Wellicht kan Marc van het Yahoo forum een antwoord geven, hij heeft ook een interessante bijdrage geleverd mbt het cystic fibrose raadsel:
Marc, 20 hours ago.
Here is an excerpt from a paper I found that explains why they are concerned about treatments for CF that may contribute to inflammation of lung tissue. As I explained in previous posts in support of a theory advanced by BioDreamer(?), any treatment that results in making lung mucous less viscous is may lead to inflammation if it adversely affects the ability of the lungs to clear particulate matter. Consequently, I think there is a possibility that the problem with ARO-eNaC may may be that it is too effective; at least when it is given to rats.
Although inflammation is a natural and protective process resulting from aggression, it plays a major role in CF lung pathology and progression. Inflammation was initially recorded by the Roman encyclopedist Aulus Cornelius Celsus in the 1st century A.D. by some typical characteristic signs of inflammation as heat (calor), pain (dolor), redness (rubor), and swelling (tumor). Chronic and exaggerated inflammation in people with CF causes damages to lung tissues that can eventually lead to respiratory failure (Cantin et al., 2015). Many recent results show that bronchial epithelial cells play a significant role in the progression of the disease. In addition to being a physical barrier, epithelial cells secrete many inflammatory factors such as cytokines, eicosanoids, enzymes, and adhesion molecules (Roesch et al., 2018). This CF airway inflammation is characterized by an excessive production of interleukin (IL)-8 secreted by airway epithelial cells, and the presence of large numbers of neutrophils and macrophages among other inflammatory cells (Hubeau et al., 2001). However, it is not the only pro-inflammatory cytokine enhanced. In the airways of CF patients, TNF-a, IL-1ß, IL-6, IL-8, IL-33, GM-CSF, and G-CSF are increased, also other molecules also play a major role such as the pro-inflammatory metabolites of arachidonic acid metabolism. Very recent results have highlighted the central role of other cytokines such as IL-17 (Roesch et al., 2018). In CF, the infiltration of inflammatory cells across the epithelium into the lumen can be very deleterious to epithelia and, as a consequence, requires robust regulation. Numerous works have tried to identify targets and strategies to reduce the exaggerated immune response that causes chronic inflammation without affecting the natural defenses against infection (Muhlebach and Noah, 2002). It is unclear whether the inflammation is a direct consequence of the cftr mutation or whether it is a consequence of infection and mucus accumulation. We do not know the contribution of infection to airway inflammation, but it must act as a catalyst and becomes self-perpetuating. Different studies have demonstrated the direct implication of the CFTR protein in this process mainly in the lung but also in extra-pulmonary tissues as the intestine or pancreas (Raia et al., 2000; Cohen and Prince, 2012; Stoltz et al., 2015; Bardin et al., 2019). Even before symptom onset, pulmonary inflammation and infection are often present in CF patients (Muhlebach and Noah, 2002). Although which comes first has been uncertain, this aspect is well reviewed in the article from Stoltz (Armstrong et al., 1995; Khan et al., 1995; Nixon et al., 2002; Stoltz et al., 2015). Moreover, new models lacking CFTR, including pigs, ferrets, and rat manifest inflammatory features typically observed with CF even in absence of infection (Rogers et al., 2008; Sun et al., 2010; Tuggle et al., 2014). For example, airways of CF piglets show no evidence of inflammation during the first hours after birth (Stoltz et al., 2010). Evidence has also demonstrated that non-infected human CF airway graft is in a pro-inflammatory state (Tirouvanziam et al., 2000; Tirouvanziam et al., 2002; Perez et al., 2007; Cantin et al., 2015). These data are reinforced by in vitro experiments using specific CFTR inhibitor. For example, Perez et al. have shown that Inh-172 treatment conducted in significant increase in IL-8 secretion in basal but also in response to P. aeruginosa infection (Perez et al., 2007). All these data support the hypothesis that mutations in cftr gene make epithelial cells intrinsically more pro-in?ammatory compared with healthy cells (Perez et al., 2007; Cantin et al., 2015), which, once infection is introduced, sets the stage for mucosal damage and chronic airway infection (Tirouvanziam et al., 2000).
Although the link between CFTR deficiency and host inflammatory response remains unclear, this aspect has long been recognized as a central pathological feature, and consequently, an important therapeutic target. Some have hypothesized that in CF, the unfolded proteins accumulation on the endoplasmic reticulum induced a proteinopathy responsible for inflammation, impaired trafficking, altered metabolism, cholesterol, and lipids accumulation, and impaired autophagy at the cellular level. Some have speculated that chloride dysregulation participated in a stress-inducing