E3 ubiquitin ligase Cblb regulates the acute inflammatory response underlying lung injury.

The E3 ubiquitin ligase Cblb has a crucial role in the prevention of chronic inflammation and autoimmunity. Here we show that Cblb also has an unexpected function in acute lung inflammation. Cblb attenuates the sequestration of inflammatory cells in the lungs after administration of lipopolysaccharide (LPS). In a model of polymicrobial sepsis in which acute lung inflammation depends on the LPS receptor (Toll-like receptor 4, TLR-4), the loss of Cblb expression accentuates acute lung inflammation and reduces survival. Loss of Cblb significantly increases sepsis-induced release of inflammatory cytokines and chemokines. Cblb controls the association between TLR4 and the intracellular adaptor MyD88. Expression of wild-type Cblb, but not expression of a Cblb mutant that lacks E3 ubiquitin ligase function, prevents the activity of a reporter gene for the transcription factor nuclear factor-kappaB (NF-kappaB) in monocytes that have been challenged with LPS. The downregulation of TLR4 expression on the cell surface of neutrophils is impaired in the absence of Cblb. Our data reveal that Cblb regulates the TLR4-mediated acute inflammatory response that is induced by sepsis.

Caveolin-1 deficiency dampens Toll-like receptor 4 signaling through eNOS activation.

Caveolin-1 (Cav1), the scaffolding protein of caveolae, has been shown to play an important role in host defense and inflammation. However, the underlying molecular basis for these actions remains elusive. Here, using double mutant mice with genetic deletions of Cav1 and NOS3, we show that chronic endothelial nitric oxide synthase (eNOS) activation secondary to loss of Cav1 serves a crucial immunomodulatory function through tyrosine nitration-mediated impairment of interleukin-1 receptor associated kinase (IRAK)4, a signaling component required for nuclear factor-kappaB activation and innate immunity. We observed an eNOS-dependent decrease in the plasma concentration of pro-inflammatory cytokines and marked improvement of survival in Cav1(-/-) mice following lipopolysaccharide challenge. Activation of eNOS secondary to loss of Cav1 resulted in decreased activation of nuclear factor-kappaB in response to lipopolysaccharide challenge, and thereby protected the animals from lipopolysaccharide-induced lung injury. IRAK4 was prominently nitrated in Cav1-deficient endothelial cells, whereas eNOS deletion in Cav1-deficient endothelial cells resulted in marked decrease of IRAK4 nitration and restored the inflammatory response after lipopolysaccharide challenge. Furthermore, in vitro nitration of IRAK4 resulted in impairment of the kinase activity. Thus, eNOS activation secondary to loss of Cav1 signals dampening of the innate immune response to lipopolysaccharide through IRAK4 nitration and the resultant impairment of kinase activity, and consequently mitigates inflammatory lung injury.

Requirement of alpha(4)beta(1) and alpha(5)beta(1) integrin expression in bone-marrow-derived progenitor cells in preventing endotoxin-induced lung vascular injury and edema in mice.

The goal of this study was to determine the role of integrin-mediated adhesion of bone-marrow-derived progenitor cells (BMPCs) as a requirement for the endothelial barrier protection in a lung injury model. C57BL mice were used as the source for BMPCs, which were characterized as CD34(+) and fetal liver kinase-1 (Flk1)(+) and also an expression of a repertoire of integrins. We used a mouse model of bacterial lipopolysaccharide (LPS)-induced lung vascular injury and edema formation to test the effects of BMPC integrin expression in preventing endothelial barrier injury. Adhesion of BMPCs to purified extracellular matrix proteins induced focal adhesion kinase (Fak) phosphorylation and formation of branching point structures in a alpha(4) and alpha(5) integrin-dependent manner. BMPCs expressing red fluorescent protein (RFP) were administered via the retro-orbital venous route in mice treated intraperitonially with LPS (7.5 mg/kg body weight). We observed increased retention of RFP-labeled Flk1(+) and CD34(+) BMPCs for up to 8 weeks in mice injured with LPS. BMPC transplantation increased survival by 50% (at 72-96 hours after LPS) and reduced lung vascular injury and extravascular water content induced by LPS. However, blocking with anti-alpha(4) or anti-alpha(5) integrin antibody or shRNA-mediated silencing of alpha(4) or alpha(5) integrins in donor BMPCs failed to prevent the vascular injury or edema formation and mortality. Thus, alpha(4) and alpha(5) integrin-dependent adhesion of BMPCs in lung tissue plays a critical role in preventing lung vascular injury and increasing survival in a mouse model of LPS-induced acute lung injury.

Gastric adenocarcinoma arising from fundic gland polyps in a patient with familial adenomatous polyposis syndrome.

Familial adenomatous polyposis (FAP) is a rare hereditary syndrome characterized by multiple colorectal polyps and early development of colorectal cancer. Although FAP uniformly involves the large bowel, it may also produce lesions in the stomach and upper intestinal tract. Fundic gland polyps are the most common gastric lesion in FAP. In the general population, these polyps are considered benign and have no malignant potential. However, in FAP patients, fundic gland polyps have been occasionally recognized as precursor lesions from which invasive cancer may develop. Herein, we present a case of gastric adenocarcinoma arising from fundic gland polyps in an FAP patient. We also review reported cases of gastric cancer in FAP and FAP variant patients in an effort to better understand the pathology, clinical course, and optimal screening and treatment strategies for this disease manifestation.

Inhibition of proliferation by omega-3 fatty acids in chemoresistant pancreatic cancer cells.

BACKGROUND: Pancreatic cancer-gemcitabine (GEM) chemoresistance has been demonstrated to be associated with enhanced NF-kB activation and antiapoptotic protein synthesis. The well-known capacity of omega-3 fatty acids (n-3 FAs) to inhibit NF-kB activation and promote cellular apoptosis has the potential to restore or facilitate gemcitabine chemosensitivity. METHODS: Four pancreatic cancer cell lines (MIA PaCa-2, BxPC-3, PANC-1, and L3.6), each with distinct basal NF-kB and differing GEM sensitivity profiles, were administered: 100 uM of (1) n-3FA, (2) n-6FA, (3) GEM, (4) n-3FA + GEM, or (5) n-6FA + GEM for 24 and 48 hours. Proliferation was assessed using the WST-1 assay. To define the mechanism(s) of altered proliferation, electron mobility shift assay for NF-kB activity, western blots of phoshoStat3, phosphoIkappaB, and poly(ADP-ribose) polymerase (PARP) cleavage were performed in the MIA PaCa-2 cell line. RESULTS: All cell lines demonstrated a time/dose-dependent inhibition of proliferation in response to n-3FA. For MIA PaCa-2 cells, n-3FA and n-3FA + GEM treatment resulted in reduction of I-kB phosphorylation and NF-kB activation when compared with n-6FA control. n-3FA and combination treatment also significantly decreased Stat3 phosphorylation, whereas GEM alone had no effect. n-3FAs and n-3FA + GEM groups demonstrated increased PARP cleavage, mirroring NF-kB activity and Stat3 phosphorylation. CONCLUSIONS: n-3 FA treatment is specifically associated with inhibition of proliferation in these four pancreatic cell lines irrespective of varied gemcitabine resistance. An experimental paradigm to screen for potential contributory mechanism(s) in altered pancreatic cancer cellular proliferation was defined, and using this approach the co-administration of n-3 FA with GEM inhibited GEM-induced NF-kB activation and restored apoptosis in the MIA PaCa-2 cell-line.

Complete eradication of hepatic metastasis from colorectal cancer by Yttrium-90 SIRT.

Yttrium-90 (Y-90) radioembolization, also known as selective internal radiation therapy (SIRT), is a regional hepatic therapy used in the treatment of unresectable colorectal cancer (CRC) liver metastases. In SIRT, Y-90 impregnated microspheres are injected into the VASCULAR SUPPLY of hepatic tumor, leading to selective irradiation and necrosis of tumor TISSUE. While several studies demonstrate improved local control and survival with SIRT, the specific indications for this therapy have yet to be defined. Typically, SIRT is given in combination with chemotherapy as multimodal treatment for unresectable hepatic CRC. However, it has also found increasing use as a salvage therapy in chemo-refractory patients. Herein, the authors describe their experience with SIRT as "stand alone" therapy in a surgically-prohibitive, chemotherapy naive patient with hepatic CRC metastasis. The results suggest that Y-90 SIRT may have potential applications beyond its usual role as a palliative or salvage therapy for unresectable hepatic CRC.

Yttrium-90 internal radiation therapy for hepatic malignancy.

Surgical resection is the only potentially curative strategy in the treatment of patients with hepatic malignancy. Unfortunately, due to advanced stage, underlying liver disease, or medical comorbidities, most patients are inoperable at the time of presentation. As a result, various locoregional therapies have emerged for otherwise unresectable hepatic tumors. One such modality is Yttrium-90 (Y(90)) internal radiation therapy. Numerous studies demonstrate the safety and potential survival benefit of intra-arterial Y(90) for primary and metastatic liver tumors. However, more data is needed in order to understand the exact role of Y(90) in the algorithm of hepatic tumor management. This review presents the available literature on Y(90) with the aim of defining the current status of Y(90) in the armamentarium of therapeutic strategies for hepatic malignancy.

Small bowel obstruction from breast cancer metastasis: a case report and review of the literature.

Small bowel obstruction from luminal gastrointestinal metastasis is a rare, but recognized, presentation of metastatic breast cancer. Herein, we report a case of a small bowel obstruction from lobular breast cancer metastasis to the terminal ileum, occurring over a decade after diagnosis and treatment of the initial primary cancer. Our review highlights the presentation and management of this unusual disease manifestation, including diagnosis of the gastrointestinal process, identification of the primary cancer, surgical treatment of the abdominal pathology, systemic therapy for metastatic disease, and survival data for patients with this disease process.

Radiofrequency ablation of primary and metastatic liver tumors: a critical review of the literature.

BACKGROUND: Surgical resection is the treatment of choice for hepatic tumors; however, for various reasons, the vast majority of patients are not operative candidates. As a result, several local ablative therapies have emerged as alternatives to resection or as adjuncts in total oncologic care. Presently, the most widely employed liver-directed treatment is radiofrequency thermal ablation. METHODS: To define the current status of radiofrequency ablation (RFA), the authors reviewed available safety and efficacy data from select studies on RFA. A MEDLINE search was performed using the keywords "tumor type" + "radiofrequency ablation" + "survival." Only those studies containing long-term survival data on greater than 50 patients were included in this analysis. CONCLUSIONS: Although RFA has been readily adopted into treatment paradigms, more rigorous trials are needed to solidify its place in the armamentarium of therapeutic strategies for hepatic malignancy.

A primer on transarterial, chemical, and thermal ablative therapies for hepatic tumors.

BACKGROUND: Surgical resection is the only potentially curative approach for patients with primary and metastatic liver tumors. Unfortunately, most patients with hepatic malignancy are precluded from resection due to multifocal disease, anatomic limitations, inadequate functional liver reserve, extrahepatic metastases, or medical comorbidities. Consequently, several methods of tumor ablation have been developed as alternate treatment strategies for patients with unresectable hepatic tumors or as adjuncts in total cancer therapy. The purpose of this review is to inclusively define the various ablation modalities available (transarterial, chemical, and thermal ablative), and to describe the procedures, general applications, and reported outcomes. DATA SOURCES: A MEDLINE and CINAHL search of the English-language literature was performed on transarterial, chemical, and thermal ablative therapies. CONCLUSIONS: Presently, radiofrequency thermal ablation is the most widely applicable liver-directed modality for hepatic tumor ablation, enabling treatment of primary and metastatic tumors. However, other transarterial and thermoablative techniques are available with accumulating data for their use. Lacking at present are studies that define the role and potential benefit of the various liver-directed modalities in the treatment algorithm for hepatic tumors.

Caveolin-1 regulates NF-kappaB activation and lung inflammatory response to sepsis induced by lipopolysaccharide.

Caveolin-1, the principal structural and signaling protein of caveolae, is implicated in NO-mediated cell signaling events, but its precise role in inflammation is not well understood. Using caveolin-1-knockout (Cav-1(-/-)) mice, we addressed the role of caveolin-1 in the lung inflammatory response to sepsis induced by i.p. injection of LPS. LPS-challenged wild-type (WT) lungs exhibited significant increases in neutrophil sequestration (approximately 16-fold), lung microvascular permeability K(f,c) (approximately 5.7-fold), and edema formation (approximately 1.6-fold). Compared with WT, Cav-1(-/-) lungs showed marked attenuation of LPS-induced neutrophil sequestration (approximately 11-fold increase) and inhibition of microvascular barrier breakdown and edema formation. Prevention of lung injury in Cav-1(-/-) mice was associated with decreased mortality in response to LPS challenge. To address the basis of the reduced inflammation and injury in Cav-1(-/-) lungs, we examined the role of NO because its plasma concentration is known to be increased in Cav-1(-/-) mice. Cav-1(-/-) mouse lungs demonstrated a significant increase in endothelial NO synthase (eNOS)-derived NO production relative to WT, which is consistent with the role of caveolin-1 as a negative regulator of eNOS activity. Cav-1(-/-) lungs concurrently showed suppression of NF-kappaB activity and decreased transcription of inducible NO synthase and ICAM-1. Coadministration of LPS with the NO synthase inhibitor nitro-L-arginine in Cav-1(-/-) mice prevented the suppression of NF-kappaB activity and restored lung polymorphonuclear leukocyte sequestration in response to LPS challenge. Thus, caveolin-1, through its ability to regulate eNOS-derived NO production, is a crucial determinant of NF-kappaB activation and the lung inflammatory response to LPS.

Sirolimus-associated interstitial pneumonitis in solid organ transplant recipients.

Sirolimus is a potent immunosuppressive agent used with increasing frequency in solid organ transplantation (SOT). However, it has been associated with rare but devastating pulmonary toxicity. We describe a case of pulmonary toxicity associated with the use of sirolimus in a 64-yr-old heart transplant recipient. We also review all reported cases of sirolimus-associated lung toxicity among SOT recipients in an effort to better understand the pathophysiology, risk factors, and outcomes of this rare but serious complication. A total of 64 cases have been reported since January 2000 including the present case. These consisted of 52 kidney, four lung, three liver, three heart, one heart-lung and one islet cell transplants. In most cases, patients presented with a constellation of symptoms consisting of fever, dyspnea, fatigue, cough, and occasionally hemoptysis. Although the risk factors for this association have not been clearly established, high dose, late exposure to the drug and male gender have been noticed among most. In almost all of the reported cases, sirolimus was added later in the course of immunosuppressive therapy, usually in an effort to attenuate the nephrotoxic effects of a previous regimen containing a calcineurin inhibitor. There were three deaths (4.8%) among 62 patients with known status at follow up; all deaths were among heart transplant recipients. Most patients (95%) resolved their clinical and radiographic findings with discontinuation or dose-reduction of the drug. Sirolimus-induced pulmonary toxicity is a rare but serious entity that should be considered in the differential diagnosis of a transplant recipient presenting with respiratory compromise. Dose-reduction or discontinuation of the drug can be life saving.