RESUMEN
Nitrites have emerged as promising therapeutic agents for cardiovascular diseases, alongside nitrates. While chronic use of organic nitrates is well recognized to lead to vascular tolerance, the tolerance associated with nitrite therapy remains incompletely understood. The aim of the present study was to investigate vascular tolerance to sodium nitrite and the underlying molecular mechanisms. Endothelium-denuded aortic rings isolated from male Balb/C mice were incubated with either the EC50 (10-4 mol/L) or EC100 (10-2 mol/L) concentration of sodium nitrite for 15 min to induce tolerance. The EC100 concentration of sodium nitrite induced vascular tolerance. Pre-incubation with captopril and losartan effectively reversed sodium nitrite-induced tolerance. Similarly, pre-incubation with L-NAME and L-arginine prevented sodium nitrite-induced tolerance. Increased levels of reactive oxidative species (ROS) and reduced bioavailability of nitric oxide (NO) were observed in tolerant aortas. Increased superoxide dismutase (SOD) activity and decreased catalase activity were also verified in tolerant aortas. Both captopril and L-NAME prevented the increased levels of ROS observed in tolerant aortas. Furthermore, pre-incubation with catalase effectively prevented sodium nitrite-induced tolerance. Our findings suggest that sodium nitrite induces vascular tolerance through a signaling pathway involving the renin-angiotensin system, nitric oxide synthase, and ROS. This study contributes to the understanding of the interactions between nitrites and vascular tolerance and highlights potential targets to overcome or prevent this phenomenon.
RESUMEN
Chronic ethanol consumption is a leading cause of mortality worldwide, with higher risks to develop pulmonary infections, including Aspergillus infections. Mechanisms underlying increased susceptibility to infections are poorly understood. Chronic ethanol consumption induced increased mortality rates, higher Aspergillus fumigatus burden and reduced neutrophil recruitment into the airways. Intravital microscopy showed decrease in leukocyte adhesion and rolling after ethanol consumption. Moreover, downregulated neutrophil activation and increased levels of serum CXCL1 in ethanol-fed mice induced internalization of CXCR2 receptor in circulating neutrophils. Bone marrow-derived neutrophils from ethanol-fed mice showed lower fungal clearance and defective reactive oxygen species production. Taken together, results showed that ethanol affects activation, recruitment, phagocytosis and killing functions of neutrophils, causing susceptibility to pulmonary A. fumigatus infection. This study establishes a new paradigm in innate immune response in chronic ethanol consumers.
Alcoholism is a chronic disease that has many damaging effects on the body. Over long periods, excessive alcohol intake weakens the immune system, putting consumers at increased risk of getting lung infections such as pneumonia. Some forms of pneumonia can be caused by the fungus Aspergillus fumigatus. This microbe does not tend to be a problem for healthy individuals, but it can be fatal for those with impaired immune systems. Here, Malacco et al. wanted to find out why excessive alcohol consumers are more prone to pneumonia. To test this, the researchers used two groups of mice that were either fed plain water or water containing ethanol. After 12 weeks, both groups were infected with Aspergillus fumigatus. The results showed that alcohol-fed mice were more susceptible to the infection caused by strong inflammation of the lungs. Normally, the immune system confronts a lung infection by activating a group of defense cells called neutrophils, which travel through the blood system to the infection site. Once in the right spot, neutrophils get to work by releasing toxins that kill the fungus. Malacco et al. discovered that after chronic alcohol consumption, neutrophils were less reactive to inflammatory signals and less likely to reach the lungs. They were also less effective in dealing with the infection. Neutrophil released fewer toxins and were thus less able to kill the microbial cells. These findings demonstrate for the first time how alcohol can affect immune cells during infection and pave the way for new possibilities to prevent fatal lung infections in excessive alcohol consumers. A next step would be to identify how alcohol acts on other processes in the body and to find a way to modulate or even revert the changes it causes.
