 2002), reliable biomarkers using serum or plasma have not been developed in preclinical models (Losco et al. 2004). Multiple technologies (toxicogenomics, genomics, proteomics, metabonomics, bioinformatics, etc.) have been proposed as tools for seeking vascular injury biomarkers (Kerns et al. 2005; Zhang et al. 2002). However, the high cost and technically demanding nature of these methods make it difficult to incorporate them in routine toxicology studies (Ishii et al. 2007). The evaluation of candidate biomarkers identified by the various "omics" methods requires direct comparison between biomarker response and histopathology findings. Therefore, histopathology remains a gold standard method in the search for vascular injury biomarkers, which may then lead to an understanding of the mechanisms underlying DIVI. The objectives of the present study were to characterize the morphological features of vascular injury in rats treated with PDE IV inhibitors SCH 351591 or SCH 534385, to provide clues concerning possible mechanisms responsible for the development of drug-induced vascular injury, and to provide the morphological basis for selecting candidate biomarkers for PDE IV-inhibitor–induced vascular injury.
Animals Sprague-Dawley rats (ten to twelve weeks old) were obtained from Charles River Laboratories (Wilmington, MA, USA) and housed separately in an environmentally controlled room (18°C–21°C, 40%–70% relative humidity) with a twelve-hour light/dark cycle. Rats were fed Certified Purina Rodent Chow #5002 (Ralston Purina Co., St. Louis, MO, USA) and water ad libitum. The experimental protocol was approved by the Institutional Animal Care and Use Committee, Center for Drug Evaluation and Research, FDA and conducted in an AAALAC-accredited facility (National Research Council 1996).
Study Design
Histopathological Studies
Immunohistochemical Studies
Semiquantitative Grading System for Vascular Injury
Statistics
Characteristic of PDE IV-inhibitor–induced Vascular Injury in Rats Fully developed vascular injury was found at seventy-two hours after rats were administered SCH 351591. On gross examination, mesenteric vessel hemorrhage was discernible. On microscopic examination, medial hemorrhage, necrosis, and apoptosis of blood vessels were found mainly in the arteries and arterioles of the mesentery, followed by, in order of decreasing incidence, in the arteries and arterioles of the pancreas, in the arterioles of the kidney (at the hilum), the liver (at the hepatic triad), the small intestine (at muscular coat), and the stomach (at lamina propria mucosa and submucosa). Vascular lesions were not found in the coronary arteries, nor were any myocardial lesions identified. Most representative vascular lesions induced by these PDE IV inhibitors were manifested in mesenteric blood vessels as follows: (a) medial hemorrhage, necrosis, and apoptosis in small- to large-sized muscular arteries (Figure 1A); (b) microvascular injury consisting of fibrin insudation (Figures 1Band 1C) and fibrin exudation (Figure 1D), demonstrated by PTAH staining; (c) EC activation (Figures 1E and 1F) and apoptosis; (d) hemorrhage of the arterioles, venules, and capillaries; and (e) perivascular inflammatory response in a variety of blood vessels (capillaries, venules, small veins, arterioles, and arteries) (Figures 1G and 1H).
Alterations in central lymphoid (thymus) and peripheral lymphoid organs (spleen and Peyer’s patches) were noted in rats treated with SCH 351591. On gross examination, the volume of the thymus and spleen decreased, whereas mesenteric lymph nodes and intestinal Peyer’s patches were enlarged compared with those in control rats. On microscopic examination, the cortex of the thymus became thinned and the T-cell zone was drastically reduced (Figures 2A and 2B). The TUNEL assay showed extensive apoptosis in the thymic cortex (Figures 2C and 2D). It was noteworthy that the number of MC and apoptotic lymphocytes of the cortex in the thymus increased with time and dose. In the spleen, the T-cell–dependent areas were also reduced (Figures 2E–2H). Microscopy also showed T-lymphocyte proliferation in mesenteric lymph nodes and at Peyer’s patches of the ileum (figures not shown).
Dose Response in Rats Treated with SCH 351591 Table 1presents the frequency and severity of overall lesion scores following treatment with SCH 351591 at a range of doses and times. Mesenteric vascular lesion scores increased in direct proportion to the administered doses over the range of 3 to 80 mkd. Rats treated with 160 mkd for one day had a lesion score of 1.7, which was comparable with the same score noted in the group that received 4.5 mkd for three days.
One rat died after two consecutive doses of 80 mkd SCH 351591. The remaining rats in the group were in moribund condition and were sacrificed less than three hours after the last dose. Two rats from the group treated with 9 mkd were removed from the study because of morbidity on day 6. Rats treated with 3 mkd SCH 351591 demonstrated mild body weight loss beginning on the third day and continuing to the ninth day (Figure 3). In rats treated with 9 mkd SCH 351591, body weight was dramatically lost from day 2 to day 9 (Figure 3). On gross examination, mesenteric vessel hemorrhage was detected in two of six rats in the 4.5 mkd group, in four of six rats in the 40 mkd group, and in three of six rats in the 80 mkd group.
On microscopic examination, in the 3 mkd group for three days, no acute vascular injury was found except for MC activation/degranulation and EC activation. In the 3 mkd group treated for nine days, activation of MC and EC was not seen, but activated MØ were noted. In addition, polyarteritis nodosa appeared at this time point. In the 4.5 mkd group treated for three days, characteristic lesions of arteriolar and arterial hemorrhage and necrosis were obvious, with cellular alterations suggestive of cell activation and inflammatory cell responses. Among these activated cells were EC, MC, and MØ. In contrast to the small size and flat shape in saline-treated control rats, EC became larger in size and appeared cuboidal in shape in drug-treated rats. MC of the mesentery were larger and had more abundant cytoplasmic granules in the vicinity of the affected microvasculature in drug-treated rats as compared to control rats (Figures 4A and 4B). Some cytoplasmic granules were found outside of the cytoplasm of MC and the cell membranes were ruptured, suggesting MC degranulation. Immunostaining for CD 63 showed a positive reaction on MC (Figures 4C and 4D). Cytoplasmic vacuoles and digested red blood cells were apparent in MØ surrounding the affected vessels (Figure 4E), indicating MØ activation and hyperactive phagocytosis. Immunoperoxidase for nitrotyrosine showed a positive reaction on MØ (Figure 4F) and EC (Figure 4H) compared with a negative reaction in control rats (Figure 4G). TUNEL assay demonstrated no EC and VSMC apoptosis in the mesenteric arteries from control rats. In contrast, apoptosis was observed in EC and VSMC in mesenteric artery (Figure 4I) and/or arterioles (Figure 4J) obtained from SCH 351591-treated rats.
In the 9 mkd group for nine days, arterial hemorrhage and necrosis, perivascular inflammation, and polyarteritis nodosa were simultaneously found. Marked proliferation of fibroblasts (Figure 4K) was associated with polyarteritis nodosa and mingled with inflammatory cells (lymphocytes, macrophages, and leukocytes) and edematous fluids.
Time Course Response in Rats Treated with SCH 351591
In rats treated with 20 mkd groups for one to seventy-two hours, arterial and arteriolar hemorrhage and necrosis was more severe at seventy-two hours than at any other time points (Table 3). As expected, the lesions were more severe at earlier times than with the 4.5 mkd dose. In addition, polyarteritis nodosa was not observed at ninety-six hours as it had been in rats treated with 4.5 mkd (Table 4).
Table 4illustrates the developmental process of mesenteric vascular injury. In rats treated with SCH 351591, the ensuing vascular injury was mediated by immune cell activation (MC, EC, MØ), followed by an early change in permeability (fibrin exudation and edema), initial recruitment of inflammatory cells from the blood into the perivascular spaces, irreversible vascular lesions (hemorrhage, necrosis, and apoptosis), and final formation of polyarteritis nodosa.
Comparison of Vascular Toxicity and Immunotoxicity between SCH 351591 and SCH 534385
Pathological Characteristics of SCH 351591- or SCH 534385-induced Vascular Injury in Rats The present study demonstrated that SCH 351591 induced time- and dose-dependent mesenteric vascular injury in SD rats. Similar to PDE IV-inhibitor–induced vascular injury in cynomolgus monkeys (Losco et al. 2004), drug-treated rats showed a time course of injury from early microvascular (insudation and exudation) followed by arterial hemorrhage and fibrinoid necrosis, mainly in small- to large-sized mesenteric blood vessels and to a lesser extent in the pancreatic vessels; inflammatory infiltration within blood vessel walls; and edema in mesenteric connective tissue. In addition to necrosis and hemorrhage, another arterial VSMC alteration consisted of fibrin deposits in the walls. Polyarteritis nodosa was a late-stage event seen in some animals. This lesion has been reported as a late-appearing finding in studies with PDE III inhibitors and with nonspecific PDE inhibitors (Hanton et al. 1995). SCH 534384, another second PDE IV inhibitor that has not been reported previously to induce DIVI in rats, resulted in vascular injury and lymphoid organ alterations similar to SCH 351591, suggesting that they may share the same mechanism of drug-induced toxicity. Both PDE IV inhibitors (SCH 351591 and SCH 534385) have similar vascular injury patterns to another PDE IV inhibitor, BYK169171 (Mecklenburg et al. 2006).
Activation of MC in Association with Vascular Injury The present study, however, revealed that SCH 351591 and SCH 534385 induced MC degranulation at sites of inflammation, indicating the release of pro-inflammatory mediators from MC. Numerous MC were associated with the affected vessels of the mesentery, particularly with the microvasculature. Morphological changes in MC were conspicuous, including an increase in the cell size and in the cytoplasmic granules (indices of MC activation), as well as extrusion of cytoplasmic granules and rupture of cell membranes (indices of MC degranulation). Many MC in drug-treated rats were positively stained with a CD 63 mAb, which recognizes the AD1 antigen as a specific surface marker of MC (Boros et al. 1995; Nishikata et al. 1992). This protein is thought to be a receptor for the tissue inhibitor of metalloproteinase-1 (TIMP-1) (Jung et al. 2006), which was detected at a high level in serum following treatment with SCH 351591 (Weaver et al. 2008) and with another PDE IV inhibitor, CI-1044 (Daguès, Pawlowski, Guigon et al. 2007).
Activation of EC in Association with Vascular Injury
Activation of MØ in Association with Vascular Injury
Peroxynitrite Formation Involved in PDE IV-inhibitor–induced Vascular Injury and Inflammation
Morphological and Cellular Basis of Biomarkers for PDE IV-inhibitor–induced Vascular Injury Finally, the present study revealed that PDE IV inhibitors induced apoptosis of T-cells and atrophy of the thymus and spleen in drug-treated rats. These findings suggest that T-lymphocytes were deleted in the thymic cortex and the thymic-dependent T-cell zone of the spleen via apoptotic pathways. The restriction of cell loss to T-cell areas is not consistent with stress-associated responses (Pruett et al. 2000). A detailed discussion of the suppressive effects of PDE IV inhibitors on the immune system is beyond the scope of this paper. In conclusion, this study has shown that two PDE IV inhibitors cause drug-induced vascular injury in both a dose-and time-dependent manner. The lesions are similar to those caused by other PDE IV inhibitors. The data provide a strong foundation to evaluate candidate biomarkers that could be used in nonclinical studies and, potentially, to clinically evaluate the safety of drugs in these classes.
The authors wish to thank Scott W. Burchiel, Ph.D., University of New Mexico, for supplying mAb CD63 and for discussing the feasibility of applying the antibody in immunohistochemical staining.
This report is not an official U.S. Food and Drug Administration guidance or policy statement. No official support or endorsement by the U.S. Food and Drug Administration is intended or should be inferred.
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Abstract
Introduction
.05 was considered statistically significant. 
receptor expression. J Exp Med, 188, 1135-45
