Current treatments fail to modify the underlying pathophysiology and disease progression of chronic obstructive pulmonary disease (COPD), necessitating alternative therapies. Here, we show that COPD subjects have increased IL-36γ and decreased IL-36 receptor antagonist (IL-36Ra) in bronchoalveolar and nasal fluid compared with control subjects. IL-36γ is derived from small airway epithelial cells (SAEC) and is further induced by a viral mimetic, whereas IL-36Ra is derived from macrophages. IL-36γ stimulates release of the neutrophil chemoattractants CXCL1 and CXCL8, as well as elastolytic matrix metalloproteinases (MMPs) from small airway fibroblasts (SAF). Proteases released from COPD neutrophils cleave and activate IL-36γ, thereby perpetuating IL-36 inflammation. Transfer of culture media from SAEC to SAF stimulated release of CXCL1, which was inhibited by exogenous IL-36Ra. The use of a therapeutic antibody that inhibits binding to the IL-36R attenuated IL-36γ–driven inflammation and cellular crosstalk. We have demonstrated a mechanism for the amplification and propagation of neutrophilic inflammation in COPD and have shown that blocking this cytokine family via a IL-36R neutralizing antibody could be a promising therapeutic strategy in the treatment of COPD.

The prevalence of asthma has increased worldwide. Asthma exacerbations triggered by upper respiratory tract viral infections remain a major clinical problem and account for hospital admissions and time lost from work. Virus-induced asthma exacerbations cause airway inflammation, resulting in worsening asthma and deterioration in the patients’ quality of life, which may require systemic corticosteroid therapy. Despite recent advances in understanding the cellular and molecular mechanisms underlying asthma exacerbations, current therapeutic modalities are inadequate for complete prevention and treatment of these episodes. The pathological role of cellular senescence, especially that involving the silent information regulator 2 homolog sirtuin (SIRT) protein family, has recently been demonstrated in stable and exacerbated chronic respiratory disease states. This review discusses the role of SIRT1 in the pathogenesis of bronchial asthma. It also discusses the role of SIRT1 in inflammatory cells that play an important role in virus-induced asthma exacerbations. Recent studies have hypothesized that SIRT1 is one of major contributors to cellular senescence. SIRT1 levels decrease in Th2 and non-Th2-related airway inflammation, indicating the role of SIRT1 in several endotypes and phenotypes of asthma. Moreover, several models have demonstrated relationships between viral infection and SIRT1. Therefore, targeting SIRT1 is a novel strategy that may be effective for treating virus-induced asthma exacerbations in the future.

Background: Sestrin 2, Endocan, and Sirtuin 1 are distinct molecules with some biologic actions associated with asthma pathophysiology. The aim of the present study was to determine the molecular level differences attributable to underlying asthma severity. Methods: We initially recruited 85 asthmatics with a wide spectrum of severity. All of the patients were optimally treated according to current guidelines. Demographics, test results of lung function, and treatment regimes of all patients were recorded. Sestrin 2, Endocan, and Sirtuin 1 were measured in different biological samples (sputum with two processing methods and serum). Results: A total of 60 patients (35 with severe asthma) were analyzed, since 25 patients failed to produce an adequate sample of sputum. Patients with severe asthma showed significantly higher values for Sestrin 2 [pg/mL], measured in both sputum supernatant and cell pellet, compared to those with mild to moderate asthma [9524 (5696, 12,373) vs. 7476 (4265, 9273) p = 0.029, and 23,748 (15,280, 32,742) vs. 10,084 (3349, 21,784), p = 0.008, respectively]. No other significant differences were observed. No significant associations were observed between biomarkers, inflammatory cells, and lung function. Conclusion: Sestrin 2 is increased in patients with severe asthma as part of a mechanism that may modify structural alterations through the imbalance between oxidative stress and antioxidant activity.

Background: Altered iron metabolism is associated with COPD pathogenesis, and elevated iron levels are observed in the COPD lung. COPD is also associated with elevated levels of senescent cells that contain increased intracellular iron. Whether this is a cause or consequence of senescence is unknown. Aim: To examine the relationship between excess intracellular iron and senescence in COPD. Methods: Total intracellular iron was detected in small airway epithelial cells (SAEC) from non-smokers (NS) and COPD patients by atomic absorbance spectrometry. Heme iron was measured using absorbance at 400 nM. SAEC were treated with ferric ammonium iron citrate (FAC) or the iron chelator, deferoxamine. Iron and senescence markers were detected by western blot. Results: Intracellular iron was increased 1.7-fold (p=0.002) and heme iron 2.1-fold in COPD SAEC compared NS cells (n=6 p=0.008). Treatment of NS and COPD SAEC with FAC induced a 3.65 (p=0.4) and 4.8-fold (p=0.02) increase in iron respectively, with COPD SAEC accumulating significantly more iron than NS cells (n=6 p=0.04). Iron chelation significantly reduced intracellular iron in COPD, but not NS SAEC (n=4 p=0.02). Elevated expression of transferrin heavy chain and transferrin receptor were detected in COPD SAEC compared to NS, correlating with alterations in senescence markers p21 and Sirtuin-1/-6 (n=6). Conclusion: Elevated levels of intracellular iron were observed in COPD SAEC compared to NS, with COPD SAEC having increased capacity to accumulate extracellular iron, possibly via increased transferrin receptor. Altered senescence markers were also seen in COPD, but whether altered iron metabolism regulates this requires further investigation.

Background: COPD is a disease of accelerated ageing, with elevated number of senescent cells within the lung. Senescent cells may prevent lung repair and drive chronic lung inflammation. Dasatinib and Quercetin (D+Q) is a senolytics combination which removes senescent cells but has not been studied in COPD. Aim: Examine the effects of D+Q on COPD airway epithelium and in a cigarette smoke mouse model. Methods: Senescence markers p16 and/or p21 were detected in air-liquid interface (ALI) airway epithelium from non-smokers (NS) and COPD and the lungs from cigarette smoke exposed mice by western blot. Cytokine profile was analysed by O-Link proteomics. Results: COPD ALIs displayed significantly higher levels of p16 (n=5), whereas p21 was unchanged compared to NS. COPD ALIs treated with D (200nM) +Q (50 μM) for 24h showed a significant reduction in p16, and reduced release of CXCL8 (p<0.05). O-Link proteomics showed significant reductions in MMP-2, IL-33, CCL3 and IL-15RA by D+Q. Cigarette smoke exposed mice had significantly increased p16 and p21 compared to air exposed mice and this was significantly decreased by D (5 mg/kg) + Q (50 mg/kg) treatment for 3 days post exposure (n=6 per group) (p<0.01). Significantly elevated numbers of macrophages and neutrophils in bronchoalveolar lavage fluid induced by cigarette smoke were reduced in D+Q treated mice, along with the chemokine KC (p<0.01). Conclusion: Our data suggest that senolytic D+Q can reduce senescent cells within COPD epithelium and in cigarette exposure mouse model. More work is needed to understand the consequences of removing senescent cells from the lung but suggest these as a possible therapeutic target.