RESUMO
In the United States, pediatric trauma resulting in traumatic brain injury (TBI) and massive hemorrhage is the leading cause of death. Although use of Resuscitative Endovascular Balloon Occlusion of the Aorta (REBOA) continues to gain favor, limited data exists on use and efficacy in pediatric patients. We describe a case using REBOA in a pediatric patient with blunt abdominal injury causing hemorrhagic shock. A 14-year-old female presented via air to a level 1 trauma center post motor vehicle collision with prolonged extraction. At landing, she was hemodynamically unstable with GCS and vitals indicating severe injuries. Further assessment indicated REBOA catheter placement with advancement to zone 1. Upon surgical stabilization, REBOA was deflated and distal pulses were maintained without complication. In cases where massive hemorrhage is the major threat to survival, REBOA may improve outcomes. Unfortunately, this patient had sustained a nonsurvivable TBI, and the family decided upon organ donation.
Assuntos
Oclusão com Balão , Lesões Encefálicas Traumáticas , Procedimentos Endovasculares , Choque Hemorrágico , Feminino , Humanos , Estados Unidos , Criança , Adolescente , Estudos Retrospectivos , Aorta , Hemorragia/etiologia , Hemorragia/terapia , Choque Hemorrágico/etiologia , Choque Hemorrágico/terapia , Ressuscitação/métodos , Oclusão com Balão/métodos , Lesões Encefálicas Traumáticas/complicações , Procedimentos Endovasculares/métodosRESUMO
INTRODUCTION: Appropriate triage of the trauma patient is critical. Low end-tidal carbon dioxide (ETCO2) is associated with mortality and hemorrhagic shock in trauma, but the relationship between low ETCO2 and important clinical variables is not known. This study investigates the association of initial in-hospital ETCO2 and patient outcomes, as well as the utility of ETCO2 as a predictive aid for blood transfusion. METHODS: Adult patients who presented to a Level One trauma center from 2019 to 2020 were eligible. Trauma bay ETCO2 measured by side-stream capnography was prospectively obtained for all trauma activations at time of initial evaluation. Using the Liu method of cut point estimation, patients were stratified as having low (≤29.5 mmHg) or normal ETCO2 (>29.5 mmHg). Multivariable regression was used to estimate the association of low ETCO2 with patient outcomes. RESULTS: A total of 955 patients underwent initial in-hospital ETCO2 measurement. Median time from arrival to ETCO2 measurement was 4 min. Among admitted patients (N = 493), 48.9% had low ETCO2. Compared to patients with normal ETCO2, those with low ETCO2 were older (median age 53 vs 46, p = 0.01) and more likely to have the highest trauma activation (27.4% vs 19.8%, p = 0.048). There was no difference in head injury. After adjustment, patients with low ETCO2 had greater odds of blood transfusion (OR 4.65, 95%CI 2.0-10.7), mortality (OR 5.10, 95%CI 1.1-24.9), inferior disposition (OR 1.64, 95%CI 1.1-2.6), and complications (OR 3.35, 95%CI 1.5-7.4). ETCO2 was more predictive of early blood transfusion than Shock Index (area under ROC = 67.6% vs 58.2%). CONCLUSIONS: Low trauma bay ETCO2 remains significantly associated with inferior clinical outcomes after adjustment. In comparison to other triage tools, low ETCO2 values may be more predictive of the need for blood transfusion. Further studies are needed to evaluate the role of ETCO2 as a decision making tool for early trauma management.
Assuntos
Desequilíbrio Ácido-Base , Transtornos Respiratórios , Adulto , Capnografia , Dióxido de Carbono , Hospitais , Humanos , Pessoa de Meia-Idade , Estudos Retrospectivos , Volume de Ventilação Pulmonar/fisiologiaRESUMO
BACKGROUND: Accurate and timely injury identification is critical but difficult to achieve in trauma patients who die shortly after arrival to the hospital. Autopsy has historically been used to detect injuries, but few undergo formal autopsy. This study investigates the utility of post-mortem computed tomography (PMCT) for injury identification in a diverse trauma population. METHODS: Cross-sectional study of adult trauma patients who died within 24 hours of arrival to a Level I trauma center were included. Among patients with PMCT, injury severity score (ISS) and number of injuries (NOI) were calculated either from physical exam alone (pre-PMCT) or exam and imaging (post-PMCT). ISS and NOI before and after PMCT were compared. A cause of death analysis was performed for patients who underwent comprehensive (ie, head, neck, and torso) PMCT. Non-parametric repeated measures tests were used, as appropriate. RESULTS: 7.3% (N = 28) of patients received PMCT. Compared to pre-PMCT, median ISS (21 vs 3.5) and NOI (5 vs 2) were greater post-PMCT (P < .001, respectively). Autopsy rate was 13.2% overall; 82.5% of autopsies were due to a penetrating mechanism, and median time to autopsy reporting was 38.5 days. Among 17 patients who received comprehensive PMCT, 64.7% had a single cause of death identified, and the remaining were classified as either multiple potential contributors or unknown. DISCUSSION: PMCT is a readily available method to identify injuries in trauma patients who expire shortly upon presentation. Given the low autopsy rate for blunt trauma and delay in reporting, PMCT is an important adjunct for trauma providers.
Assuntos
Ferimentos não Penetrantes , Adulto , Autopsia/métodos , Causas de Morte , Estudos Transversais , Humanos , Tomografia Computadorizada por Raios X/métodosRESUMO
INTRODUCTION: Current guidelines continue to lead to under- and over-triage of injured patients in the pre-hospital setting. End-tidal carbon dioxide (ETCO2) has been correlated with mortality and hemorrhagic shock in trauma patients. This study examines the correlation between ETCO2 and in-hospital outcomes among non-intubated patients in the pre-hospital setting. METHODS: We retrospectively studied a cohort of non-intubated adult trauma patients with initial pre-hospital side-stream capnography-obtained ETCO2 presenting via ground transport from a single North Carolina EMS agency to a level one trauma center from January 2018 to December 2018. Using the Liu method, the optimal threshold for low ETCO2 was ≤ 28.5 mmHg. RESULTS: Initial pre-hospital ETCO2 was recorded for 324 (22.0%) of 1473 patients with EMS data. Patients with low ETCO2 (N = 98, 30.3% of cohort) were older (median 58y vs 45y), but mechanisms of injury and scene vital signs were similar (p>0.05) between low and normal/high ETCO2 cohorts. Median injury severity score (ISS) did not differ significantly between the low and normal/high ETCO2 groups (5 vs 8, p=0.48). Compared to normal/high ETCO2, low ETCO2 correlated with increased unadjusted odds of mortality (OR 5.06), in-hospital complications (OR 2.06), and blood transfusion requirement (OR 3.05), p<0.05. Low ETCO2 was associated with 7.25 odds of mortality (95% CI 2.19,23.97, p=0.001) and 3.94 odds of blood transfusion (95% CI 1.32-11.78) after adjusting for age, ISS, and scene GCS. All but one of the massive transfusion patients (N = 8/9) had a low pre-hospital ETCO2. CONCLUSIONS: Low initial pre-hospital ETCO2 associates with poor clinical outcomes despite similar ISS and mechanisms of injury. ETCO2 is a potentially useful pre-hospital point-of-care tool to aid triage of trauma patients as it may identify hemorrhaging patients and predict mortality.
Assuntos
Capnografia , Dióxido de Carbono , Adulto , Hospitais , Humanos , Estudos Retrospectivos , Centros de TraumatologiaRESUMO
BACKGROUND: End-tidal carbon dioxide (ETCO2) is routinely used during elective surgery to monitor ventilation. The role of ETCO2 monitoring in emergent trauma operations is poorly understood. We hypothesized that ETCO2 values underestimate plasma carbon dioxide (pCO2) values during resuscitation for hemorrhagic shock. METHODS: Multicenter trial was performed analyzing the correlation between ETCO2 and pCO2 levels. RESULTS: Two hundred fifty-six patients resulted in 587 matched pairs of ETCO2 and pCO2. Correlation between these two values was very poor with an R of 0.04. 40.2% of patients presented to the operating room acidotic and hypercarbic with a pH less than 7.30 and a pCO2 greater than 45 mm Hg. Correlation was worse in patients that were either acidotic or hypercarbic. Forty-five percent of patients have a difference greater than 10 mm Hg between ETCO2 and pCO2. A pH less than 7.30 was predictive of an ETCO2 to pCO2 difference greater than 10 mm Hg. A difference greater than 10 mm Hg was predictive of mortality independent of confounders. CONCLUSION: Nearly one half (45%) of patients were found to have an ETCO2 level greater than 10 mm Hg discordant from their PCO2 level. Reliance on the discordant values may have contributed to the 40% of patients in the operating room that were both acidotic and hypercarbic. Early blood gas analysis is warranted, and a lower early goal of ETCO2 should be considered. LEVEL OF EVIDENCE: Therapeutic, level IV.
Assuntos
Dióxido de Carbono/análise , Hipoventilação/diagnóstico , Ressuscitação/métodos , Choque Hemorrágico/terapia , Ferimentos e Lesões/cirurgia , Adulto , Gasometria/métodos , Feminino , Humanos , Hipoventilação/sangue , Hipoventilação/etiologia , Hipoventilação/terapia , Masculino , Pessoa de Meia-Idade , Monitorização Fisiológica/métodos , Plasma/química , Valor Preditivo dos Testes , Valores de Referência , Ressuscitação/efeitos adversos , Estudos Retrospectivos , Choque Hemorrágico/sangue , Choque Hemorrágico/diagnóstico , Choque Hemorrágico/etiologia , Volume de Ventilação Pulmonar , Ferimentos e Lesões/sangue , Ferimentos e Lesões/complicações , Adulto JovemRESUMO
BACKGROUND: Significant mortality and morbidity are associated with alterations in the pulmonary vasculature. While techniques have been described for quantitative morphometry of whole-lung arterial trees in larger animals, no methods have been described in mice. We report a method for the quantitative assessment of murine pulmonary arterial vasculature using high-resolution computed tomography scanning. METHODS: Mice were harvested at 2 weeks, 4 weeks, and 3 months of age. The pulmonary artery vascular tree was pressure perfused to maximal dilation with a radio-opaque casting material with viscosity and pressure set to prevent capillary transit and venous filling. The lungs were fixed and scanned on a specimen computed tomography scanner at 8-µm resolution, and the vessels were segmented. Vessels were grouped into categories based on lumen diameter and branch generation. RESULTS: Robust high-resolution segmentation was achieved, permitting detailed quantitation of pulmonary vascular morphometrics. As expected, postnatal lung development was associated with progressive increase in small-vessel number and arterial branching complexity. CONCLUSIONS: These methods for quantitative analysis of the pulmonary vasculature in postnatal and adult mice provide a useful tool for the evaluation of mouse models of disease that affect the pulmonary vasculature.
Assuntos
Camundongos Endogâmicos C57BL , Modelos Animais , Artéria Pulmonar/diagnóstico por imagem , Artéria Pulmonar/crescimento & desenvolvimento , Microtomografia por Raio-X , Animais , Masculino , Camundongos , Artéria Pulmonar/anatomia & histologiaRESUMO
Premenopausal women and intact female rodents sustain smaller cerebral infarctions than males. Several sex-dependent differences have been identified as potential contributors, but many questions remain unanswered. Mice exhibit wide variation in native collateral number and diameter (collateral extent) that is dependent on differences in genetic background, aging, and other comorbidities and that contributes to their also-wide differences in infarct volume. Likewise, variation in infarct volume correlates with differences in collateral-dependent blood flow in patients with acute ischemic stroke. We examined whether extent of pial collateral arterioles and posterior communicating collateral arteries (PComAs) differ depending on sex in young, aged, obese, hypertensive, and genetically different mice. We combined new data with meta-analysis of our previously published data. Females of C57BL/6J (B6) and BALB/cByJ (BC) strains sustained smaller infarctions than males after permanent MCA occlusion. This protection was unchanged in BC mice after introgression of the B6 allele of Dce1, the major genetic determinant of variation in pial collaterals among mouse strains. Consistent with this, collateral extent in these and other strains did not differ with sex. Extent of PComAs and primary cerebral arteries also did not vary with sex. No dimorphism was evident for loss of pial collateral number and/or diameter (collateral rarefaction) caused by aging, obesity, and hypertension, nor for collateral remodeling after pMCAO. However, rarefaction was greater in females with long-standing hypertension. We conclude that smaller infarct volume in female mice is not due to greater collateral extent, greater remodeling, or less rarefaction caused by aging, obesity, or hypertension.
Assuntos
Isquemia Encefálica/fisiopatologia , Infarto Cerebral/patologia , Circulação Colateral , Caracteres Sexuais , Animais , Artérias Cerebrais/patologia , Circulação Cerebrovascular/fisiologia , Circulação Colateral/fisiologia , Modelos Animais de Doenças , Camundongos Endogâmicos C57BL , Acidente Vascular Cerebral/genética , Acidente Vascular Cerebral/fisiopatologiaRESUMO
Early provision of enteral nutrition (EN) in critically ill and injured patients has become standard practice in surgical intensive care units (ICUs) due to its proven role in reducing septic complications. Increasingly, intensivists are confronted with patients with an open abdomen due to the use of damage control surgery and the recognition of the abdominal compartment syndrome; the role and timing of EN in these challenging patients continue to be debated. Patients with an open abdomen are often among the sickest in the ICU and hence could benefit from early nutrition support. However, the exposed abdominal viscera can understandably create anxiety regarding the initiation of EN; there is theoretic concern over exacerbation of bowel distention with resultant inability to close the abdomen and an increased aspiration risk due to paralytic ileus. Recent studies have investigated the utility of EN in the patient with an open abdomen, addressing these clinical concerns. The goal of this clinical review is to provide guidance to physicians caring for these complex patients.
Assuntos
Abdome/fisiopatologia , Traumatismos Abdominais/fisiopatologia , Cuidados Críticos/métodos , Nutrição Enteral/efeitos adversos , Abdome/cirurgia , Traumatismos Abdominais/complicações , Traumatismos Abdominais/cirurgia , Nutrição Enteral/métodos , Humanos , Unidades de Terapia Intensiva/normas , Hipertensão Intra-Abdominal/etiologia , Fatores de Tempo , Resultado do TratamentoRESUMO
RATIONALE: Collaterals lessen tissue injury in occlusive disease. However, aging causes progressive decline in their number and smaller diameters in those that remain (collateral rarefaction), beginning at 16 months of age in mice (i.e., middle age), and worse ischemic injury-effects that are accelerated in even 3-month-old eNOS(-/-) mice. These findings have found indirect support in recent human studies. OBJECTIVE: We sought to determine whether other cardiovascular risk factors (CVRFs) associated with endothelial dysfunction cause collateral rarefaction, investigate possible mechanisms, and test strategies for prevention. METHODS AND RESULTS: Mice with nine different models of CVRFs of 4-12 months of age were assessed for number and diameter of native collaterals in skeletal muscle and brain and for collateral-dependent perfusion and ischemic injury after arterial occlusion. Hypertension caused collateral rarefaction whose severity increased with duration and level of hypertension, accompanied by greater hindlimb ischemia and cerebral infarct volume. Chronic treatment of wild-type mice with L-N (G)-nitro-arginine methylester caused similar rarefaction and worse ischemic injury which were not prevented by lowering arterial pressure with hydralazine. Metabolic syndrome, hypercholesterolemia, diabetes mellitus, and obesity also caused collateral rarefaction. Neither chronic statin treatment nor exercise training lessened hypertension-induced rarefaction. CONCLUSION: Chronic CVRF presence caused collateral rarefaction and worse ischemic injury, even at relatively young ages. Rarefaction was associated with increased proliferation rate of collateral endothelial cells, effects that may promote accelerated endothelial cell senescence.
Assuntos
Circulação Colateral/fisiologia , Membro Posterior/irrigação sanguínea , Isquemia/fisiopatologia , Animais , Doenças Cardiovasculares , Proliferação de Células , Feminino , Imuno-Histoquímica , Isquemia/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , NG-Nitroarginina Metil Éster/metabolismo , Neovascularização Patológica , Óxido Nítrico Sintase Tipo III/genética , Condicionamento Físico Animal , Quinolinas/química , Renina/genética , Fatores de Risco , Fatores de TempoRESUMO
RATIONALE: Severity of tissue injury in occlusive disease is dependent on the extent (number and diameter) of collateral vessels, which varies widely among healthy mice and humans. However, the causative genetic elements are unknown. Recently, much of the variation among different mouse strains, including C57Bl/6J (B6, high extent) and BALB/cByJ (Bc, low extent), was linked to a quantitative trait locus on chromosome 7 (Candq1). OBJECTIVE: We used congenic mapping to refine Candq1 and its candidate genes to create an isogenic strain set with large differences in collateral extent to assess their impact and the impact of Candq1, alone, on ischemic injury. METHODS AND RESULTS: Six congenic strains possessing portions of Candq1 introgressed from B6 into Bc were generated and phenotyped. Candq1 was refined from 27 to 0.737 Mb with full retention of effect, that is, return or rescue of phenotypes from the poor values in Bc to nearly those of wild-type B6 in the B6/B6 congenic mice as follows: 83% rescue of low pial collateral extent and 4.5-fold increase in blood flow and 85% reduction of infarct volume after middle cerebral artery occlusion; 54% rescue of low skeletal muscle collaterals and augmented recovery of perfusion (83%) and function after femoral artery ligation. Gene deletion and in silico analysis further delineated the candidate genes. CONCLUSIONS: We have significantly refined Candq1 (now designated determinant of collateral extent 1; Dce1), demonstrated that genetic background-dependent variation in collaterals is a major factor underlying differences in ischemic tissue injury, and generated a congenic strain set with wide allele dose-dependent variation in collateral extent for use in investigations of the collateral circulation.
Assuntos
Encéfalo/irrigação sanguínea , Mapeamento Cromossômico/métodos , Circulação Colateral/genética , Membro Posterior/irrigação sanguínea , Infarto da Artéria Cerebral Média/genética , Isquemia/genética , Animais , Modelos Animais de Doenças , Feminino , Genômica/métodos , Haplótipos , Heterozigoto , Infarto da Artéria Cerebral Média/fisiopatologia , Isquemia/fisiopatologia , Masculino , Camundongos , Camundongos Congênicos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Locos de Características QuantitativasRESUMO
OBJECTIVE: Therapeutic arteriogenesis, that is, expansive remodeling of preexisting collaterals, using single-action factor therapies has not been as successful as anticipated. Modulation of factors that act as a master switch for relevant gene programs may prove more effective. Transcriptional coactivator p300-CBP-associated factor (PCAF) has histone acetylating activity and promotes transcription of multiple inflammatory genes. Because arteriogenesis is an inflammation-driven process, we hypothesized that PCAF acts as multifactorial regulator of arteriogenesis. APPROACH AND RESULTS: After induction of hindlimb ischemia, blood flow recovery was impaired in both PCAF(-/-) mice and healthy wild-type mice treated with the pharmacological PCAF inhibitor Garcinol, demonstrating an important role for PCAF in arteriogenesis. PCAF deficiency reduced the in vitro inflammatory response in leukocytes and vascular cells involved in arteriogenesis. In vivo gene expression profiling revealed that PCAF deficiency results in differential expression of 3505 genes during arteriogenesis and, more specifically, in impaired induction of multiple proinflammatory genes. Additionally, recruitment from the bone marrow of inflammatory cells, in particular proinflammatory Ly6C(hi) monocytes, was severely impaired in PCAF(-/-) mice. CONCLUSIONS: These findings indicate that PCAF acts as master switch in the inflammatory processes required for effective arteriogenesis.
Assuntos
Arterite/fisiopatologia , Isquemia/fisiopatologia , Neovascularização Fisiológica/imunologia , Fatores de Transcrição de p300-CBP/genética , Fatores de Transcrição de p300-CBP/imunologia , Acetilação , Animais , Arterite/imunologia , Arterite/metabolismo , Células Cultivadas , Modelos Animais de Doenças , Inibidores Enzimáticos/farmacologia , Regulação da Expressão Gênica/imunologia , Membro Posterior/irrigação sanguínea , Histonas/metabolismo , Isquemia/imunologia , Isquemia/metabolismo , Camundongos , Camundongos Knockout , Monócitos/imunologia , Monócitos/patologia , Linfócitos T/imunologia , Linfócitos T/patologia , Terpenos/farmacologia , Transcriptoma , Fatores de Transcrição de p300-CBP/antagonistas & inibidoresRESUMO
OBJECTIVE: Heparin-binding epidermal growth factor-like growth factor (HB-EGF) is a potent mitogen for smooth muscle cells and has been implicated in atherosclerosis, tissue regeneration after ischemia, vascular development, and tumor angiogenesis. We examined the hypothesis that HB-EGF participates in angiogenesis and collateral growth in ischemia. METHODS AND RESULTS: During 3 weeks after femoral artery ligation, no attenuation occurred in recovery of hindlimb perfusion or distal saphenous artery flow in HB-EGF-null (HB-EGF(-/-)) versus wild-type mice. Lumen diameters of remodeled collaterals in gracilis muscle were similar by morphometry (87+/-8 versus 94+/-6 microm) and angiography, although medial thickening was reduced. Gastrocnemius muscle underwent comparable angiogenesis (41% and 33% increase in capillary-to-muscle fiber ratio). Renal renin mRNA, arterial pressure, and heart rate during anesthesia or conscious unrestrained conditions were similar between groups. These latter findings validate comparisons of perfusion data and also suggest that differences in arterial pressure and/or renin-angiotensin activity are not masking an otherwise inhibitory effect of HB-EGF absence. Four days after ligation, EGF receptor phosphorylation increased in muscle by 104% in wild-type but by only 30% in HB-EGF(-/-) mice. This argues against compensation by other EGF receptor ligands. CONCLUSIONS: Our results suggest that HB-EGF is not required for arteriogenesis or angiogenesis in hindlimb ischemia.
Assuntos
Fator de Crescimento Epidérmico/fisiologia , Isquemia/fisiopatologia , Neovascularização Fisiológica/fisiologia , Animais , Cardiomegalia/genética , Cardiomegalia/fisiopatologia , Fator de Crescimento Epidérmico/genética , Receptores ErbB/metabolismo , Artéria Femoral/fisiologia , Fator de Crescimento Semelhante a EGF de Ligação à Heparina , Membro Posterior/irrigação sanguínea , Peptídeos e Proteínas de Sinalização Intercelular , Isquemia/genética , Ligadura , Camundongos , Camundongos Mutantes , Músculo Esquelético/irrigação sanguínea , Fenótipo , FosforilaçãoRESUMO
Nonsteroidal anti-inflammatory drugs (NSAIDs) have been shown to have chemopreventive activity, but the mechanisms involved are not clearly understood. Although NSAIDs inhibit cyclooxygenase activity, they also increase the expression of a divergent member of the transforming growth factor-beta superfamily, termed NSAID-activated gene 1 (NAG-1), a protein with an antitumorigenic and proapoptotic activity that could in part be linked to the chemoprevention activity of NSAIDs. NAG-1 is induced by some NSAIDs, but the mechanisms responsible are not clear. In this report, we have identified a cis-acting element responsive to NSAIDs located within the -73 to -51 region of the NAG-1 promoter. This region contains overlapping EGR-1 and Sp1 binding sites, and mutations in this region suggest that the transcription factors have an important role in NSAID-induced NAG-1 expression. EGR-1 was found to play a critical role in the induction of NAG-1 by sulindac sulfide and other NSAIDs. NSAIDs increase EGR-1 protein expression that occurs before the induction of NAG-1 expression, supporting the hypothesis that EGR-1 is necessary for NSAID-induced NAG-1 expression. Thus, NSAIDs induce the expression of EGR-1, a tumor suppressor gene, providing a novel mechanism to explain, in part, the antitumorigenic properties of some NSAIDs. NAG-1 seems to be an important downstream target protein of this transcription factor, EGR-1, and may mediate the chemopreventive activity of some NSAIDs.
Assuntos
Antineoplásicos/metabolismo , Inibidores de Ciclo-Oxigenase/farmacologia , Citocinas/biossíntese , Proteínas de Ligação a DNA/biossíntese , Proteínas de Ligação a DNA/genética , Genes Supressores de Tumor/efeitos dos fármacos , Proteínas Imediatamente Precoces/biossíntese , Proteínas Imediatamente Precoces/genética , Fatores de Transcrição/biossíntese , Fatores de Transcrição/genética , Regulação para Cima/efeitos dos fármacos , Anti-Inflamatórios não Esteroides/farmacologia , Linhagem Celular Tumoral , Citocinas/genética , Citocinas/fisiologia , Proteínas de Ligação a DNA/fisiologia , Proteína 1 de Resposta de Crescimento Precoce , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/fisiologia , Genes Supressores de Tumor/fisiologia , Fator 15 de Diferenciação de Crescimento , Humanos , Proteínas Imediatamente Precoces/fisiologia , Regiões Promotoras Genéticas/efeitos dos fármacos , Fatores de Transcrição/fisiologia , Regulação para Cima/fisiologia , Dedos de Zinco/efeitos dos fármacos , Dedos de Zinco/fisiologiaRESUMO
Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used for their anti-inflammatory effects and have been shown to have chemopreventive effects as well. NSAIDs inhibit cyclooxygenase (COX) activity to exert their anti-inflammatory effects, but it is not clear whether their antitumorigenic ability is through COX inhibition. Using subtractive hybridization, we previously identified a novel member of the transforming growth factor-beta superfamily that has antitumorigenic activity from indomethacin-treated HCT-116 human colorectal cancer cells. On further investigation of this library, we now report the identification of a new cDNA corresponding to the thymosin beta-4 gene. Thymosin beta-4 is a small peptide that is known for its actin-sequestering function, and it is associated with the induction of angiogenesis, accelerated wound healing, and metastatic potential of tumor cells. However, only selective NSAIDs induce thymosin beta-4 expression in a time- and concentration-dependent manner. For example, indomethacin and SC-560 [5-(4-chlorophenyl)-1-(4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazole] induce thymosin beta-4 expression whereas sulindac sulfide does not. We show that selective NSAIDs induce actin cytoskeletal reorganization, a precursory step to many dynamic processes regulating growth and motility including tumorigenesis. This is the first report to link thymosin beta-4 induction with NSAIDs. These data suggest that NSAIDs alter the expression of a diverse number of genes and provide new insights into the chemopreventive and biological activity of these drugs.