En la otra ventana: Una didáctica de la poesía desde la poesía misma

For some time, chronic inflammation has been closely linked to, and is now considered a risk factor for the development of cancer in many tissues. Research by many groups suggests that unresolved inflammation increases the probability of tumor formation through two general pathways [61]. First, chronic inflammation results in the unabated recruitment of inflammatory leukocytes. As previously discussed, the infiltrating leukocytes enter the tissue and secrete cell- damaging substances. Neutrophils release superoxide radicals non-specifically into the affected tissue, with the intention of causing damage to the DNA of invading pathogens. Because this process is not directed toward pathogen in particular, but is rather a more general process, the host tissue is also at risk for DNA damage [61]. Any breakages in the DNA of surviving cells will be repaired by the DNA breakage repair enzymes; however, as a result of this process, point

mutations are introduced into the cell’s genome. If introduced into the DNA of an oncogene, such as a growth factor receptor or cell cycle kinase, then these mutations can result in unchecked cell growth leading to the development of neoplastic cells that can grow into tumors [61, 62]. In addition to introducing genetic mutations in the host tissue cells, chronic inflammation also results in the prolonged production and secretion of proinflammatory cytokines both locally and systemically, which continue to promote the recruitment of damaging leukocytes [61].

Proinflammatory cytokines are the first step in an inhibitory feedback loop that drives the tissue repair process, therefore promotion of proinflammatory mediator generation also encourages the production of tissue repair molecules, such as growth factors and remodeling enzymes.

The second pathway that is thought to contribute to chronic inflammation’s role in tumor formation is the prolonged activation of the wound healing program [61]. As mentioned

inflammation is the self-limiting, terminal process of the inflammatory response. Unlike acute inflammation, the wound healing program during chronic inflammation begins anew following each new wave of inflammatory cell infiltration. This process, when tightly controlled is absolutely necessary to inhibit further recruitment of inflammatory leukocytes and thus, limits further unnecessary damage to the tissue. The wound healing process is designed to inhibit further inflammation and protect the inflamed environment by creating a local temporary

immunosuppressive, proliferation supporting microenvironment [33]. During chronic

inflammation, this activation of the tissue repair-promoting process is prolonged and sustained, which results in an environment rich in anti-inflammatory and proliferative growth factors [6]. This results in a decrease in immunosurveillance in a tissue environment that is rapidly growing and dividing. Taken together with the increase in the DNA mutation rates from the free radicals generated by the inflammatory leukocytes, chronic inflammation works to create an environment that is well suited to initiate and sustain neoplastic cell formation and tumor immune escape.

In the process of chronic inflammation the inflammatory stimuli persist, which results in the unlimited activation of the inflammatory response. As described previously, the initiation of the inflammatory process also induces the activation of the tissue repair process. As part of this process, the tissue cells, inflammatory leukocytes, and adaptive immune cells work in concert to inhibit further inflammatory function, and to stimulate fibroblasts to proliferate and secrete factors that help to restore the tissue to homeostasis [61]. During chronic inflammation, this system is dysregulated, which results in what has been described as an “unhealing” or “overhealing” wound [60]. The “unhealing” wound is described as a region of inflammation that does not resolve to homeostatic conditions [60]. Dysregulation in the transition between inflammation and tissue repair often results in both systems being active simultaneously [61]. Activation of the early

inflammatory response and wound repair process is dangerous because it creates an environment rich in both inflammation stimulatory factors, including IL-6, IL-1β, and TNF-α, and rich in immunosuppressive factors, including IL-4, IL-10, and TGF-β. These “mixed signals” result in a wound that constantly initiates the tissue repair process, but is unable to reduce the

proinflammatory leukocytes infiltration. Thus, immune cells are recruited to the site of

inflammation, damage the tissue, then become transformed into cells that drive wound healing, including M2 and Th2 phenotype effector cells [57].

1.10.3.1 Wound healing environment establishes localized immunosuppression

In order for newly established neoplastic cells to survive, and eventually grow into a tumor mass, they must first escape detection and removal by the immune system. One such mechanism of immune escape is closely tied with the hallmark characteristics of the tissue repair response [60]. In order to stem the flow of inflammatory leukocytes into the site of inflammation, many immunosuppressive factors are secreted into the local environment. These factors include anti- inflammatory cytokines, such as IL-10, IL-4, and TGF-β [63], and lipid mediators, including protectins, resolvins, and lipoxins [30]. These soluble factors have many different targets, but all function in concert to produce a microenvironment is protected from aggressive, proinflammatory cells and supports cell proliferation and return to homeostasis. One such example is the secretion of anti-inflammatory mediators is IL-10, which causes tissue macrophages to polarize into type 2 macrophages [57]. These cells produce soluble factors including IL-4, IL-13, IL-10, TGF-β, PDGF, and VEGF that promote tissue growth and development, while also inhibiting the inflammatory immune response [34]. These factors have many different targets including the promotion of further M2 polarization, the differentiation of activated T cells into Tregs, and the promotion of proliferation and angiogenesis [34, 64]. Tregs decrease the proliferative ability of

both CD4+ and CD8+ T cells, as well as convert professional antigen presenting dendritic cells into T cell killing cells [65]. These mechanisms decrease the likelihood that antigen presenting cells will present tumor antigen to the local T cells, thus increasing the survival capability of the neoplastic cell. With every neoplastic cell division, the tumor will become more difficult to eliminate, and will exert greater influence over the immune system both locally and systemically. Many mechanisms supporting immune evasion exist, however chronic inflammation drastically increases the chances of neoplasm survival by combining increased risk of abnormal cell

generation with immune suppressive systems in a predominantly proliferative microenvironment [61].