Recent epidemiological reports on Chinese population affected by novel coronavirus showed a wide spread of clinical and biochemical alterations, suggesting a relationship between progression of lung ...damage to acute respiratory distress syndrome and the systemic inflammatory response, triggering an irreversible multiple organ damage and disseminated intravascular coagulation. Bedside ultrasound assessment provides integrated information, describing a multisystemic and dynamic clinical scenario for every patient. Furthermore, this approach allows to concentrate multiple information in the hands of a single operator, also limiting the risk of exposure to infection for healthcare professionals. As per our experience, herewith reported, we described the characteristics of 10 patients with SARS-CoV-2 infection. Ultrasound findings were related to clinical information, blood test analysis, and results of instrumental tests, such as chest X-ray and chest CT. According to our ultrasound data, COVID-19 appears to be a systemic pathology even in those cases of mild to moderate disease. By this multisystem ultrasound approach, we could immediately recognize patients with a diffuse organ involvement and a more severe clinical pattern; moreover, we can protect healthcare workers and limit infection within health facilities.
Hepatic artery thrombosis (HAT) is one of the principal causes of morbidity and graft loss following liver transplantation. There are several risk factors for the development of HAT; technical ...aspects of the arterial anastomosis are important particularly for early thrombosis, but the improvement of surgical technique has lessened this problem. Apart from technical causes, other risk factors include a variety of conditions such as low donor/recipient age ratio, immunologic factors, clotting abnormalities, tobacco use, and infections. In particular, cytomegalovirus (CMV) infection of endothelial cells has been recently suggested as an infective cause of HAT, as it is known to be followed by a rapid procoagulant response. Thus, latent CMV in an allograft may become activated and promote or contribute to vascular thrombosis. This review evaluates these aspects, focusing on data relating CMV infection or viremia to HAT following liver transplantation. (
Live Transpl 2001;7:75-81.)
AIM： To investigate the effects of troglitazone （TGZ）, an anti-diabetic drug which activates peroxisome proliferatoractivated receptor-y （PPAR-y）, for liver tissue repair, and the development of ...ductular reaction, following common bile duct ligation （BDL） in rats. METHODS： Rats were supplemented with TGZ （0.2% w/w in the pelleted food） for i wk before BDL or sham operation. Animals were killed at 1, 2, or 4 wk after surgery. RESULTS： The development of liver fibrosis was reduced in rats receiving TGZ, as indicated by significant decreases of procollagen type I gene expression and liver hydroxyproline levels. Accumulation of a-smooth-muscle actin （SMA）-expressing cells surrounding newly formed bile ducts following BDL, as well as total hepatic levels of SMA were partially inhibited by TGZ treatment, indicating the presence of a reduced number and/or activation of hepatic stellate cells （HSC） and myofibroblasts. Development of the ductular reaction was inhibited by TGZ, as indicated by histochemical evaluation and hepatic activity of γ-glutamyltransferase （GGT）. CONCLUSION： Treatment with thiazolidinedione reduces ductular proliferation and fibrosis in a model of chronic cholestasis, and suggests that limiting cholangiocyte proliferation may contribute to the lower development of scarring in this system.
Following liver injury, hepatic stellate cells (HSC) undergo proliferation and migrate into damaged areas in response to chemotactic factors. HSC have been shown to regulate leukocyte trafficking by ...secreting monocyte chemotactic protein‐1 (MCP‐1), a chemokine that recruits monocytes and lymphocytes. In this study, we explored whether MCP‐1 exerts biological actions on HSC. HSC were isolated from normal human livers, cultured on plastic, and studied in their myofibroblast‐like phenotype, and three different cells lines were used. Chemotaxis was measured in modified Boyden chambers. Phosphatidylinositol 3‐kinase (PI 3‐K) was assayed on phosphotyrosine immunoprecipitates. Exposure of HSC to MCP‐1 stimulated migration of HSC in a dose‐dependent fashion. Maximal stimulation was obtained with 250 ng/mL MCP‐1, which resulted in a 3‐ to 4‐fold stimulation of cell migration. Checkerboard analysis showed that the increase in cell migration was almost completely a result of chemotaxis rather than chemokinesis. In contrast, in quiescent HSC, MCP‐1 did not exert any effect on cell migration. In leukocytes, MCP‐1 activates the pertussis toxin‐sensitive CCR2 receptor. However, transcripts for CCR2 could not be shown in HSC, and pertussis toxin only modestly inhibited MCP‐1‐induced migration. Exposure of HSC to MCP‐1 was associated with an increase in cytosolic calcium concentration, PI 3‐K activity, protein tyrosine phosphorylation. Blocking calcium influx or pretreatment of HSC with the PI 3‐K inhibitor wortmannin markedly reduced cell migration. This study shows, for the first time, a potential direct profibrogenic action of MCP‐1 via HSC chemotaxis. MCP‐1–dependent signals in these cells are not transduced by CCR2 and may be mediated by alternative chemokine receptors.
Background & Aims: Proliferation and migration of hepatic stellate cells (HSCs) and expression of chemokines are involved in the pathogenesis of liver inflammation and fibrogenesis. Peroxisome ...proliferator–activated receptor (PPAR)-γ is a receptor transcription factor that controls growth and differentiation in different tissues. We explored the effects of PPAR-γ agonists on the biological actions of cultured human HSCs. Methods: HSCs were isolated from normal human liver tissue and used in their myofibroblast-like phenotype or immediately after isolation. Activation of PPAR-γ was induced with 15-deoxy-Δ12,14-prostaglandin J2 or with troglitazone. Results: PPAR-γ agonists dose-dependently inhibited HSC proliferation and chemotaxis induced by platelet-derived growth factor. This effect was independent of changes in postreceptor signaling or expression of c-fos and c-myc and was associated with inhibition of cell cycle progression beyond the G1 phase. Activation of PPAR-γ also resulted in a complete inhibition of the expression of monocyte chemotactic protein 1 at the gene and protein levels. Comparison of quiescent and culture-activated HSCs revealed a marked decrease in PPAR-γ expression in activated cells. Conclusions: Activation of PPAR-γ modulates profibrogenic and proinflammatory actions in HSCs. Reduced PPAR-γ expression may contribute to confer an activated phenotype to HSCs.
GASTROENTEROLOGY 2000;119:466-478
Background: Bacterial infections have been postulated as a trigger for variceal bleeding in cirrhotic patients, and impair coagulation evaluated by thrombelastography (TEG). Endogenous heparinoids ...have been detected after variceal bleeding and during liver transplantation in some cirrhotics using heparinase-modified-TEG.
Aim: To assess if bacterial infection is associated with endogenous heparinoids in cirrhotics, thus impairing coagulation.
Methods: Native and heparinase-modified-TEG (cleavage of heparin and heparan-sulphate) was performed in 60 cirrhotics (Grade A, 2; B, 30; C, 28): 30 infected septicaemia, 6 (culture positive); 6 (culture negative); spontaneous bacterial peritonitis, 10; chest infection, 4; others, 4, 30 not infected, and five infected patients without liver diseases, comparing TEG parameters
r,
α, and
ma. Eight cirrhotics were studied before and after infection. The diagnosis of presence and type of infection was based on international standard criteria.
Results: A significant heparin effect was found only in infected cirrhotics (28 of 30) with significant changes in
r (
P=0.0003),
α (
P<0.0001), and
ma (
P<0.0001), but in none of those not infected. This effect completely reversed in the eight evaluated after resolution of infection. There was no heparin effect in infected non-cirrhotics.
Conclusions: A heparin effect was only found in cirrhotic patients with infection, further confirming that infection significantly modifies coagulation in cirrhotic patients.
Late hepatic artery thrombosis (HAT) is a rare complication after orthotopic liver transplantation (OLT), conventionally described as occurring more than 30 days after surgery. Only a few reports ...document its course. In a consecutive series of 634 OLTs (704 grafts), 11 patients (1.7%) had late HAT, diagnosed a median of 6 months (range, 1.8 to 79 months) after OLT. Clinical variables were compared with those of 415 patients without HAT who had a complete database and follow-up, including cytomegalovirus (CMV) surveillance. At presentation, 11 patients had fever, 4 patients had jaundice. Hepatic abscesses were present in 6 patients (3 patients with biliary leak), 4 patients had biliary tree necrosis (2 patients with biliary leak), and 1 patient had no biliary complications. Five patients (45%) underwent accessory hepatic artery anastomosis versus 73 patients (17%) without HAT (P < .05). Five patients (45%) with late HAT had CMV infection versus 14% without HAT (P < .05). Two episodes of late HAT (11 and 79 months) occurred in patients who underwent re-OLT for early HAT (3.9%). Re-OLT was performed in 8 patients a median of 11 days (range, 3 to 37 days) after diagnosis (preceded by intravenous antibiotics and percutaneous drainage). The other 3 patients underwent partial hepatectomy (1 patient), external percutaneous drainage as unfit for surgery (1 patient), and antibiotic therapy only (1 patient). Death occurred in 4 patients who underwent re-OLT (50%) because of septicemia at 11, 23, and 60 days after re-OLT and 17 days after a third OLT. There was one late death (30 months) after partial hepatectomy (hepatitis C recurrence) and one death 6 months after long-term biliary drainage because of sepsis. The 5 survivors have good health with normal liver function test results at a median 52 months (range, 6 to 57 months). In conclusion, late HAT presents with fever caused by hepatic abscesses or biliary leak associated with biliary ischemia and necrosis. CMV infection and accessory hepatic artery anastomosis are risk factors for late HAT in our cohort. Early intervention followed by re-OLT can salvage patients. (Liver Transpl 2003;9:605-611.)
Monocyte chemotactic protein (MCP)-1 is a chemoattractant and activator for circulating monocytes and T lymphocytes. We investigated MCP-1 protein and gene expression during chronic liver disease at ...different stages, using immunohistochemistry and in situ hybridization, respectively. In normal liver, a modest expression of MCP-1 was confined to few peri-sinusoidal cells and to bile duct epithelial cells. During chronic hepatitis, MCP-1 immunostaining and gene expression were evident in the inflammatory infiltrate of the portal tract. In tissue from patients with active cirrhosis, MCP-1 expression was clearly up-regulated and was present in the portal tract, in the epithelial cells of regenerating bile ducts, and in the active septa surrounding regenerating nodules. A combination of in situ hybridization for MCP-1 and immunohistochemistry showed that activated stellate cells and monocyte/macrophages contribute to MCP-1 expression in vivo together with bile duct epithelial cells. Comparison of serial sections of liver biopsies from patients with various degrees of necro-inflammatory activity showed that infiltration of the portal tracts with monocytes/macrophages is directly correlated with the expression of MCP-1. These data expand previous in vitro studies showing that secretion of MCP-1 may contribute to the formation and maintenance of the inflammatory infiltrate observed during chronic liver disease.
Hepatic stellate cells (HSC) coordinate the liver wound-healing response through secretion of several cytokines and chemokines, including CCL2 (formerly known as monocyte chemoattractant protein-1). ...In this study, we evaluated the role of different proteins of the MAPK family (ERK, p38(MAPK), and JNK) in the regulation of CCL2 expression by HSC, as an index of their proinflammatory activity. Several mediators activated all three MAPK, including TNF, IL-1, and PDGF. To assess the relative role of the different MAPKs, specific pharmacological inhibitors were used; namely, SB203580 (p38(MAPK)), SP600125 (JNK), and PD98059 (MEK/ERK). The efficacy and specificity of the different inhibitors in our cellular system were verified analyzing the enzymatic activity of the different MAPKs using in vitro kinase assays and/or testing the inhibition of phosphorylation of downstream substrates. SB203580 and SP600125 dose-dependently inhibited CCL2 secretion and gene expression induced by IL-1 or TNF. In contrast, inhibition of ERK did not affect the upregulation of CCL2 induced by the two cytokines. Finally, activin A was also found to stimulate CCL2 expression and to activate ERK, JNK, p38, and their downstream targets. Unlike in cells exposed to proinflammatory cytokines, all three MAPKs were required to induce CCL2 secretion in response to activin. We conclude that members of the MAPK family differentially regulate cytokine-induced chemokine expression in human HSC.
Activated hepatic stellate cells (HSC) regulate the liver “wound-healing” response through expression of chemokines, including monocyte chemoattractant protein-1 (MCP-1), which participate in the ...formation of the inflammatory infiltrate during liver injury. Cyclooxygenase (COX) catalyzes the conversion of arachidonic acid into prostaglandins, which may contribute to the inflammatory response. In this study, we investigated the effects of COX inhibitors on the expression of MCP-1 in cultured HSC. Pretreatment of HSC with nonspecific COX inhibitors such as indomethacin or ibuprofen markedly reduced the expression of MCP-1 caused by exposure to tumor necrosis factor α (TNF-α) or interleukin-1α (IL-1α). NS-398, a specific COX-2 inhibitor, also resulted in a dose-dependent inhibition of MCP-1 gene and protein expression. These effects were dependent on reduced MCP-1 transcription, as established using a reporter plasmid. In contrast, the up-regulation of MCP-1 expression caused by interferon gamma (IFN-γ) was not sensitive to COX inhibitors. Quiescent HSC did not show detectable expression of COX-2, which became evident after activation in culture, and while TNF-α and IL-1α markedly increased the expression of COX-2, IFN-γ did not have any effects. Pretreatment of HSC with the stable cyclic adenosine monophosphate (cAMP) analog, 8-bromo cAMP, reverted the effects of the COX-2 inhibitor, but not of a nuclear factor-κB (NF-κB) inhibitor, demonstrating that prostaglandins modulate MCP-1 expression via production of cAMP. On the other hand, the action of NF-κB inhibitors was negligible in IFN-γ—stimulated cells. These findings indicate that cross-talk between cytokines and a prostaglandin-cAMP pathway differentially regulates the proinflammatory potential of HSC, contributing to the modulation of liver tissue inflammation. (HEPATOLOGY 2001;33:713-721.)
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