Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
Sharma, N.
THE ROLE OF REGULATOR OF G PROTEIN SIGNALING 5 (RGS5) IN LUNGS
PhD-Studium (Doctor of Philosophy); Humanmedizin; [ Dissertation ] Medizinische Universität Graz; 2021. pp. 97
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- Autor*innen der Med Uni Graz:
- Betreuer*innen:
- Heinemann Akos
- Olschewski Andrea
- Olschewski Horst
- Altmetrics:
- Abstract:
- Inflammation plays an important role in the initiation and progression of acute lung injury and fibrosing interstitial lung diseases (ILD). The regulator of G protein signaling (RGS) represents a widespread system of controllers of cellular responses. The activities of the R4 subfamily of RGS have been elucidated in allergic pulmonary diseases over the past years. However, the R4 signaling involved in other inflammatory lung diseases with a strong cellular immune response is limited. Thus, our study aimed to enlighten the functional relevance of the R4 family member, RGS5, as a potential control element in this context. Gene profiling of the R4 subfamily showed strongly increased RGS5 expression in human fibrosing lung disease samples. In line with the patient’s data, RGS5 expression was markedly increased in murine lungs following bleomycin injury. In the acute phase of pulmonary fibrosis, RGS knock-out mice (RGS-/-) had preserved lung function while control mice showed significant combined ventilatory disorders three days after bleomycin application as compared to saline-treated mice. Analysis of specific immune cell subpopulations in bronchoalveolar lavage fluid (BALF) and lung tissue showed a significant attenuation of neutrophils in the BALF of RGS5-/- animals, and lowered myeloperoxidase (MPO) enzymatic activity in lung tissue. In contrast, the long-term effects of bleomycin were not significantly changed in RGS5-/- mice. In the LPS lung injury model, RGS5-/- also failed to recruit neutrophils into the lung, which was accompanied by reduced tissue myeloperoxidase levels after 24 hours. Our in-vitro assays showed impaired migration of RGS5-/- neutrophils towards chemokines despite preserved Ca2+ signaling. Importantly, RGS5-/- neutrophils showed delayed ERK dephosphorylation and increased RhoA activation which might play a role in reduced neutrophil migration in our model. In a conclusion, loss of RGS5 preserves lung function and attenuates inflammation in the acute phase of bleomycin-induced pulmonary fibrosis and LPS-induced lung injury. Targeting RGS5, a potential control element, might alleviate the severity of exacerbations in interstitial lung diseases.