Living in a Hostile World: Inflammation, New Drug Development, and Coronavirus

Abstract

We present a brief history of the immune response and show that Metchnikoff’s theory of inflammation and phagocytotic defense was largely ignored in the 20th century. For decades, the immune response was believed to be triggered centrally, until Lafferty and Cunningham proposed the initiating signal came from the tissues. This shift opened the way for Janeway’s pattern recognition receptor theory, and Matzinger’s danger model. All models failed to appreciate that without inflammation, there can be no immune response. The situation changed in the 1990s when cytokine biology was rapidly advancing, and the immune system’s role expanded from host defense, to the maintenance of host health. An inflammatory environment, produced by immune cells themselves, was now recognized as mandatory for their attack, removal and repair functions after an infection or injury. We explore the cellular programs of the immune response, and the role played by cytokines and other mediators to tailor the right response, at the right time. Normally, the immune response is robust, self-limiting and restorative. However, when the antigen load or trauma exceeds the body’s internal tolerances, as witnessed in some COVID-19 patients, excessive inflammation can lead to increased sympathetic outflows, cardiac dysfunction, coagulopathy, endothelial and metabolic dysfunction, multiple organ failure and death. Currently, there are few drug therapies to reduce excessive inflammation and immune dysfunction. We have been developing an intravenous (IV) fluid therapy comprising adenosine, lidocaine and Mg2+ (ALM) that confers a survival advantage by preventing excessive inflammation initiated by sepsis, endotoxemia and sterile trauma. The multi-pronged protection appears to be unique and may provide a tool to examine the intersection points in the immune response to infection or injury, and possible ways to prevent secondary tissue damage, such as that reported in patients with COVID-19.

Comparison of intra-articular administration of adenosine, lidocaine and magnesium solution and tranexamic acid for alleviating postoperative inflammation and joint fibrosis in an experimental model of knee arthroplasty

“…In contrast, following a rapid, early rise in plasma inflammatory cytokines in the ALM group, concentrations of these mediators returned to preoperative levels by day 3. Systemic inflammation is important for optimal healing and functional recovery after trauma, however when delayed or overexpressed inflammation can lead to slow healing and organ dysfunction [ 5 ]. The rapid return of systemic inflammatory mediators to baseline by day 3 in ALM-treated animals indicates a more optimal healing environment for tissue recovery compared to TXA-treated animals.…”

“…The early return of granulocytes and monocytes to baseline in TXA-treated animals is intriguing and may be due to TXA’s effect to inhibit plasmin, which is a potent facilitator of granulocyte and monocyte migration to sites of inflammation [ 39 , 40 ]. This was not the case in the ALM-treated animals and may reflect differences in the effect of TXA and ALM on the initiation and progression of inflammatory and immune responses within the implanted knee (see below) [ 5 ].…”

“…Accumulation of fibrotic tissue within the operated knee leads to restricted joint function and pain, with significant impact to patient quality of life [ 2 , 3 ]. Dysregulation of early inflammatory and immune responses triggered during surgery, and in the first postoperative week, are implicated in the pathogenesis of knee stiffness and arthrofibrosis [ 4 , 5 ]. Frontline strategies to minimise surgery-induced inflammation and improve joint tissue healing and patient outcomes following TKA are lacking.…”

“…Recently, intra-articular (IA) administration of ALM was shown to modulate inflammatory responses in the early postoperative period and alleviate post-TKA fibrosis in a rat model of TKA [ 28 ]. In contrast to TXA, which acts downstream of coagulation pathways initiated as a result of surgery-induced inflammation, ALM appears to modulate very early coagulation, inflammatory and central nervous system (CNS) responses, favouring a permissive tissue healing environment [ 5 , 21 – 23 , 28 – 30 ]. We hypothesised that compared to TXA, topical administration of ALM during TKA would reduce postoperative coagulopathy and systemic inflammation, and that this would correspond to improved tissue healing in the operated knee.…”

Personalized health and the coronavirus vaccines—Do individual genetics matter?

“…Different genetic factors or risk loci, mostly related to key host antiviral defense mechanisms and mediators of inflammation, have been reported since the beginning of the pandemic. [29,30] Among them, a gene cluster on chromosome 3 inherited from Neanderthals has been identified as a potential predictor a COVID-19 severity. [31] Likewise, some novel GWAS significant hits on chr12q24.13 (rs10735079, p = 1.6 × 10 -8 ) in a gene cluster encoding antiviral restriction enzyme activators (OAS1-3); on chr19p13.2-3 (rs2109069, p = 2.3 × 10 -12 and rs2109069, p = 3.9 × 10 -12 ) near the gene encoding tyrosine kinase 2 (TYK2) and within the gene encoding dipeptidyl peptidase 9 (DPP9), respectively, as well as on chr21q22.1 (rs2236757, p = 5 × 10 -8 ) in the interferon receptor gene (IFNAR2) and the monocyte/macrophage chemotactic receptor (CCR2), have also been postulated as potential predictors of critical illness caused by COVID-19.…”