Severe disruption and disorganization of dermal collagen fibrils in early striae gravidarum.

BACKGROUND: Striae gravidarum (SG), or stretch marks of pregnancy, begin as erythematous streaks and mature into hypopigmented atrophic bands. OBJECTIVES: In order to investigate molecular alterations that may promote atrophy of SG, we investigated dermal type I collagen fibrils, which provide human skin with support. METHODS: We obtained skin samples of recently developed, erythematous abdominal SG from pregnant women. To examine the organization of collagen fibrils, second-harmonic generation imaging was performed using multiphoton microscopy. Immunostaining was used to determine protein expression and localization of type I procollagen, the precursor of type I collagen fibrils. Real-time polymerase chain reaction was used to determine gene expression levels. RESULTS: In control (hip) and stretched normal-appearing perilesional abdominal skin, dermal collagen fibrils were organized as tightly packed, interwoven bundles. In SG, collagen bundles appeared markedly separated, especially in the mid-to-deep dermis. In the spaces separating these bundles, loosely packed wavy collagen fibrils lacking organization as bundles were present. These disorganized fibrils persisted into the postpartum period and failed to form densely packed bundles. Numerous large fibroblasts displaying type I procollagen expression were in close proximity to the disorganized fibrils, suggesting that the fibrils are newly synthesized. Supporting this possibility, immunostaining and gene expression of type I procollagen were increased throughout the dermis of SG. CONCLUSIONS: Early SG display marked separation of collagen bundles and emergence of disorganized collagen fibrils that fail to form bundles. These alterations may reflect ineffective repair of collagen bundles disrupted by intense skin stretching. Persistent disruption of the collagenous extracellular matrix likely promotes formation and atrophy of SG.

The balancing act of foraging: mammalian herbivores trade-off multiple risks when selecting food patches.

Animals face multiple risks while foraging such as the risk of acquiring inadequate energy from food and the risk of predation. We evaluated how two sympatric rabbits (pygmy rabbits, Brachylagus idahoensis, and mountain cottontail rabbits, Sylvilagus nuttallii) that differ in size, use of burrows, and habitat specialization in the sagebrush-steppe of western North America respond to different types and levels of perceived risks (i.e., fitness cost × probability of occurrence), including fiber and toxins in food, exposure to predation, and distance from a refuge. We measured food intake by the rabbits at paired food patches that varied in these risks and used the method of paired comparisons to create a relative ranking of habitat cues, which revealed an animal's perceived risk on a single scale representing an integrated response to a variety of risks. Pygmy rabbits perceived exposure to predation risk and distance from a burrow as riskier than did cottontails, whereas cottontails perceived dietary toxin as riskier. Pygmy rabbits consumed lower quality food, containing higher fiber or toxins, thereby avoided feeding in exposed patches or traveling far from their burrow to forage. In contrast, cottontails fed in exposed patches and traveled farther from the burrow to obtain higher quality food. We have shown how risks can be integrated into a single model that allows animals to reveal their perceptions of risks on a single scale that can be used to create a spatially explicit landscape of risk.

Marked disruption and aberrant regulation of elastic fibres in early striae gravidarum.

BACKGROUND: Striae gravidarum (SG), or 'stretch marks' of pregnancy, begin as erythematous streaks, and mature over months to years to become permanent scar-like bands that may be hypopigmented, atrophic and lax. OBJECTIVES: To investigate early molecular alterations that may promote laxity of mature SG, we investigated the dermal elastic fibre network, which provides human skin with elastic properties. METHODS: We obtained skin samples of newly developed, erythematous abdominal SG in healthy pregnant women. The elastic fibre network was examined by Verhoeff elastic staining and immunofluorescence staining of skin sections. Gene expression was measured by real-time polymerase chain reaction. RESULTS: The normal elastic fibre network appeared markedly disrupted in SG, compared with perilesional abdominal skin or control (normal-appearing hip skin). This disruption was accompanied by the emergence of short, disorganized, thin, thread-like 'fibrils', which were observed prominently in the mid-to-deep dermis. These fibrils were rich in tropoelastin (the main component of normal elastic fibres), and persisted into the postpartum period without forming normal-appearing elastic fibres. The emergence of these fibrils was accompanied by increased gene expression of tropoelastin and fibrillin-1, but not other elastic fibre components, including fibrillin-2 and fibulin-1, -2 or -5. CONCLUSIONS: In early SG, the elastic fibre network appears markedly disrupted, and newly synthesized tropoelastin-rich fibrils emerge, likely as a result of uncoordinated synthesis of elastic fibre components. Because they are thin and disorganized, tropoelastin-rich fibrils likely do not function as normal elastic fibres do. These observations provide the foundations for elucidating pathogenic mechanisms by which laxity may develop in SG.

Hypertension, snoring, and obstructive sleep apnoea during pregnancy: a cohort study.

OBJECTIVE: To assess the frequency of obstructive sleep apnoea among women with and without hypertensive disorders of pregnancy. DESIGN: Cohort study. SETTING: Obstetric clinics at an academic medical centre. POPULATION: Pregnant women with hypertensive disorders (chronic hypertension, gestational hypertension, or pre-eclampsia) and women who were normotensive. METHODS: Women completed a questionnaire about habitual snoring and underwent overnight ambulatory polysomnography. MAIN OUTCOME MEASURES: The presence and severity of obstructive sleep apnoea. RESULTS: Obstructive sleep apnoea was found among 21 of 51 women with hypertensive disorders (41%), but in only three of 16 women who were normotensive (19%, chi-square test, P=0.005). [Author correction added on 16 June 2014, after first online publication: Results mentioned in the abstract were amended.] Non-snoring women with hypertensive disorders typically had mild obstructive sleep apnoea, but >25% of snoring women with hypertensive disorders had moderate to severe obstructive sleep apnoea. Among women with hypertensive disorders, the mean apnoea/hypopnoea index was substantially higher in snorers than in non-snorers (19.9±34.1 versus 3.4±3.1, P=0.013), and the oxyhaemoglobin saturation nadir was significantly lower (86.4±6.6 versus 90.2±3.5, P=0.021). Among women with hypertensive disorders, after stratification by obesity, the pooled relative risk for obstructive sleep apnoea in snoring women with hypertension compared with non-snoring women with hypertension was 2.0 (95% CI 1.4-2.8). CONCLUSIONS: Pregnant women with hypertension are at high risk for unrecognised obstructive sleep apnoea. Although longitudinal and intervention studies are urgently needed, given the known relationship between obstructive sleep apnoea and hypertension in the general population, it would seem pertinent that hypertensive pregnant women who snore should be tested for obstructive sleep apnoea, a condition believed to cause or promote hypertension.

Preclinical studies of a PARP targeted, Meitner-Auger emitting, theranostic radiopharmaceutical for metastatic ovarian cancer.

Advanced ovarian cancer currently has few therapeutic options. Poly(ADP-ribose) polymerase (PARP) inhibitors bind to nuclear PARP and trap the protein-inhibitor complex to DNA. This work investigates a theranostic PARP inhibitor for targeted radiopharmaceutical therapy of ovarian cancer in vitro and PET imaging of healthy mice in vivo. METHODS: [77Br]RD1 was synthesized and assessed for pharmacokinetics and cytotoxicity in human and murine ovarian cancer cell lines. [76Br]RD1 biodistribution and organ uptake in healthy mice were quantified through longitudinal PET/CT imaging and ex vivo radioactivity measurements. Organ-level dosimetry following [76/77Br]RD1 administration was calculated using RAPID, an in-house platform for absorbed dose in mice, and OLINDA for equivalent and effective dose in human. RESULTS: The maximum specific binding (Bmax), equilibrium dissociation constant (Kd), and nonspecific binding slope (NS) were calculated for each cell line. These values were used to calculate the cell specific activity uptake for cell viability studies. The half maximal effective concentration (EC50) was measured as 0.17 (95 % CI: 0.13-0.24) nM and 0.46 (0.13-0.24) nM for PARP(+) and PARP(-) expressing cell lines, respectively. The EC50 was 0.27 (0.21-0.36) nM and 0.30 (0.22-0.41) nM for BRCA1(-) and BRCA1(+) expressing cell lines, respectively. When measuring the EC50 as a function of cellular activity uptake and nuclear dose, the EC50 ranges from 0.020 to 0.039 Bq/cell and 3.3-9.2 Gy, respectively. Excretion through the hepatobiliary and renal pathways were observed in mice, with liver uptake of 2.3 ± 0.4 %ID/g after 48 h, contributing to estimated absorbed dose values in mice of 19.3 ± 0.3 mGy/MBq and 290 ± 10 mGy/MBq for [77Br]RD1 and [76Br]RD1, respectively. CONCLUSION: [77Br]RD1 cytotoxicity was dependent on PARP expression and independent of BRCA1 status. The in vitro results suggest that [77Br]RD1 cytotoxicity is driven by the targeted Meitner-Auger electron (MAe) radiotherapeutic effect of the agent. Further studies investigating the theranostic potential, organ dose, and tumor uptake of [76/77Br]RD1 are warranted.

[Unusual intensive care course in a patient with head injuries]. / Ungewöhnlicher intensivmedizinischer Verlauf bei einem Patienten nach Schädel-Hirn-Trauma.

This article reports the case of a patient who developed a sudden impairment of gas exchange, renal function and a distended abdomen 13 days after admission to the intensive care unit. The combination of a sudden platelet drop, the timing of heparin administration and evidence of thromboembolic events by computed tomography (CT) led to the suspected diagnosis of heparin-induced thrombocytopenia (HIT) type II which was confirmed by laboratory testing. HIT is a life-threatening complication of heparin anticoagulation and CT is an important diagnostic instrument for detecting the location and extent of thromboembolic manifestations, thereby enabling the initiation of therapy to prevent further complications.

Ribosome processing in HeLa cells. Studies on structural aspects of precursor and mature ribosomes.

Mature ribosomes, their subunits, and their ribonucleoprotein precursors were extracted from HeLa cells and prepared for electron microscopy by a method based on adsorption of nucleic acid to a charged grid. Images so obtained revealed the presence of two types of ribonuclease-sensitive fibrils of consistent morphology. One of these types of fibril is present on the 80S and 55S nucleolar ribonucleoprotein precursors and the mature 60S subunit. The other type is restricted to the 80S precursor. The morphology of the fibrils and their distribution in the various preparations suggest identification with known secondary structural features of isolated pre-rRNA.

Treatment and prevention of rat glioblastoma by immunogenic C6 cells expressing antisense insulin-like growth factor I RNA.

Rat C6 glioma cells express insulin-like growth factor I (IGF-I) and form rapidly growing tumors in syngeneic animals. When transfected with an episome-based vector encoding antisense IGF-I complementary DNA, these cells lost tumorigenicity. Subcutaneous injection of IGF-I antisense-transfected C6 cells into rats prevented formation of both subcutaneous tumors and brain tumors induced by nontransfected C6 cells. The antisense-transfected cells also caused regression of established brain glioblastomas when injected at a point distal to the tumor. These antitumor effects result from a glioma-specific immune response involving CD8+ lymphocytes. Antisense blocking of IGF-I expression may reverse a phenotype that allows C6 glioma cells to evade the immune system.

[An unusual breast tumor]. / Ein ungewöhnlicher Mammatumor.

The presented case shows how difficult it can be to diagnose rare diseases if they present with masses in atypical locations. In an extensive further diagnostic workup other characteristic findings then point to the correct diagnosis.

Dual-energy CT angiography of the lung in patients with suspected pulmonary embolism: initial results.

To evaluate the feasibility of dual-energy CT angiography (CTA) of the lung in patients with suspected pulmonary embolism (PE). 24 patients with suspected PE were examined with a single-acquisition, dual-energy CTA protocol (A-system: 140 kV/65 mAsref, B-system: 80kV/190 mAsref) on a dual-source CT system. Lung perfusion was visualized by color-coding voxels containing iodine and air using dedicated dual-energy postprocessing software. Perfusion defects were classified by two blinded radiologists as being consistent or non-consistent with PE. Subjective image quality of perfusion maps and CTA was rated using a 5-point scale (1: excellent, 5: poor). The reading of a third independent radiologist served as the standard of reference for the diagnosis of PE. In all patients with PE (n=4), perfusion defects classified as being consistent with PE were identified in lung areas affected by PE. Both readers did not record perfusion defects classified as being consistent with PE in any of the patients without PE. Thus, on a per patient basis the sensitivity and specificity for the assessment of PE was 100% for both readers. On a per segment basis the sensitivity and specificity ranged between 60-66.7% and 99.5-99.8%. The interobserver agreement was good (k= 0.81). Perfusion defects rated as non-consistent with PE were most frequently caused by streak artifacts from dense contrast material in the great thoracic vessels. The median score of the image quality of both the perfusion maps and CTA was 2. In conclusion, dual-energy CTA of pulmonary embolism is feasible and allows the assessment of perfusion defects caused by pulmonary embolism. Further optimization of the injection protocol is required to reduce artifacts from dense contrast material.

Predictive value of PET-CT imaging versus AGO-scoring in patients planned for cytoreductive surgery in recurrent ovarian cancer.

OBJECTIVE: To assess the predictive value of positron emission tomography computed tomography (PET-CT) imaging in comparison to AGO-scoring in patients planned for cytoreductive surgery in recurrent ovarian cancer. MATERIALS AND METHODS: 33 patients who had received a PET-CT for suspicion of recurrent ovarian cancer between 12/2003 and 08/2007 were included in the retrospective analysis. Indication for PET-CT was based on blood tumor markers Ca 125 or Ca 72-4 and clinical symptoms. Scanning was performed on a Philips Gemini System covering the body from the neck to the thighs one hour after administration of 200MBq fluorodesoxyglucose. PET-CT, surgery and the patient records were reviewed to analyze the predictive value of PET-CT in comparison to an AGO-scoring system based on clinical parameters with regard to the prediction of full resectability of abdominal tumor spread. RESULTS: The statistical analysis of this data showed a sensitivity of 73% (95% C.I., 39-94%) and specificity of 80% (95% C.I., 29-97%) for AGO-scoring with a positive predictive value of 89% and a negative predictive value of 57%. PET-CT achieved a sensitivity of 100% (95% C.I., 72-100%) and specificity of 60% (95% C.I. 15-94%), with a positive predictive value of 85% and negative predictive value of 100%. Further analysis of the data of operated patients with concordant PET-CT and AGO-score (12/16) showed a very good prediction of full resectability with a sensitivity of 100% (95% C.I., 63-100%), specificity of 75% (95% C.I., 20-96%), positive predictive value of 89% and negative predictive value of 100%. CONCLUSION: PET-CT and the AGO-score offer good tools to determine patients for full resectability in recurrent ovarian cancer. PET-CT has a higher negative and the AGO score a higher positive predictive value, and the combination of both improves the diagnostic accuracy.

A novel mitogen-activated protein kinase phosphatase is an important negative regulator of lipopolysaccharide-mediated c-Jun N-terminal kinase activation in mouse macrophage cell lines.

We have isolated a cDNA homologous to known dual-specificity phosphatases from a mouse macrophage cDNA library and termed it MKP-M (for mitogen-activated protein kinase phosphatase isolated from macrophages). Three other presumed splice variant isoforms have also been identified for MKP-M. The longest and most abundant mRNA contains an open reading frame corresponding to 677 amino acids and produces an 80-kDa protein. The deduced amino acid sequence of MKP-M is most similar to those of hVH-5 (or mouse M3/6) and VHP1, a Caenorhabditis elegans tyrosine phosphatase. It includes an N-terminal rhodanase homology domain, the extended active-site sequence motif (V/L)X(V/I)HCXAG(I/V)SRSXT(I/V)XXAY(L/I)M (where X is any amino acid), and a C-terminal PEST sequence. Northern blot analysis revealed a dominant MKP-M mRNA species of approximately 5.5 kb detected ubiquitously among all tissues examined. MKP-M was constitutively expressed in mouse macrophage cell lines, and its expression levels were rapidly increased by lipopolysaccharide (LPS) stimulation but not by tumor necrosis factor alpha (TNF-alpha), gamma interferon, interleukin-2 (IL-2), or IL-15 stimulation. Immunocytochemical analysis showed MKP-M to be present within cytosol. When expressed in COS7 cells, MKP-M blocks activation of mitogen-activated protein kinases with the selectivity c-Jun N-terminal kinase (JNK) >> p38 = extracellular signal-regulated kinase. Furthermore, expression of a catalytically inactive form of MKP-M in a mouse macrophage cell line increased the intensity and duration of JNK activation and TNF-alpha secretion after LPS stimulation, suggesting that MKP-M is at least partially responsible for the desensitization of LPS-mediated JNK activation and cytokine secretion in macrophages.

Inhibitors of blood coagulation factors Xa and IIa synergize to reduce thrombus weight and thrombin generation in vivo and in vitro.

BACKGROUND: Many compounds currently in development for treatment of thrombotic disorders demonstrate high specificity for single targets of blood coagulation such as factor Xa (FXa) or thrombin. AIM: The aim of this study is to determine if inhibition of both FXa and thrombin by simultaneous administration of PD0313052 and argatroban, respectively, synergistically increases the effect of either drug alone in vivo and in vitro. METHODS AND RESULTS: Analyses of thrombin generation from combined inhibition in human plasma using statistical methods of Bliss independence identified a synergistic reduction in thrombin production 30% lower than predicted by simple additivity. The greatest synergy occurred at concentrations of each compound below their individual IC50 values. In a rabbit arterio-venous shunt model (RAV) of thrombosis, co-administration of PD0313052 and argatroban reduced thrombus weight (TW) to a much greater degree than expected by additivity alone producing a synergistic decrease of 45% over the level predicted by additivity. Analyses of thrombin generation in plasma samples from the RAV also demonstrated 38% synergy ex vivo. Furthermore, at plasma concentrations with the greatest synergistic effect, no increase in bleeding or appreciable change in prothrombin time, activated partial thromboplastin time, or activated clotting time was observed, but thrombus weight reduction was greater than twofold higher than that expected from simple additivity. CONCLUSIONS: These results demonstrate a significant synergistic antithrombotic effect of combining low doses of PD0313052 and argatroban and support the hypothesis that simultaneous targeting of multiple coagulation enzymes may offer an improved therapeutic index in the prevention and treatment of thrombosis.

[Quantification of right ventricular function in congenital heart disease: correlation of 3D echocardiography and MRI as complementary methods]. / Quantifizierung der rechtsventrikulären Funktion bei angeborenen Herzfehlern: Korrelation von 3D-Echokardiographie und MRT als sich ergänzende Methoden.

PURPOSE: In congenital heart disease, the exact determination of the right ventricular function is of high importance for therapeutic and especially surgical planning. The aim of this study was to correlate the parameters of the right ventricular function in MRI and 3D echocardiography to determine the agreement of both modalities. MATERIALS AND METHODS: In 18 patients suffering from congenital heart disease, 3D echocardiography was performed using a Philips Sonos 7500 system. In MRI short axis slices with a 4-mm distance were acquired using an SSFP sequence on a Siemens Sonata or Symphony System. Volumetry for both modalities was performed on an external workstation (Tomtec) using the EchoView software. RESULTS: Enddiastolic and endsystolic volumes showed a highly significant correlation with coefficients of 0.996 and 0.990, respectively. In echocardiography there was a systematic slight underestimation of enddiastolic volumes and overestimation of endsystolic volumes. The Wilcoxon test did not show significant differences between the volumes and ejection fractions assessed by both modalities. CONCLUSION: There is an excellent correlation in the quantification of right ventricular volumes in MRI and 3D echocardiography, which allows a comparison of acquired volumes in clinical follow-up.

DX-8951f, a hexacyclic camptothecin analog, on a daily-times-five schedule: a phase I and pharmacokinetic study in patients with advanced solid malignancies.

PURPOSE: To assess the feasibility of administering DX-8951f (exatecan mesylate), a water-soluble, camptothecin analog, as a 30-minute intravenous infusion daily for 5 days every 3 weeks, determine the maximum-tolerated dose (MTD) and pharmacokinetic (PK) behavior of DX-8951f, and seek preliminary evidence of anticancer activity. PATIENTS AND METHODS: Patients with advanced solid malignancies were treated with escalating doses of DX-8951f. After three patients were treated at the first dose level, doses were to be escalated in increments of 100%, using a single patient at each dose level unless moderate toxicity was observed. The MTD, defined as the highest dose level at which the incidence of dose-limiting toxicity did not exceed 20%, was calculated separately for minimally pretreated (MP) and heavily pretreated (HP) patients. The PK and excretory profiles of DX-8951, the anhydrous form of DX-8951f, were also characterized. RESULTS: Thirty-six patients were treated with 130 courses of DX-8951f at six dose levels ranging from 0.1 to 0.6 mg/m(2)/d. Brief, noncumulative neutropenia was the most common toxicity observed. Severe myelosuppression (neutropenia that was protracted and/or associated with fever and/or severe thrombocytopenia) was consistently experienced by HP and MP patients at doses exceeding 0.3 and 0.5 mg/m(2)/d, respectively. Nonhematologic toxicities (nausea, vomiting, and diarrhea) were also observed, but these effects were rarely severe. Objective antitumor activity included partial responses in one patient each with platinum-resistant extrapulmonary small-cell and fluoropyrimidine- and irinotecan-resistant colorectal carcinoma, and minor responses in patients with prostate, hepatocellular, thymic, primary peritoneal, and irinotecan-resistant colorectal carcinomas. The PKs of total DX-8951 were linear and well fit by a three-compartment model. CONCLUSION: The recommended doses for phase II studies of DX-8951f as a 30-minute infusion daily for 5 days every 3 weeks are 0.5 and 0.3 mg/m(2)/d for MP and HP patients, respectively. The characteristics of the myelosuppressive effects of DX-8951f, paucity of severe nonhematologic toxicities, and antitumor activity against a wide range of malignancies warrant broad disease-directed evaluations of DX-8951f on this schedule.

A phase I and pharmacokinetic study of 1843U89, a noncompetitive inhibitor of thymidylate synthase, in patients with advanced solid malignancies.

This study was performed to assess the feasibility of administering 1843U89, a potent, noncompetitive inhibitor of thymidylate synthase that does not require polyglutamation for activity, as a 2-min i.v. infusion daily for 5 days every 3 weeks, to determine whether folic acid supplementation ameliorates the toxic effects of 1843U89 and permits further dose escalation, and to recommend doses of 1843U89 administered without and with folic acid for further clinical evaluations. The study also sought to characterize the pharmacokinetic behavior of 1843U89 and to seek preliminary evidence of anticancer activity. Patients with advanced solid malignancies were treated with escalating doses of 1843U89 as a 2-min i.v. infusion daily for 5 days every 3 weeks. Initially, patients were treated in the absence of high-dose folic acid until dose-limiting toxicity was consistently noted. Next, patients were treated with escalating doses of 1843U89 preceded by 1000 mg of folic acid administered p.o. 30 min before each of the 5 daily doses of 1843U89. Patients (32) received 101 total courses of 1843U89 at doses ranging from 1 to 6 mg/m(2)/day with and without folic acid. At the 2 mg/m(2)/day dose level without folic acid, 2 of 7 new patients experienced dose-limiting toxicity, principally neutropenia, mucositis, and malaise in 3 of 11 courses. 1843U89 doses were further increased with folic acid to 6 mg/m(2)/day, but repetitive treatment was not feasible at this dose level because of an unacceptable high incidence of severe neutropenia and mucositis. Other toxicities included thrombocytopenia, rash, and fever. In contrast, repetitive treatment at the 5 mg/m(2)/day dose level was feasible. The pharmacokinetics of 1843U89 were neither dose dependent nor affected by folic acid. On day 1, clearance, terminal half-life, and steady-state volume of distribution values averaged 47.1 +/- 21.7 ml/min/m(2), 7.72 +/- 4.09 h, and 16.7 +/- 8.8 liter/m(2)/h, respectively. The results of the study indicate that the administration of 1843U89 as a 2-min infusion daily for 5 days every 3 weeks without and with folic acid is feasible at 1843U89 doses as high as 2 and 5 mg/m(2)/day, respectively. Because folic acid pretreatment results in no diminution of the antitumor activity of 1843U89 in preclinical studies and ameliorates the toxic effects of 1843U89 in both preclinical models and cancer patients, the therapeutic index of 1843U89 may be enhanced by folic acid pretreatment and, therefore, the development of 1843U89 with folic acid is warranted. However, the question of whether to administer 1843U89 at a dose of 2 mg/m(2)/day with folic acid, which is associated with negligible toxicity, or at its highest feasible dose with folic acid, 5 mg/m(2)/day, should be addressed in appropriately designed trials.

Reviewing the use of carbon monoxide-releasing molecules (CO-RMs) in biology: implications in endotoxin-mediated vascular dysfunction.

The inducible stress protein heme oxygenase-1 (HO-1) has been linked to tissue and organ protection against the deleterious actions of many pathological conditions, including endotoxin challenge. Similar protection can be achieved by the main products of heme oxygenase activity, namely bilirubin and carbon monoxide (CO). Since the identification of novel chemical compounds that liberate CO in biological systems (CO-releasing molecules or CO-RMs), our group and others have had access to a convenient and simple pharmacological tool that enables to study the role of CO in physiological functions. This article will review the scientific literature published to date on CO-RMs, with emphasis on the in vitro, ex vivo and in vivo experimental models employed to determine the contribution of CO to cellular mechanisms. In addition, we will report on the effect of heme oxygenase-related substances, such as bilirubin, CORM-3 and hemin, in a model of endotoxin-induced hypotension. Among the three different approaches examined, CORM-3 proved the most effective agent in reducing the fall in blood pressure caused by endotoxin. Furthermore, heme oxygenase-related substances affected the endotoxin-stimulated induction and distribution of hepatic HO-1 and inducible nitric oxide synthase (iNOS). Thus, it emerges that CO-RMs could exert important biological actions in the context of endotoxic-mediated dysfunction.