Increase, Inflammation

Inflammation is complex to define. 

Villeneuve et al. (2018) analyzed the varied biological responses, provided guidance to simplify the  process representing inflammation in adverse outcome pathways, and recommended 3 key steps: 1. Tissue resident cell activation 2. Increased Pro-inflammatory mediators 3. Leukocyte recruitment/activation.  Tissue resident cell activation generally occurs when healthy tissue is exposed to a stressor, or when damage occurs, initiating a signal response of pro-inflammatory mediators (ex. cytokines).  Pro-inflammatory mediators result in the production of lipids and proteins, signaling, and initiate leukocyte recruitment/activation.  Leukocyte recruitment/activation initiate inflammation and other morphological changes. 

Some empirical research studies that illustrate inflammation pathways:

• A review of inflammation caused by microplastics in mammals (Wright and Kelly, 2017).  Inflammation and immune responses are caused by irritation via microplastics inhalation.
• Increased inflammatory interleukin gene expression in lab mice brains with damaged hypoglossal nerves (Gamo et al., 2008).  Inflammatory genes interleukin-1beta and interleukin-6, and tumor necrosis factor-alpha levels were increased after physical injury.
• Increased inflammation in the freshwater fish Danio rerio exposed to polystyrene microplastics (Lu et al., 2016).  Oxidative stress indicator enzymes superoxide dismutase and catalase were increased in livers, along with histopathological changes in inflammation and necrosis, in response to accumulation of microplastics.
• Inhibited inflammatory interleukin gene expression in guts and increased mucus production in guts in the freshwater fish Danio rerio exposed to polystyrene microplastics (Jin et al., 2018).  Gene expression of tumor necrosis factor-alpha, interleukin-1alpha, interleukin-1beta, interferon, interleukin-6, interleukin-8, interleukin-10 were changed, with most genes showing statistically significant increases and a dose-response relationship, due to exposure to polystyrene microplastics.  In additional, gut microbiota was altered.
• Significant intestinal damage including intestinal fold disruption, enterocyte damage, broken tissue, and inflammation in the freshwater fish Danio rerio exposed to microplastics (Lei et al., 2018).  Growth and reproductive effects were seen in addition to the histology observations, and associated with accumulation of microplastics.

In cancer, inflammation is a cascade of events created by the host in response to the spread of the cancer (Coussens and Werb, 2002). In response to an injury or the presence of cancer, the host heals itself through inflammation. Indeed, the activation and the migration of  leukocytes (neutrophils, monocytes and eosinophils) to the wound induces the healing process. These inflammatory cells provide an extracellular matrix that forms upon which fibroblast and endothelial cells proliferate and migrate in order to recreate a normal environment. Damage to the epithelial layer initiate inflammatory reactions (Palmer et al. 2011).  In cancer, this inflammatory state induces cell proliferation, increases the production of reactive oxygen species leading to oxidative DNA damage, and reduces DNA repair (Coussens and Werb, 2002).

Inflammation is generally detected in histopathological examination of organs (ex. liver, intestines) or in changes in gene expression (ex. interleukins).  Activation of the innate immune response and the release of various inflammatory cytokines can also be assessed (Flake and Morgan, 2017).

Flake, G.P., and Morgan, D.L. 2017. Pathology of diacetyl and 2,3-pentanedione airway lesions in a rat model of obliterative bronchiolitis. Toxicology, 388, 40–47. https://doi.org/10.1016/j.tox.2016.10.013

Palmer, S.M., Flake, G.P., Kelly, F.L., Zhang, H.L., Nugent, J.L., Kirby, P.J., Zhang, H.L., Nugent, J.L., Kirby, P.J., Foley, J.F., Gwinn, W.M., and Morgan, D.L. 2011. Severe airway epithelial injury, aberrant repair and Bronchiolitis obliterans develops after diacetyl instillation in rats. PLoS ONE, 6(3). https://doi.org/10.1371/journal.pone.0017644

Coussens L.M. and Werb Z. Inflammation and cancer. Nature. 2002 Dec 19-26;420(6917):860-7. doi: 10.1038/nature01322. PMID: 12490959; PMCID: PMC2803035.

Gamo, K., Kiryu-Seo, S., Konishi, H., Aoki, S., Matushima, K., Wada, K., and Kiyama, H.  2008.  G-protein-coupled receptor screen reveals a role for chemokine recepteor CCR5 in suppressing microglial neurotoxicity.  Journal of Neuroscience 28: 11980-11988.

Jin, Y., Xia, J., Pan, Z., Yang, J., Wang, W., and Fu, Z.  2018.  Polystyrene microplastics induce microbiota dysbiosis and inflammation in the gut of adult zebrafish.  Environmental Pollution 235: 322-329.

Lei, L., Wu, S., Lu, S., Liu, M., Song, Y., Fu, Z., Shi, H., Raley-Susman, K.M., and He, D.  2018.  Microplastic particles cause intestinal damage and other adverse effects in zebrafish Danio rerio and nematode Caenorhabditis elegans.  Science of the Total Environment 619-620: 1-8.