Lung and Eye Disease Develop Concurrently in Supplemental Oxygen-Exposed Neonatal Mice.

Bronchopulmonary dysplasia (BPD) and retinopathy of prematurity (ROP) are two debilitating disorders that develop in preterm infants exposed to supplemental oxygen to prevent respiratory failure. Both can lead to lifelong disabilities, such as chronic obstructive pulmonary disease and vision loss. Due to the lack of a standard experimental model of coincident disease, the underlying associations between BPD and ROP are not well characterized. To address this gap, we used the robust mouse model of oxygen-induced retinopathy exposing C57BL/6 mice to 75% oxygen from postnatal day 7 to 12. The cardinal features of ROP were replicated by this strategy, and the lungs of the same mice were simultaneously examined for evidence of BPD-like lung injury, investigating both the short- and long-term effects of early-life supplemental oxygen exposure. At postnatal days 12 and 18, mild lung disease was evident by histopathologic analysis together with the expected vasculopathy in the inner retina. At later time points, the lung lesion had progressed to severe airspace enlargement and alveolar simplification, with concurrent thinning in the outer layer of the retina. In addition, critical angiogenic oxidative stress and inflammatory factors reported to be dysregulated in ROP were similarly impaired in the lungs. These data shed new light on the interconnectedness of these two neonatal disorders, holding potential for the discovery of novel targets to treat BPD and ROP.

Loss of STAT6 promotes autoimmune disease and atopy on a susceptible genetic background.

Atopy and autoimmunity are usually considered opposed immunological manifestations. Lyn(-/-) mice develop lupus-like autoimmune disease yet have coexistent intrinsic allergic traits and are prone to severe, persistent asthma induced exogenously. Recently it has been proposed that the Th2 environment and IgE auto-Abs promotes autoimmune disease in Lyn(-/-) mice. To examine this apparent contradiction, we derived Lyn(-/-) mice with a null mutation in STAT6, a regulator of Th2 immunity that integrates signaling from the IL-4/IL-13 receptor complex. Atopy and spontaneous peritoneal eosinophilia, characteristic of Lyn(-/-) mice, were lost in young Lyn(-/-)STAT6(-/-) mice; however, autoimmune disease was markedly exacerbated. At a time-point where Lyn(-/-) mice showed only mild autoimmune disease, Lyn(-/-)STAT6(-/-) mice had maximal titres of IgG and IgA auto-Abs, impaired renal function, myeloid expansion and a highly activated T cell compartment. Remarkably, low level IgE auto-Abs but not IgG1 auto-Abs were a feature of some aged Lyn(-/-)STAT6(-/-) mice. Furthermore, aged Lyn(-/-)STAT6(-/-) mice showed dramatically increased levels of serum IgE but minimal IgG1, suggesting that class-switching to IgE can occur in the absence of an IgG1 intermediate. The results show that Lyn-deficient mice can overcome the effects of disabling Th2 immunity, highlighting the importance of Lyn in controlling Th2 responses. Our data also indicates that, under certain conditions, STAT6-independent factors can promote IgE class-switching. This work has important clinical implications as many experimental therapies designed for the treatment of asthma or atopy are based on targeting the STAT6 axis, which could potentially reveal life endangering autoimmunity or promote atopy in susceptible individuals.

The Influence of Innate Lymphoid Cells and Unconventional T Cells in Chronic Inflammatory Lung Disease.

The lungs are continuously subjected to environmental insults making them susceptible to infection and injury. They are protected by the respiratory epithelium, which not only serves as a physical barrier but also a reactive one that can release cytokines, chemokines, and other defense proteins in response to danger signals, and can undergo conversion to protective mucus-producing goblet cells. The lungs are also guarded by a complex network of highly specialized immune cells and their mediators to support tissue homeostasis and resolve integrity deviation. This review focuses on specialized innate-like lymphocytes present in the lung that act as key sensors of lung insults and direct the pulmonary immune response. Included amongst these tissue-resident lymphocytes are innate lymphoid cells (ILCs), which are classified into five distinct subsets (natural killer, ILC1, ILC2, ILC3, lymphoid tissue-inducer cells), and unconventional T cells including natural killer T (NKT) cells, mucosal-associated invariant T (MAIT) cells, and γδ-T cells. While ILCs and unconventional T cells together comprise only a small proportion of the total immune cells in the lung, they have been found to promote lung homeostasis and are emerging as contributors to a variety of chronic lung diseases including pulmonary fibrosis, allergic airway inflammation, and chronic obstructive pulmonary disease (COPD). A particularly intriguing trait of ILCs that has recently emerged is their plasticity and ability to alter their gene expression profiles and adapt their function in response to environmental cues. The malleable nature of these cells may aid in rapid responses to pathogen but may also have downstream pathological consequences. The role of ILC2s in Th2 allergic airway responses is becoming apparent but the contribution of other ILCs and unconventional T cells during chronic lung inflammation is poorly described. This review presents an overview of our current understanding of the involvement of ILCs and unconventional T cells in chronic pulmonary diseases.

Granulocyte-CSF links destructive inflammation and comorbidities in obstructive lung disease.

Chronic obstructive pulmonary disease (COPD) is an incurable inflammatory lung disease that afflicts millions of people worldwide, and it is the fourth leading cause of death. Systemic comorbidities affecting the heart, skeletal muscle, bone, and metabolism are major contributors to morbidity and mortality. Given the surprising finding in large prospective clinical biomarker studies that peripheral white blood cell count is more closely associated with disease than inflammatory biomarkers, we probed the role of blood growth factors. Using the SHIP-1-deficient COPD mouse model, which manifests a syndrome of destructive lung disease and a complex of comorbid pathologies, we have identified a critical and unexpected role for granulocyte-CSF (G-CSF) in linking these conditions. Deletion of G-CSF greatly reduced airway inflammation and lung tissue destruction, and attenuated systemic inflammation, right heart hypertrophy, loss of fat reserves, and bone osteoporosis. In human clinical translational studies, bronchoalveolar lavage fluid of patients with COPD demonstrated elevated G-CSF levels. These studies suggest that G-CSF may play a central and unforeseen pathogenic role in COPD and its complex comorbidities, and identify G-CSF and its regulators as potential therapeutic targets.