Pim1 kinase protects airway epithelial cells from cigarette smoke-induced damage and airway inflammation

Abstract

Exposure to cigarette smoke (CS) is the main risk factor for developing chronic obstructive pulmonary disease and can induce airway epithelial cell damage, innate immune responses, and airway inflammation. We hypothesized that cell survival factors might decrease the sensitivity of airway epithelial cells to CS-induced damage, thereby protecting the airways against inflammation upon CS exposure. Here, we tested whether Pim survival kinases could protect from CS-induced inflammation. We determined expression of Pim kinases in lung tissue, airway inflammation, and levels of keratinocyte-derived cytokine (KC) and several damage-associated molecular patterns in bronchoalveolar lavage in mice exposed to CS or air. Human bronchial epithelial BEAS-2B cells were treated with CS extract (CSE) in the presence or absence of Pim1 inhibitor and assessed for loss of mitochondrial membrane potential, induction of cell death, and release of heat shock protein 70 (HSP70). We observed increased expression of Pim1, but not of Pim2 and Pim3, in lung tissue after exposure to CS. Pim1-deficient mice displayed a strongly enhanced neutrophilic airway inflammation upon CS exposure compared with wild-type controls. Inhibition of Pim1 activity in BEAS-2B cells increased the loss of mitochondrial membrane potential and reduced cell viability upon CSE treatment, whereas release of HSP70 was enhanced. Interestingly, we observed release of S100A8 but not of double-strand DNA or HSP70 in Pim1-deficient mice compared with wild-type controls upon CS exposure. In conclusion, we show that expression of Pim1 protects against CS-induced cell death in vitro and neutrophilic airway inflammation in vivo. Our data suggest that the underlying mechanism involves CS-induced release of S100A8 and KC.

Inhibition of Pim1 kinase reduces viral replication in primary bronchial epithelial cells

“…In childhood asthma, exacerbations due to HRV-C have been associated with more severe exacerbations than other HRV groups [7,8]. In stable children with CF the presence of HRV-C or HRV-A2 is associated with an increased frequency of exacerbations [9].…”

“…Pim1 kinase is a constitutively active serine/threonine kinase known to be involved in cell survival by increasing the threshold for apoptosis [6,7]. We have shown previously that Pim1 kinase is highly expressed in the bronchial airway epithelium and that pharmacological inhibition of Pim1 kinase increases the sensitivity of bronchial epithelial cells to cell death upon challenge with cigarette smoke extract [8]. Therefore, we hypothesised that inhibition of Pim1 kinase activity in virally infected PBECs would enhance the onset of cell death, resulting in reduced viral replication.…”

Silymarin attenuates cigarette smoke extract-induced inflammation via simultaneous inhibition of autophagy and ERK/p38 MAPK pathway in human bronchial epithelial cells

“…CS exposure has been shown to induce an abnormal inflammatory response in the small airways and alveoli, contributing to airway remodeling and subsequent reduction of the airflow, which is the main characteristic of COPD1. It has been demonstrated that bronchial epithelium acts as a main source of overproduction of various cytokines, chemokines and adhesion molecules that modulate other elements of the airway wall and immune cells against CS23. Therefore, mapping the molecular mechanisms for CS-induced alterations in bronchial epithelial cells may offer clues into COPD pathogenesis and treatment.…”

Single-Nucleotide Polymorphisms and Cancer Risk, Tumor Recurrence, or Survival of Head and Neck Cancer Patients

“…As a consequence of the inflammation microenvironment and massive cell death induced by HPV or smoking, chronic inflammation occurs [14,26,28,29] . Increasing inflammation-related proteins, CRP and cytokines, and TNFα in the plasma of H&N cancer patients supported our assumption [12] .…”