Week 5 - Inflammation and CVD Flashcards
Why is the inflammatory response important?
- An acute inflammatory response is initiated when the damaged/infected tissue sends out signals (cytokines known specifically as chemokines) to recruit phagocytic immune cells to the tissue site, where they destroy infected or damaged tissue.
- As this is happening, other pro-inflammatory cytokines (e.g TNF-alpha, IL-6) released by the immune cells in the tissues, endothelial cells and adipocytes circulate in the blood and then stimulate the liver to release acute phase proteins such as C-reactive protein (CRP) and fibrinogen.
- This response is short-lasting, over a few days and is ‘switched off’ by anti-inflammatory immune cells and cytokines supressing the action of the inflammatory cells.
What is chronic low-grade (A.K.A systemic) inflammation?
- This is when the acute response doesn’t get ‘switched off’ (an anti inflammatory response) after the damaged or infected tissue is repaired because the stimulus for the inflammatory response remains (a chronic, or long-lasting response, occurring over months and years.
- For example tissue hypoxia in adipocytes related to obesity, causes persistently high levels of triglycerides in the blood enhancing FFA uptake by immune cells, there is therefore high levels of toxins in the blood (e.g from smoking, or from other illness, such as kidney disease) and in some cases, long lasting infections.
- It is known as low grade because there is a persistent low-level elevation of circulating inflammatory cytokines (such as IL-6) and acute phase proteins (such as CRP).
- It’s also particularly important to remember that IL-6 and CRP are not just markers (indicators) that a long-lasting inflammatory response is happening, but also play a role in sustaining the inflammation and damage, particularly with regard to the development of CVD.
Ridker et al (2017)
Was the first to show that blocking inflammatory pathways lowers risk of non-fatal heart attack, non-fatal stroke and also death from CVD.
What are thought to be the underlying mechanisms for the so-called anti-inflammatory effect of exercise?
1) If the exercise is associated with negative energy balance there will be a loss of adipose tissue. Adipose tissue is the major site of IL-6 release when you are at rest, so it follows that if you have less of this tissue, there’s less capacity for both the adipocytes and tissue resident immune cells to release inflammatory cytokines.
2) Exercise is having some more direct effects on the cells that are involved in releasing the inflammatory cytokines.
- Studies (e.g. Viana et al 2014) have shown that with regular moderate intensity exercise there is an altered cytokine production from immune cells, whereby the cells are less likely to be activated but, when they are, they produce fewer pro-inflammatory cytokines and more anti-inflammatory cytokines - these are the ones that help to regulate and prevent an excessive inflammatory response.
3) At higher intensities of exercise (60-70% VO2max, typically also lasting at least 1 hour) skeletal muscle can release of large amounts of proinflammatory IL-6 directly from the contracting myocytes in a manner that is proportional to exercise intensity and duration.
This provides a short sharp spike in IL-6 levels in the circulation (lasting only a matter of hours), that stimulates a counteracting and longer lasting anti-inflammatory response, by the release of anti-inflammatory cytokines, such as IL-10 and IL-1ra from immune cells in the blood.
Endurance athletes have higher levels of IL-10 in their blood at rest compared to non athletes
Elhakeem et al 2018:
- Examined associations of objectively measured physical activity (PA) and sedentary time with cardiovascular disease biomarkers at age 60 to 64 years
- Greater light PA and moderate-to-vigorous intensity PA and less sedentary time in early old age were associated with more favourable cardiovascular biomarker profiles.
- Fat mass partially mediated these associations but more strongly in women than men.
- Differences in IL-6, tissue plasminogen activator, and leptin by sedentary time and light activity were independent of higher intensity activity.
- Activities that can reduce fat mass may be most beneficial for cardiovascular health
Less sedentary time and greater time spent in LPA and MVPA and higher PAEE were all associated with more favourable CVD biomarker profiles even after adjustment for a wide range of covariates. For CRP, IL‐6, leptin, and less so for adiponectin, associations were stronger among women than men (on both relative and absolute scales), but sex differences were largely explained by the greater fat mass of women for a given body mass index.
Anti-inflammatory effects of PA
Decreases in pro‐inflammatory markers C‐reactive protein (CRP) and interleukin‐6 (IL‐6)
Decreases in leptin and increases in adiponectin levels with exercise induced fat loss.
PA improves endothelial function in terms of its ability to release the protein tissue-plasminogen activator (t-PA
CRP and IL-6
- Greater sedentary time was associated with higher CRP and IL-6 and associations were stronger in women than men. Greater time in LPA and MVPA was related to lower CRP and IL-6 in both sexes.
Endothelial markers (t-PA)
- Higher sedentary time was related to higher t-PA in both men and women
- Higher light PA was related to lower t-PA in both sexes
PA and Adipokines (Leptin and Adiponectin):
- Greater sedentary time was associated with higher leptin and lower adiponectin
- Greater Light PA was associated with lower leptin and higher adiponectin in women but not men
- MVPA was related to lower leptin and higher adiponectin in both sexes, but associations with leptin were stronger in women.
The MESA (Vella et al 2017)
This study examined whether associations of physical activity and obesity-related inflammatory markers were independent of central adiposity.
* The associations with leptin, interleukin-6, and resistin were independent of total and central adiposity whereas the association between moderate-to-vigorous physical activity and adiponectin was attenuated by central adiposity .
* Moderate-to-vigorous physical activity was associated with a more favourable profile of inflammatory markers, independent of relevant cardiometabolic disease risk factors including central obesity
Dyslipidaemia
defined as a total cholesterol/HDL-cholesterol ratio >5.0 or if the participant was taking medication to reduce cholesterol.
Diabetes
Defined as fasting glucose ≥126 mgIdL-1 or use of hypo-glycaemic medication.
Discussion from the MESA study
- Central adipose tissue is known to produce proinflammatory cytokines, whereas low total body fat is associated with higher levels of adiponectin.
- It has been suggested that exercise may regulate the synthesis of proinflammatory cytokines by acutely increasing levels of IL-6, which in turn stimulates production of anti-inflammatory cytokines IL-1 receptor antagonist and IL-10, and suppressing TNF-> through IL-6–dependent and IL-6–independent pathways
Visceral adipose tissue produces less adiponectin than subcutaneous adipose tissue, so a lower proportion of total fat in the visceral depot makes increases in adiponectin more likely.
The association between moderate-to-vigorous physical activity and TNF-αwas attenuated by BMI
