José Maurício S C Mota | University of Sao Paulo (original) (raw)

Papers by José Maurício S C Mota

Organ dysfunction is a major concern in sepsis pathophysiology and contributes to its high mortal... more Organ dysfunction is a major concern in sepsis pathophysiology and contributes to its high mortality rate. Neutrophil extracellular traps (NETs) have been implicated in endothelial damage and take part in the pathogenesis of organ dysfunction in several conditions. NETs also have an important role in counteracting invading microorganisms during infection. The aim of this study was to evaluate systemic NETs formation, their participation in host bacterial clearance and their contribution to organ dysfunction in sepsis. C57Bl/6 mice were subjected to endotoxic shock or a polymicrobial sepsis model induced by cecal ligation and puncture (CLP). The involvement of cf-DNA/NETs in the physiopathology of sepsis was evaluated through NETs degradation by rhDNase. This treatment was also associated with a broad-spectrum antibiotic treatment (ertapenem) in mice after CLP. CLP or endotoxin administration induced a significant increase in the serum concentrations of NETs. The increase in CLP-induced NETs was sustained over a period of 3 to 24 h after surgery in mice and was not inhibited by the antibiotic treatment. Systemic rhDNase treatment reduced serum NETs and increased the bacterial load in non-antibiotic-treated septic mice. rhDNase plus antibiotics attenuated sepsis-induced organ damage and improved the survival rate. The correlation between the presence of NETs in peripheral blood and organ dys-function was evaluated in 31 septic patients. Higher cf-DNA concentrations were detected in septic patients in comparison with healthy controls, and levels were correlated with sepsis severity and organ dysfunction. In conclusion, cf-DNA/NETs are formed during sepsis and are associated with sepsis severity. In the experimental setting, the degradation of NETs by rhDNase attenuates organ damage only when combined with antibiotics, confirming that NETs take part in sepsis pathogenesis. Altogether, our results suggest that NETs are important for host bacterial control and are relevant actors in the pathogenesis of sepsis.

Survivors from sepsis are in an immunosuppressed state that is associated with higher longterm mo... more Survivors from sepsis are in an immunosuppressed state that is associated with higher longterm mortality and risk of opportunistic infections. Whether this contributes to neoplastic proliferation, however, remains unclear. Tumor-associated macrophages (TAMs) can support malignant cell proliferation, survival, and angiogenesis. We addressed the relationship between the post-sepsis state, tumor progression and TAM accumulation, and phenotypic and genetic profile, using a mouse model of sepsis resolution then B16 melanoma in mice. In addition, we measured the serum concentrations of TNFα, TGFβ, CCL2, and CXCL12, and determined the effect of in vivo CXCR4/CXCL12 inhibition in this context. Mice that
survived sepsis showed increased tumor progression both in the short and long term and survival times were shorter. TAM accumulation, TAM local proliferation, and serum concentrations of TGFβ, CXCL12, and TNFα were increased. Naïve mice inoculated with B16 together with macrophages from post-sepsis mice also had faster tumor progression and shorter survival. Post-sepsis TAMs had less expression of MHC-II and leukocyte activationrelated genes. Inhibition of CXCR4/CXCL12 prevented the post-sepsis–induced tumor progression, TAM accumulation, and TAM in situ proliferation. Collectively, our data show that the post-sepsis state was associated with TAM accumulation through CXCR4/CXCL12, which contributed to B16 melanoma progression.

Chemotherapy-induced hemorrhagic cystitis (HC) remains a common and lifethreatening clinical comp... more Chemotherapy-induced hemorrhagic cystitis (HC) remains a common and lifethreatening clinical complication, mainly due to the increasing usage of alkylating agents during conditioning regimen for hematopoietic cell transplantation.

Chemotherapy-induced hemorrhagic cystitis (HC) remains a common and life-threatening clinical com... more Chemotherapy-induced hemorrhagic cystitis (HC) remains a common and life-threatening clinical complication, mainly due to the increasing usage of alkylating agents during conditioning regimen for hematopoietic cell transplantation. Currently, mesna and hyperhydration are the two more employed preventive measures. However, these prophylactic approaches have been proven not to be completely effective, since cystoscopic and histopathologic bladder damage are evidenced. Therefore, understanding the pathogenesis of HC must be the cornerstone for the development of novel therapeutic strategies. The purpose of this review is to examine the current knowledge regarding the pathogenesis of HC, describing the importance of transcription factors (nuclear factor kappaB), cytokines (tumor necrosis factor-
alpha,interleukin-1Beta,-4, -6, and -8), enzymes (inducible nitric oxide synthase and cyclooxygenase-2), among other mediators, for the bladder injury. We also discuss the currently available animal models and future perspectives on the management of HC.

BACKGROUND: Amifostine has been widely tested as a cytoprotective agent against a number of aggre... more BACKGROUND:
Amifostine has been widely tested as a cytoprotective agent against a number of aggressors in different organs. Recently, a gastroprotective effect was observed for this drug in a model of indomethacin-induced gastric injury. Our objective was to investigate the effect of amifostine on ethanol-induced gastric injury and the role played in this mechanism by afferent sensory neurons, non-protein sulfhydryl groups, nitric oxide, ATP-sensitive potassium channels, and cyclooxygenase-2.
METHODS:
Rats were treated with amifostine (22.5, 45, 90, or 180 mg/kg, PO or SC). After 30 min, the rats received absolute ethanol (5 ml kg(-1), PO). One hour later, gastric damage was quantified with a planimeter. Samples from the stomach were also taken for histopathological assessment and for assays of non-protein sulfhydryl groups. The other groups were pretreated with L-NAME (10 mg kg(-1), IP), glibenclamide (10 mg kg(-1), PO), or celecoxib (10 mg kg(-1), PO). After 30 min, the animals were given amifostine (90 mg kg(-1), PO or SC), followed 30 min later by gavage with absolute ethanol (5 ml kg(-1)). Other rats were desensitized with capsaicin (125 mg kg(-1), SC) 8 days prior to amifostine treatment.
RESULTS:
Amifostine administration PO and SC significantly and dose-dependently reduced ethanol-induced macroscopic and microscopic gastric damage by restoring glutathione levels in the stomach mucosa. Amifostine-promoted gastroprotection against ethanol-induced stomach injury was reversed by pretreatment with neurotoxic doses of capsaicin, but not by L-NAME, glibenclamide, or celecoxib.
CONCLUSIONS:
Amifostine protects against ethanol-induced gastric injury by increasing glutathione levels and stimulating the afferent sensory neurons in the stomach.

Context -Methotrexate and other anticancer agents can induce intestinal mucositis, which is one o... more Context -Methotrexate and other anticancer agents can induce intestinal mucositis, which is one of the most common limiting factor that prevent further dose escalation of the methotrexate. Objectives -To evaluate the gastric emptying and gastrointestinal transit of liquids in methotrexate-induced intestinal mucositis. Methods -Wistar rats received methotrexate (2.5 mg/kg/day for 3 days, subcutaneously) or saline. After 1, 3 and 7 days, sections of duodenum, jejunum and ileum were removed for assessment of epithelial damage and myeloperoxidase activity (biochemical marker of granulocyte infiltration). Others rats were pre-treated with methotrexate or saline, gavage-fed after 3 or 7 days with a standard test liquid meal, and sacrificed 10, 20 or 30-min later. Gastric and small intestine dye recoveries were measured by spectrophotometry. Results -After 3 days of methotrexate, there was an epithelial intestinal damage in all segments, with myeloperoxidase activity increase in both in duodenum and ileum. Seven days after methotrexate, we observed a complete reversion of this intestinal damage. There was an increase in gastric dye recoveries after 10, 20, and 30-min post-prandial intervals after 3 days, but not after 7 days, of methotrexate. Intestine dye recoveries were decreased in the first and second segments at 10 min, in the third at 20 min, and in the second and third at 30 min, only after 3 days of methotrexate treatment. Conclusion -Methotrexate-induced intestinal mucositis delays gastric emptying and gastrointestinal transit of liquids in awake rats. HEADINGS -Mucositis. Methotrexate. Gastric emptying. Gastrointestinal transit. Rats. Soares PMG, Lopes LO, Mota JMSC, Belarmino-Filho JN, Ribeiro RA, Souza MHLP. Methotrexate-induced intestinal mucositis delays gastric emptying and gastrointestinal transit of liquids in awake rats Arq Gastroenterol 81 v. 48 -no.1

Background: 5-Fluorouracil (5-FU) induces intestinal mucositis, which is characterized by epithel... more Background: 5-Fluorouracil (5-FU) induces intestinal mucositis, which is characterized by epithelial ulcerations in the mucosa and clinical manifestations, such as pain and dyspeptic symptoms. Cytokines participate in the inflammatory and functional events of intestinal mucositis. IL-4 is an important mediator of intestinal inflammation, with either anti-inflammatory or pro-inflammatory functions, depending on the model of intestinal inflammation. This study aimed to evaluate the role of IL-4 in 5-FU-induced intestinal mucositis. Methods: IL-4 +/+ or IL-4 À/À mice (25-30 g) were intraperitoneally injected with 5-FU (450 mg/Kg) or saline (C). After 3 days, the mice were sacrificed and the duodenum was evaluated for epithelial damage, MPO activity and cytokine concentration. Results: 5-FU induced significant damage in the intestinal epithelium of IL-4 +/+ mice (reduction in the villus/crypt ratio: control = 3.31 ± 0.21 lm, 5-FU = 0.99 ± 0.10 lm). However, the same treatment did not induce significant damage in IL-4 À/À mice (5-FU = 2.87 ± 0.19 lm) compared to wild-type mice. 5-FUinduced epithelial damage increased the MPO activity (neutrophil number) and the level of proinflammatory cytokines (IL-4, TNF-a, IL-1b and CXCL-8) in the duodenum. These results were not observed in IL-4 À/À mice treated with 5-FU. Conclusion: Our data suggest that IL-4 participates as a pro-inflammatory cytokine in a 5-FU-induced intestinal damage model and suggests that IL-4 antagonists may be novel therapeutics for this condition.

Background Amifostine has been widely tested as a cytoprotective agent against a number of aggres... more Background Amifostine has been widely tested as a cytoprotective agent against a number of aggressors in different organs. Recently, a gastroprotective effect was observed for this drug in a model of indomethacin-induced gastric injury. Our objective was to investigate the effect of amifostine on ethanol-induced gastric injury and the role played in this mechanism by afferent sensory neurons, nonprotein sulfhydryl groups, nitric oxide, ATP-sensitive potassium channels, and cyclooxygenase-2. Methods Rats were treated with amifostine (22.5, 45, 90, or 180 mg/kg, PO or SC). After 30 min, the rats received absolute ethanol (5 ml kg -1 , PO). One hour later, gastric damage was quantified with a planimeter. Samples from the stomach were also taken for histopathological assessment and for assays of non-protein sulfhydryl groups. The other groups were pretreated with L-NAME (10 mg kg -1 , IP), glibenclamide (10 mg kg -1 , PO), or celecoxib (10 mg kg -1 , PO). After 30 min, the animals were given amifostine (90 mg kg -1 , PO or SC), followed 30 min later by gavage with absolute ethanol (5 ml kg -1 ). Other rats were desensitized with capsaicin (125 mg kg -1 , SC) 8 days prior to amifostine treatment. Results Amifostine administration PO and SC significantly and dose-dependently reduced ethanol-induced macroscopic and microscopic gastric damage by restoring glutathione levels in the stomach mucosa. Amifostine-promoted gastroprotection against ethanol-induced stomach injury was reversed by pretreatment with neurotoxic doses of capsaicin, but not by L-NAME, glibenclamide, or celecoxib. Conclusions Amifostine protects against ethanol-induced gastric injury by increasing glutathione levels and stimulating the afferent sensory neurons in the stomach.

Purpose Gastrointestinal mucositis is a common side effect of cancer chemotherapy. Platelet-activ... more Purpose Gastrointestinal mucositis is a common side effect of cancer chemotherapy. Platelet-activating factor (PAF) is produced during gut inflammation. There is no evidence that PAF participates in antineoplastic-induced intestinal mucositis. This study evaluated the role of PAF in 5-fluorouracil (5-FU)-induced intestinal mucositis using a pharmacological approach and PAF receptor knockout mice (PAFR -/-). Methods Wild-type mice or PAFR -/mice were treated with 5-FU (450 mg/kg, i.p.). Other mice were treated with saline or BN52021 (20 mg/kg, s.c.), an antagonist of the PAF receptor, once daily followed by 5-FU administration. After the third day of treatment, animals were sacrificed and tissue samples from the duodenum were removed for morphologic evaluation. In addition, myeloperoxidase activity and the cytokine concentration were measured. Results 5-FU treatment decreased the duodenal villus height/crypt depth ratio, increased MPO activity, and increased the concentration of TNF-a, IL-1b and KC in comparison with saline-treated animals. In PAFR -/mice and PAFR antagonist-treated mice, 5-FU-dependent intestinal damage was reduced and a decrease in duodenal villus height/crypt depth ratio was attenuated. However, the 5-FU-dependent increase in duodenum MPO activity was not affected. Without PAFR activation, 5-FU treatment did not increase the TNF-a, IL-1b and KC concentration. Conclusions In conclusion, our study establishes the role of PAFR activation in 5-FU-induced intestinal mucositis. This study implicates treatment with PAFR antagonists as novel therapeutic strategy for this condition.

Aim To evaluate gastrointestinal motility during 5-Xuorouracil (5-FU)-induced intestinal mucositi... more Aim To evaluate gastrointestinal motility during 5-Xuorouracil (5-FU)-induced intestinal mucositis. Materials and methods Wistar rats received 5-FU (150 mg kg ¡1 , i.p.) or saline. After the 1st, 3rd, 5th, 15th and 30th day, sections of duodenum, jejunum and ileum were removed for assessment of epithelial damage, apoptotic and mitotic indexes, MPO activity and GSH concentration. In order to study gastrointestinal motility, on the 3rd or 15th day after 5-FU treatment, gastric emptying in vivo was measured by scintilographic method, and stomach or duodenal smooth muscle contractions induced by CCh were evaluated in vitro. Results On the third day of treatment, 5-FU induced a sig-niWcant villi shortening, an increase in crypt depth and intestinal MPO activity and a decrease in villus/crypt ratio and GSH concentration. On the Wrst day after 5-FU there was an increase in the apoptosis index and a decrease in the mitosis index in all intestinal segments. After the 15th day of 5-FU treatment, a complete reversion of all these parameters was observed. There was a delay in gastric emptying in vivo and a signiWcant increase in gastric fundus and duodenum smooth muscle contraction, after both the 3rd and 15th day.

Aim: To evaluate the effect of inhibiting inducible nitric oxide synthase (iNOS), by aminoguanidi... more Aim: To evaluate the effect of inhibiting inducible nitric oxide synthase (iNOS), by aminoguanidine, or leukocyte infi ltration, by fucoidin, on gastropathy induced by two different doses of indomethacin in rats. Methods: Rats were treated with saline, aminoguanidine (50 or 100 mg.kg -1 , i. p.) or fucoidin (25 mg.kg -1 , i. v.). Indomethacin was then given at a dose of 5 or 20 mg.kg -1 . At the end of 3 h, macroscopic gastric damage and myeloperoxidase (MPO) activity were assessed. Results: Aminoguanidine reduced the gastric damage induced by indomethacin at 20 mg.kg -1 , but increased gastric MPO activity. However, aminoguanidine did not infl uence the gastric damage induced by indomethacin at 5 mg.kg -1 . Fucoidin prevented both the gastric damage and the increase in gastric MPO activity induced by indomethacin at 20 mg. kg -1 , but not at 5 mg.kg -1 . Conclusion: Indomethacin at a dose of 20 mg.kg -1 , but not at 5 mg.kg -1 , induced gastropathy dependent on neutrophil infi ltration and iNOS-generated NO.

Aim: Acrolein (ACR) is a urinary metabolite of cyclophosphamide (CPS) and ifosfamide (IFS), which... more Aim: Acrolein (ACR) is a urinary metabolite of cyclophosphamide (CPS) and ifosfamide (IFS), which has been demonstrated to be the causative agent of hemorrhagic cystitis (HC), induced by these compounds. In this study, we investigate the participation of cyclooxygenase-2 (COX-2) on ACR-induced HC.

This study was designed to evaluate the protective effect of amifostine on indomethacin-induced g... more This study was designed to evaluate the protective effect of amifostine on indomethacin-induced gastric damage, and the role of increased gastric non-protein sulfhydryl groups (NP-SH) and decreased leukocyte adherence in this event. Wistar rats were pretreated with amifostine (10, 30, or 90 mg/kg intraperitoneal (i.p.) or subcutaneous (s.c.)) or saline. After 30 min, the rats received indomethacin (20 mg/kg, by gavage) and were then killed 3 hr later. Macroscopic and microscopic gastric damage, concentration of gastric NP-SH, prostaglandin E2 (PGE2), and mesenteric leukocyte adherence (intravital microscopy) were assessed. Amifostine prevented significantly (P < 0.05), macroscopic or microscopic, indomethacin-induced gastric damage, and Supported by Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq).

OBJECTIVE: To investigate the possible protective effect of recombinant human interleukin-11 (rhI... more OBJECTIVE:
To investigate the possible protective effect of recombinant human interleukin-11 (rhIL-11) against ifosfamide (IFS)-induced hemorrhagic cystitis (HC).
MATERIALS AND METHODS:
Male Swiss mice (20-30g) were pretreated with rhIL-11 (25-625 mg, subcutaneously.) 30 min before intraperitoneal injection of IFS (400 mg/kg) or with saline (control group). Twelve hours later, HC was evaluated by bladder wet weight (BWW) to quantify edema, Evans blue extravasation (EBE) to measure vascular permeability, and macroscopic and microscopic analysis. All bladders were assessed by histopathological analysis.
RESULTS:
rhIL-11 (at 125 and 625 mg) attenuated the IFS- induced increase of BWW (37.48% and 45.44%, respectively, p < 0.05) and EBE (62.35% and 56.47%, respectively, p < 0.05). IFS- induced macroscopic edema and hemorrhage and microscopic alterations, were also prevented by rhIL-11 at 625 microg. (p < 0.05).
CONCLUSION:
Our results demonstrate a protective effect of rhIL-11 on experimental IFS- induced HC, not previously reported.

Introduction: Ifosfamide (IFS) is an antineoplastic alkylating agent whose major side effect is h... more Introduction: Ifosfamide (IFS) is an antineoplastic alkylating agent whose major side effect is hemorrhagic cystitis (HC). This toxicity is attributed to the renal excretion of acrolein (ACR), a highly urotoxic IFS metabolite. Despite the clinical use of mesna to prevent HC, a significant percent (~33%) of patients present with at last one feature of HC, mainly hematuria. Aim: To investigate the use of two antioxidants-amifostine and glutathione-for the prevention of experimental IFS-and ACR-induced HC. Materials and methods: Male Swiss mice were treated intraperitoneal (i.p.) with saline (control), glutathione (125, 250 or 500 mg/kg) or amifostine (25, 50 or 100 mg/kg), and 30 min later they received a single i.p. injection of IFS at a dose of 400 mg/kg. To investigate the systemic effects of the antioxidants on ACR-induced HC, the animals were treated with saline, amifostine (50 mg/kg, i.p.) or glutathione (500 mg/kg, i.p.), and 30 min afterward with 75 lg ACR intravesically (i.ve.). In another set of experiments, the antioxidants were injected directly into the bladder, where the mice received a single i.ve injection of ACR (75 lg) plus amifostine (1.5 mg/kg) or glutathione (2 mg/kg). HC was measured 3 h after IFS or ACR injection according to bladder wet weight, macroscopic (edema and hemorrhage) and microscopic changes, i.e., edema, hemorrhage, cellular infiltration, fibrin deposition and urothelial desquamation. Results: Pretreatments with amifostine or glutathione prevented IFS-induced HC in a dose-dependent manner. Furthermore, ACR-induced HC was also prevented by systemic (i.p.) or local (i.ve.) pretreatment with glutathione or amifostine. The greatest protective effect was seen with local amifostine treatment (2 mg/kg i.ve.) (P < 0.05). Conclusions: Glutathione and amifostine show a beneficial effect in experimental IFS-and ACRinduced HC. Thus, they should be investigated as an alternative treatment to prevent HC observed in patients undergoing IFS treatment.