Fibroblast-mediated intercellular crosstalk in the healthy and diseased heart

Cardiac fibroblasts constitute a major cell population in the heart. They secrete extracellular matrix components and various other factors shaping the microenvironment of the heart. In silico analysis of intercellular communication based on single-cell RNA sequencing revealed that fibroblasts are the source of the majority of outgoing signals to other cell types. This observation suggests that fibroblasts play key roles in orchestrating cellular interactions that maintain organ homeostasis but that can also contribute to disease states. Here, we will review the current knowledge of fibroblast interactions in the healthy, diseased, and aging heart. We focus on the interactions that fibroblasts establish with other cells of the heart, specifically cardiomyocytes, endothelial cells and immune cells, and particularly those relying on paracrine, electrical, and exosomal communication modes

Ethyl pyruvate ameliorates hepatic injury following blunt chest trauma and hemorrhagic shock by reducing local inflammation, NF-kappaB activation and HMGB1 release

Background: The treatment of patients with multiple trauma including blunt chest/thoracic trauma (TxT) and hemorrhagic shock (H) is still challenging. Numerous studies show detrimental consequences of TxT and HS resulting in strong inflammatory changes, organ injury and mortality. Additionally, the reperfusion (R) phase plays a key role in triggering inflammation and worsening outcome. Ethyl pyruvate (EP), a stable lipophilic ester, has anti-inflammatory properties. Here, the influence of EP on the inflammatory reaction and liver injury in a double hit model of TxT and H/R in rats was explored. Methods: Female Lewis rats were subjected to TxT followed by hemorrhage/H (60 min, 35±3 mm Hg) and resuscitation/R (TxT+H/R). Reperfusion was performed by either Ringer`s lactated solution (RL) alone or RL supplemented with EP (50 mg/kg). Sham animals underwent all surgical procedures without TxT+H/R. After 2h, blood and liver tissue were collected for analyses, and survival was assessed after 24h. Results: Resuscitation with EP significantly improved haemoglobin levels and base excess recovery compared with controls after TxT+H/R, respectively (p<0.05). TxT+H/R-induced significant increase in alanine aminotransferase levels and liver injury were attenuated by EP compared with controls (p<0.05). Local inflammation as shown by increased gene expression of IL-6 and ICAM-1, enhanced ICAM-1 and HMGB1 protein expression and infiltration of the liver with neutrophils were also significantly attenuated by EP compared with controls after TxT+H/R (p<0.05). EP significantly reduced TxT+H/R-induced p65 activation in liver tissue. Survival rates improved by EP from 50% to 70% after TxT+H/R. Conclusions: These data support the concept that the pronounced local pro-inflammatory response in the liver after blunt chest trauma and hemorrhagic shock is associated with NF-κB. In particular, the beneficial anti-inflammatory effects of ethyl pyruvate seem to be regulated by the HMGB1/NF-κB axis in the liver, thereby, restraining inflammatory responses and liver injury after double hit trauma in the rat

24-hour survival rate of all groups is represented.

<p>Sham group underwent all surgical procedures without induction of blunt chest trauma (TxT) and hemorrhagic shock with resuscitation (H/R). The groups received either ringer`s lactated (RL) or ethyl pyruvate (EP) as resuscitation solution after TxT and hemorrhagic shock. A total of 30 animals were randomly assigned to sham, TxT+H/R_RL or TxT+H/R_EP group (n = 10 per group) for the survival analysis.</p

Oxygen saturation (sO₂, %) values of all groups before the onset of blunt chest trauma (TxT) (baseline), after TxT (post TxT), after hemorrhagic shock (post H), after resuscitation (post R) and at sacrifice (2 h post R).

<p>The groups received either ringer`s lactated solution (RL) or ethyl pyruvate (EP) as resuscitation solution after TxT and hemorrhagic shock (TxT+H/R). Sham group underwent all surgical procedures without induction of TxT+H/R. Haemoglobin (tHb) (B) and base excess (C) of all groups during experimentation period are shown. *: p <0.05 <i>vs</i>. both other groups; #: p <0.05 <i>vs</i>. TxT+H/R_RL. Sham: n = 6, TxT+H/R_RL: n = 8 and TxT+H/R_EP: n = 8.</p

Neutrophils in liver sections were identified by chloroacetate esterase cytochemistry (CAE) and counted in 25 high power fields.

<p>Sham group underwent all surgical procedures without induction of blunt chest trauma (TxT) and hemorrhagic shock with resuscitation (H/R). The groups received either ringer`s lactated (RL) or ethyl pyruvate (EP) as resuscitation solution after TxT and hemorrhagic shock. *: p <0.05 <i>vs</i>. both other groups. Representative ICAM-1 stained liver sections from sham (B), TxT+H/R_RL (C) and TxT+H/R_EP (D) groups are shown. Sham: n = 6, TxT+H/R_RL: n = 8 and TxT+H/R_EP: n = 8.</p

Increased susceptibility of human endothelial cells to infections by SARS-CoV-2 variants

Coronavirus disease 2019 (COVID-19) spawned a global health crisis in late 2019 and is caused by the novel coronavirus SARS-CoV-2. SARS-CoV-2 infection can lead to elevated markers of endothelial dysfunction associated with higher risk of mortality. It is unclear whether endothelial dysfunction is caused by direct infection of endothelial cells or is mainly secondary to inflammation. Here, we investigate whether different types of endothelial cells are susceptible to SARS-CoV-2. Human endothelial cells from different vascular beds including umbilical vein endothelial cells, coronary artery endothelial cells (HCAEC), cardiac and lung microvascular endothelial cells, or pulmonary arterial cells were inoculated in vitro with SARS-CoV-2. Viral spike protein was only detected in HCAECs after SARS-CoV-2 infection but not in the other endothelial cells tested. Consistently, only HCAEC expressed the SARS-CoV-2 receptor angiotensin-converting enzyme 2 (ACE2), required for virus infection. Infection with the SARS-CoV-2 variants B.1.1.7, B.1.351, and P.2 resulted in significantly higher levels of viral spike protein. Despite this, no intracellular double-stranded viral RNA was detected and the supernatant did not contain infectious virus. Analysis of the cellular distribution of the spike protein revealed that it co-localized with endosomal calnexin. SARS-CoV-2 infection did induce the ER stress gene EDEM1, which is responsible for clearance of misfolded proteins from the ER. Whereas the wild type of SARS-CoV-2 did not induce cytotoxic or pro-inflammatory effects, the variant B.1.1.7 reduced the HCAEC cell number. Of the different tested endothelial cells, HCAECs showed highest viral uptake but did not promote virus replication. Effects on cell number were only observed after infection with the variant B.1.1.7, suggesting that endothelial protection may be particularly important in patients infected with this variant