Biology subjects

Mall, M. A.

Publications and source records attributed to Mall, M. A..

3 recordsLinked to original sources

bioRxiv2020

Tamoxifen reduces inflammatory infiltration of neutrophils in the airways.

ABSTRACTTamoxifen is a drug of choice for treatment of breast cancer but it has also been reported to bear anti-inflammatory activity. Previously, we have observed that tamoxifen treatment successfully reduced inflammation in horses affected by equine asthma syndrome. More notorious, tamoxifen was effective at reducing the infiltration of neutrophils in the inflamed airways by a mechanism that increases efferocytosis, allowing the resolution of inflammation. Due to the emerging increase in patients with chronic inflammatory lung diseases, there is an urgent need for therapies that help reduce airway inflammation. Thus we tested the effect of tamoxifen on airway neutrophil infiltration by using three different mouse models for acute and chronic inflammation of the lung. We found that the drug was able to produce a significant reduction in neutrophils in all scenarios. Ussing chamber experiments demonstrated that tamoxifen has no effect on fluid secretion and absorption, discarding a possible reduction in mucociliary clearance due to the known ion-channel blocking effects of tamoxifen. Since this drug has been largely used in human medicine, tamoxifen might be a “low hanging fruit” for a novel anti-inflammatory therapy for airway diseases characterized by neutrophilic inflammation.Competing Interest StatementThe authors have declared no competing interest.View Full Text

pharmacology and toxicology↗

bioRxiv2020

Lack of Kcnn4 improves mucociliary clearance in muco-obstructive lung disease.

Airway mucociliary clearance (MCC) is the main mechanism of lung defense keeping the airways free of infection and mucus obstruction. Airways surface liquid (ASL) volume, ciliary beating and mucus are central for proper MCC, and are critically regulated by sodium (Na+) absorption and anion secretion. Impaired MCC is a key feature of muco-obstructive disease. The calcium-activated potassium (K+)channel KCa.3.1, encoded by the Kcnn4 gene, participates in intestinal ion secretion and previous studies showed that its activation increase Na+ absorption in airway epithelia, suggesting that hyperpolarization induced by KCa3.1 was sufficient to drive Na+ absorption. However, its role in airway epithelial function is not fully understood. We therefore aimed to elucidate the role of KCa3.1 in MCC in a genetically engineered mouse model. We show that KCa3.1 inhibition reduced Na+ absorption in mouse and human airway epithelium. Furthermore, the genetic deletion of Kcnn4 enhanced cilia beating frequency (CBF) and MCC ex vivo and in vivo. Kcnn4 was silenced in the Scnn1b-transgenic mouse (Scnn1btg/+), a model of muco-obstructive lung disease triggered by increased epithelial Na+-absorption, leading to improvements in MCC and reduction of Na+-absorption. KCa3.1 deletion did not change the amount of mucus but did reduce mucus adhesion, neutrophil infiltration and emphysema. Our data support that KCa3.1 inhibition attenuated muco-obstructive disease in the Scnn1btg/+ mice. K+-channel modulation may be a novel therapeutic strategy to treat muco-obstuctive lung diseases.

physiology↗

bioRxiv2019

Antigen-driven PD1+Tox+Eomes+ and PD1+Tox+BHLHE40+ synovial T lymphocytes regulate chronic inflammation in situ

Introduction/AbstractT lymphocytes accumulate in inflamed tissues of patients with chronic inflammatory diseases (CIDs) and express pro-inflammatory cytokines upon re-stimulation in vitro1-29. Further, a significant genetic linkage to MHC genes suggests that T lymphocytes play an important role in the pathogenesis of CIDs including juvenile idiopathic arthritis (JIA)30-33. However, the functions of T lymphocytes in established disease remain elusive. Here we dissect the heterogeneity of synovial T lymphocytes in JIA patients by single cell RNA-sequencing. We identify subpopulations of T lymphocytes expressing genes reflecting recent activation by antigen in situ. A PD-1+TOX+EOMES+ population of CD4+ T lymphocytes expressed immune regulatory genes and chemoattractant genes for myeloid cells. A PD-1+TOX+BHLHE40+ population of CD4+, and a mirror population of CD8+ T lymphocytes expressed genes driving inflammation, and genes supporting B lymphocyte activation. This analysis points out that multiple types of T lymphocytes have to be targeted for therapeutic regeneration of tolerance in arthritis.

immunology↗