Proliferation Of Pro-inflammatory Cytokines Research Articles

Why do obese patients with oa have more pain?

The prevalence of obesity, osteoarthritis (OA) and chronic pain are rising globally and are major contributors to a progressive decline in physical function and quality of life. There is an established positive association between obesity and chronic pain. While substantial evidence supports this association in individuals with OA, the reasons underlying it remain unclear, with considerable insights gained from studying the effects of weight loss. Research on the impact of obesity in OA has mainly focused on its effects on joint loads, joint alignment, changes on imaging and biomarkers, with fewer studies considering the mediating role of these aspects on symptomatic change. In addition to increased joint loads, obesity creates low-grade systemic inflammation and in local adipose tissues (e.g. infrapatellar fat pad (IFP)) via the proliferation of pro-inflammatory cytokines and adipokines. The generation of OA pain through mechanical and inflammatory stimuli is well established via the activation of nociceptors in most joint tissues. Pain is a hallmark of OA disease progression, ranging from intermittent mechanical pain with activity to constant pain, thought to be largely due to low-grade inflammation. In addition, it is known that a subset of individuals with OA will have altered nociceptive signalling, manifesting in peripheral or central sensitization of pain, a process potentially enhanced in obese individuals. Historically, study of the relationship between obesity and pain in people with OA has used BMI ≥30kg/m2 as an indicator of obesity. A dose-response relationship has been observed between BMI and pain severity. Studies report that weight loss of as little as 5%, achieved either naturally or surgically, results in joint pain reduction. However, BMI is limited as a marker of obesity as it does not account for type of adipose tissue (i.e. subcutaneous or visceral), its distribution (abdomen vs extremities), or type of mass (muscle vs fat). These limitations are important since adipose tissue is metabolically active, a storer of macrophages, producing and releasing pro-inflammatory cytokines and adipokines (e.g. TNF-α, IL-6, leptin, adiponectin). Cytokines and adipokines are known contributors to extracellular matrix degradation, a process that ultimately leads to joint space narrowing. Adipokines are prominent in serum and can be considered a central driver of inflammation, while some are found in synovial fluid or the IFP, presenting a mechanism for a local effect. Thus it is unclear if pain improvement after weight loss is due to lower joint loads, lower levels of inflammation or a combination of both. Complicating the issue further is the prescription of opioids, which is higher for those who are obese compared to non-obese individuals and can lead to opioid-induced hyperalgesia. Despite OA clinical guidelines opposing their use, rates of opioid consumption continue to be a problem. Studies from preclinical models investigating obesity, pain, and OA are limited, but have contributed to evidence supporting the role of systemic and local inflammation being associated with pain sensitization to thermal and mechanical stimuli. Most recently, the critical role of signaling from fat cells in the development of pain sensitization was highlighted in a study of mice models with lipodystrophy. Initially protected from pain sensitization, lipodystrophic mice with transplanted adipose tissue developed hyperalgesia and allodynia. Knowledge from clinical studies has progressed with use of more detailed measurements of obesity, such as the type of adiposity. Recent advances include evidence on the contribution of visceral or subcutaneous adiposity, measured by dual x-ray absorptiometry, to pain in people with knee OA, indicating that visceral but not subcutaneous fat is associated with worsening knee pain. These results which accounted for BMI, support the systemic effects of obesity on pain in OA and implicate visceral fat as a driver of pain. In addition, there has been further study of the presence of bone marrow lesions (BMLs) and synovitis/effusion, which have been associated with pain or sensitization, and these changes can be more severe in obese individuals. Conflicting evidence exists regarding changes in BMLs and improvement in pain after weight loss. Evidence for the mediating role of synovitis/effusion in pain improvement after weight loss is limited, indicating a non-significant indirect effect. However, combined evidence regarding changes in cytokines, IFP volume and pain severity in obese individuals suggest that further research into synovitis/effusion is warranted. Gaps and opportunities for expanding our understanding of the mechanisms underlying the relationship between obesity and pain in individuals with OA will be discussed.

Expansion of the non-classical monocyte pool predicts elevated mood disturbance in post-menopausal women with and without HIV infection

Human Immunodeficiency Virus (HIV-1) infection is associated with expansion of the non-classical monocyte pool. These monocytes transmigrate across the blood-brain-barrier and induce proliferation of pro-inflammatory cytokines. Although this expansion has been linked to HIV-associated neurocognitive impairment, associations with psychological functioning are unclear. Flow cytometric analysis yielded the proportion of gated non-classical, intermediate and classical monocytes in 22 post-menopausal women (11 HIV+ and 11 HIV-negative) aged 55.77 years (SD = 6.32). A regression model tested variance in the proportion of non-classical monocytes accounted for by HIV status and scores on the Profile of Mood States questionnaire. Accounting for HIV status, mood disturbance accounted for 28% of the variance in non-classical monocytes, R2 = 0.275, F(2,21) = 3.69, p = 0.047. For every 1 unit increase in mood disturbance, the proportion of non-classical monocytes increased by nearly 10%, B = 0.096, SE = 0.04, t = 2.59 p = 0.018. However, HIV status did not predict variance in the proportion of mononuclear cells B = 1.18, SE = 2.37, t = 0.498, p > 0.05, suggesting expansion of the non-classical monocyte pool is associated with increasing levels of mood disturbance, independent of HIV infection. More work is needed to determine whether peripheral or neural-inflammation resulting from activation of non-classical monocytes potentially drives and/or may be driven by distress in HIV positive individuals.