Wygrecka, MalgorzataGessler, TobiasEhrlich, KristinKristinEhrlich2025-04-012025-04-012025https://jlupub.ub.uni-giessen.de/handle/jlupub/20443https://doi.org/10.22029/jlupub-19794Pneumonia accounts for one of the ten main causes of death worldwide with highest incident rates in small children and elderly people. Generally, men are more susceptible to an infection and show elevated rates of hospitalization. The role of FXII as a coagulation factor has been highly questioned as people deficient in FXII do not show any kind of bleeding disorder and with the discovery of a TF- dependent coagulation pathway in vivo, FXII seemed to be dispensable for hemostasis. Therefore, current studies focus on alternative roles of FXII. A growing number of evidence supports the theory that FXII is directly and indirectly associated with inflammatory processes and thrombosis and thereby is playing an important role for innate host defense against infection. Multiple sources showed that FXII does not only lead to fibrin formation but also to production and release of proinflammatory cytokines and stimulation of neutrophils. Although previous studies highlighted the role of FXII and its downstream products during ARDS, a common complication of pulmonary infection, corresponding data for FXII in the context of pneumonia is missing. The present study investigated levels of FXII, FXIIa and HK in plasma of 140 CAP patients and 60 sex- and age-matched healthy donors by performing analysis of data collected via western blot and ELISA. The results were further analyzed to determine sex-specific differences and correlations with CRP levels, CRB-65-score and mortality. Additionally, FXII levels in BALF of 20 CAP patients and 10 donors was measured by western blot and ELISA. Finally, immunohistochemical stainings for FXII and pro-SP-C, CD-68 and vWF in human lung tissue of 3 CAP patients were performed. Previous studies showed that levels of FXII and its inhibitor decline simultaneously during infection, hypothesizing a progressive consumption of both. In contrast to that I found elevated levels of FXIIa-C1INH-complexes in plasma of CAP patients, while no parallel decrease of FXII levels was observed. That could be a sign of either inhibited degradation of FXII or stimulation of production and secretion of FXII. Multiple studies suggest neutrophils as a source of FXII and show a proinflammatory influence of estrogen on neutrophil function. In line with these findings the present work shows sex specific differences with regard to FXII and HK levels in CAP patients. Female CAP patients showed higher amounts of FXII than sex-matched donors, while HK levels in women suffering from CAP were decreased in comparison to sex-matched donors. As estradiol is known to stimulate FXII production and studies have shown an association between estradiol levels and FXII levels in plasma, these observations let me speculate that changes of FXII plasma levels may be influenced by alterations of estradiol levels in the healthy elderly population as well as in the context of pulmonary infection. Epidemiological data show that male individuals are more prone to infectious diseases than female individuals. These sex- specific differences in the susceptibility to but also the outcome of pulmonary infection are hypothesized to originate from sex-hormone-dependent but also sex-hormone- independent variations of innate and adaptive immune responses. The results presented add further evidence to sex specific differences in the context of pulmonary infection and emphasize the need to support further research on that matter. Moreover, the sex-specific differences in FXII and HK levels let me speculate about the role of FXII and its downstream products with regard to immunothrombosis as women are more prone to thrombosis and elevated levels of estrogens are related to an increased risk of thromboembolic events. Currently contradictory results have been published, leaving the question of a rather protective or a harmful role of FXII and its downstream products in the context of inflammation and related coagulopathy unanswered. That is why further studies regarding this question need to be performed. Although I would have expected more correlations of FXII and its downstream products with clinical parameters, only a negative correlation of CRP levels and FXII levels in women with CAP, as well as a corresponding positive correlation with CRP levels and FXIIa-C1INH complexes in female CAP patients was detected. Furthermore, a negative correlation of HK levels and the CRB-65 score in female CAP patients was found. The weak correlations to CRP and CRB-65 score imply a supplementary, rather than a substitutive role of FXII, FXIIa and HK in the prediction of disease outcome of CAP. Finally, elevated levels of FXII in BALF of CAP patients were shown, indicating local production or accumulation of plasma-derived FXII in CAP lungs. Via immunolocalization of FXII to endothelial cells a binding of FXII to endothelial cells has been proposed in this study. While FXII-uPAR-associated signalling seems to have a rather protective role in the context of inflammation the consequent activation of the KKS by FXIIa can result in extensive vascular inflammation. Immunolocalization of FXII to the surface of macrophages implies a binding of FXII to macrophages with a probable consequent activation of FXII into FXIIa leading to a secretion of pro-inflammatory cytokines and fatal disease outcome. Moreover, FXII was immunolocalized to ATII cells which, together with endothelial cells, play an important role in maintaining a functioning capillary-alveolar barrier, which is essential for host defense. In this study a possible association of FXII and the regulation of ATII cell function is proposed. All in all, the work presented shows altered levels of FXII, FXIIa and HK during CAP with sex-specific differences, indicating that FXII plays an important role in the context of pulmonary inflammation and associated coagulopathy. Not only the role of FXII as an effector of host defense but especially sex-specific effects of FXII should be investigated further in the future. Only then we will be able to draw conclusions on individual disease outcome and can develop personalized therapeutic strategies.enAttribution-ShareAlike 4.0 Internationalddc:610