BACKGROUND: Diabetes mellitus is a systemic disorder associated with inflammation and oxidative stress which may target many organs such as the kidney, retina, and the vascular system. The pathophysiology, mechanisms, and consequences of diabetes on these organs have been studied widely. However, no work has been done on the concept of the lung as a target organ for diabetes and its implications for lung diseases. AIM: In this review, we aimed to investigate the effects of diabetes and hypoglycemic agent on lung diseases, including asthma, chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis, pulmonary hypertension, and lung cancer. We also reviewed the potential mechanisms by which these effects may affect lung disease patients. RESULTS: Our results suggest that diabetes can affect the severity and clinical course of several lung diseases. CONCLUSIONS: Although the diabetes-lung association is epidemiologically and clinically well-established, especially in asthma, the underlying mechanism and pathophysiology are not been fully understood. Several mechanisms have been suggested, mainly associated with the pro-inflammatory and proliferative properties of diabetes, but also in relation to micro- and macrovascular effects of diabetes on the pulmonary vasculature. Also, hypoglycemic drugs may influence lung diseases in different ways. For example, metformin was considered a potential therapeutic agent in lung diseases, while insulin was shown to exacerbate lung diseases; this suggests that their effects extend beyond their hypoglycemic properties.

/pdf/diabetes-and-lung-disease-a-neglected-relationship-1wwwwkkj14.pdf

Diabetes and Lung Disease: A Neglected Relationship.

Airway epithelial cells (AECs) orchestrate inflammatory responses to airborne irritants that enter the respiratory system. A viscous mucus layer produced by goblet cells in the airway epithelium also contributes to a physiological defense mechanism through the physical and chemical barriers it provides. Dysregulation or impairment in these functions has been implicated as a cause of the chronic inflammation and tissue remodeling that constitute major pathological features of asthma. In particular, mucus hypersecretion leading to airway obstruction and impaired pulmonary function is associated with morbidity and mortality in asthma patients. Peroxisome proliferator-activated receptor γ (PPARγ) is a ligand-activated transcription factor involved in a variety of cellular processes. Accumulating evidence indicates that PPARγ agonists antagonize exaggerated inflammatory responses, yet PPARγ's precise role in airway remodeling/mucus hypersecretion has yet to be defined. In this study, we created an AEC-specific PPARγ (AEC-PPARγ) deletion to investigate PPARγ's functions in a murine model of allergic airway disease. AEC-PPARγ deficiency exaggerated airway hyperresponsiveness, inflammation, cytokine expression, and tissue remodeling. We also found that PPARγ directly bound to a PPAR response element found in MUC5AC and repressed gene expression. Likewise, PPARγ regulated mucin and inflammatory factors in primary human bronchial epithelial cells. In light of the current standard therapies' limited and inadequate direct effect on airway mucus hypersecretion, our study showing AEC-PPARγ's role as a transcriptional repressor of MUC5AC highlights this receptor's potential as a pharmacological target for asthma.

Airway Epithelial Cell Peroxisome Proliferator-Activated Receptor γ Regulates Inflammation and Mucin Expression in Allergic Airway Disease.

Cigarette smoke-induced airway inflammationmucus over-production is one of the most important pathogenic features of chronic airway diseases. This study aimed to investigate the effect of berberine, a plant alkaloid with strong anti-inflammatory property, on cigarette smoke-induced airway inflammation and mucushypersecretion in mice. Mice with exposure to cigarette smoke wereintraperitonealy injected with berberin (5, 10 mg/kg·d). Inflammatory cytokines TNF-α, IL-1β and MCP-1 levels in bronchoalveolar lavage fluid were determined by ELISA.Lung tissue was examined for histopathological lesions and goblet cell hyperplasia. The expression of signaling proteins in lung tissue, ERK and P38 were detected using Western Blot. Cigarette smoke exposure significantly increased the release of inflammatory cytokines TNF-α, IL-1β, MCP-1 and inflammatory cells in bronchoalveolar lavage fluid, and it also induced goblet cell hyperplasiaand the expression of mucin-5ac in the airway of mice. Pretreatment of berberineinhibited cigarette smoke-induced airway inflammation and mucus production. Cigarette smoke exposure also increased the expression of ERK and P38, meanwhile, berberineintervention can inhibit such changes. In summary, berberine inhibits cigarette smoke exposure-induced airway inflammation and mucus hypersecretion in mice, which may partly act through inhibition of ERK and P38.

Berberine attenuates cigarette smoke-induced airway inflammation and mucus hypersecretion in mice.

Expression of the pro-oncogenic mucin MUC1 is elevated by inflammation in airway epithelial cells, but the contributions of MUC1 to the development of lung cancer are uncertain. In this study, we developed our finding that cigarette smoke increases Muc1 expression in mouse lung macrophages, where we hypothesized MUC1 may contribute to cigarette smoke-induced transformation of bronchial epithelial cells. In human macrophages, cigarette smoke extract (CSE) strongly induced MUC1 expression through a mechanism involving the nuclear receptor PPAR-γ. CSE-induced extracellular signal-regulated kinase (ERK) activation was also required for MUC1 expression, but it had little effect on MUC1 transcription. RNA interference-mediated attenuation of MUC1 suppressed CSE-induced secretion of TNF-α from macrophages, by suppressing the activity of the TNF-α-converting enzyme (TACE), arguing that MUC1 is required for CSE-induced and TACE-mediated TNF-α secretion. Similarly, MUC1 blockade after CSE induction through suppression of PPAR-γ or ERK inhibited TACE activity and TNF-α secretion. Conditioned media from CSE-treated macrophages induced MUC1 expression and potentiated CSE-induced transformation of human bronchial epithelial cells in a TNF-α-dependent manner. Together, our results identify a signaling pathway involving PPAR-γ, ERK, and MUC1 for TNF-α secretion induced by CSE from macrophages. Furthermore, our results show how MUC1 contributes to smoking-induced lung cancers that are driven by inflammatory signals from macrophages.

https://cancerres.aacrjournals.org/content/canres/74/2/460.full.pdf

MUC1 in macrophage contributions to cigarette smoke-induced lung cancer

Background
Mouse models are useful for studying cigarette smoke (CS)-induced chronic pulmonary pathologies such as lung emphysema. To enhance translation of large-scale omics data from mechanistic studies into pathophysiological changes, we have developed computational tools based on reverse causal reasoning (RCR).

/pdf/transcriptional-profiling-and-targeted-proteomics-reveals-563cn52s08.pdf

Transcriptional profiling and targeted proteomics reveals common molecular changes associated with cigarette smoke-induced lung emphysema development in five susceptible mouse strains

Airway mucus hypersecretion (AMH) is a key pathophysiological feature of chronic airway inflammatory diseases such as bronchial asthma, cystic fibrosis, and chronic obstructive pulmonary disease. AMH contributes to the pathogenesis of chronic airway inflammatory diseases, and it is associated with reduced lung function and high rates of hospitalization and mortality. It has been suggested that AMH should be a target in the treatment of chronic airway inflammatory diseases. Recent evidence suggests that a key regulator of airway inflammation, hyperresponsiveness, and remodeling is peroxisome proliferator-activated receptor gamma (PPARγ), a ligand-activated transcription factor that regulates adipocyte differentiation and lipid metabolism. PPARγ is expressed in structural, immune, and inflammatory cells in the lung. PPARγ is involved in mucin production, and PPARγ agonists can inhibit mucin synthesis both in vitro and in vivo. These findings suggest that PPARγ is a novel target in the treatment of AMH and that further work on this transcription factor may lead to new therapies for chronic airway inflammatory diseases.

/pdf/pparg-as-a-potential-target-to-treat-airway-mucus-17fp29vi09.pdf

PPARγ as a Potential Target to Treat Airway Mucus Hypersecretion in Chronic Airway Inflammatory Diseases.

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PPARγ as a Potential Target to Treat Airway Mucus Hypersecretion in Chronic Airway Inflammatory Diseases.