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• Recent Publications

• P. aeruginosa tRNA-fMet halves secreted in outer membrane vesicles suppress lung inflammation in cystic fibrosis.
  Li Z, Barnaby R, Nymon A, Roche C, Koeppen K, Ashare A, Hogan DA, Gerber SA, Taatjes DJ, Hampton TH, Stanton BA
  Am J Physiol Lung Cell Mol Physiol. 2024 May 1;326(5):L574-L588. doi: 10.1152/ajplung.00018.2024. Epub 2024 Mar 5.
  PMID: 38440830

  Comparative effects of CFTR modulators on phagocytic, metabolic and inflammatory profiles of CF and nonCF macrophages.
  Aridgides DS, Mellinger DL, Gwilt LL, Hampton TH, Mould DL, Hogan DA, Ashare A
  Sci Rep. 2023 Jul 25;13(1):11995. doi: 10.1038/s41598-023-38300-9. Epub 2023 Jul 25.
  PMID: 37491532

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Lung Diseases

Cystic Fibrosis

Cystic fibrosis (CF) is a common life-limiting autosomal recessive genetic disorder, with highest prevalence in Europe, North America, and Australia. The disease is caused by mutation of a gene that encodes a chloride-conducting transmembrane channel called the cystic fibrosis transmembrane conductance regulator (CFTR), which regulates anion transport and muco-ciliary clearance in the airways. Functional failure of CFTR results in mucus retention and chronic infection and subsequently in local airway inflammation that is harmful to the lungs. CFTR dysfunction mainly affects epithelial cells, although there is evidence of a role in immune cells. Important comorbidities caused by epithelial cell dysfunction occur in the pancreas, liver, sweat glands, and vas deferens (Elborn Lancet 2016; (16):1-6).

In the lung, macrophages play a key role in inflammation and tissue repair tailoring their behavior to signals from their environment including secretion of chemotactic cytokines that attract additional monocytes/ macrophages and neutrophils to the lung.

The dominant pathology in the lung is inflammation generated primarily by failure to clear microorganisms and the generation of a toxic pro-inflammatory local microenvironment. Lung disease starts early in life with CT scan evidence of bronchiectasis in about a third of patients within the first few months. Bronchiectasis is associated with raised concentrations of neutrophil elastase, which further disrupts innate immunity, increases mucus production, damages peptides and proteins in the airway, and digests the extracellular matrix.

Physiologically, CF causes the mucus that accumulates in the lungs to be thick and sticky. The mucus clogs the lungs, causing breathing problems and making it easy for bacteria to grow. This can lead to repeated lung infections and lung damage. The symptoms and severity of CF can vary. Some people have serious problems from birth. Others have a milder version of the disease that doesn't show up until they are teens or young adults. CF is diagnosed through various tests, such as gene, blood, and sweat tests. Lung infections are treated with antibiotics which may be given intravenously, inhaled, or by mouth. Today, with improved treatments, some people who have CF are living into their forties, fifties, or older. Treatments may include chest physical therapy, nutritional and respiratory therapies, medicines, and exercise.

Chronic Obstructive Pulmonary Disorder (COPD)

Chronic obstructive pulmonary disease is a chronic heterogeneous disease of the lungs characterized by persistent and excessive inflammation, leading to tissue remodeling, alveolar lesions, airflow limitation and accelerated lung function decline. Over 300 million people suffer from COPD. It is currently the fourth leading cause of death worldwide and predicted by the World Health Organization to become the third leading cause by 2030. Cigarette smoking is the predominant risk factor for COPD, while exposure to other noxious gases has also been identified as a risk factor. Although smoking cessation can delay disease progression, there is no cure for COPD and current medication cannot reverse the long-term decline in lung function. Inhaled cigarette smoke first encounters the airway epithelium, which forms a continuous and highly regulated barrier. The exposure of airway epithelium to noxious particles like cigarette smoke causes the release of pro-inflammatory mediators, including damage-associated molecular patterns and cytokines like interleukin (IL)-1, IL-8 and tumor necrosis factor (TNF)-α. Inflammatory cytokines cause lung infiltration by inflammatory cells that further amplify the inflammation and release proteases and reactive oxidative species that damage the parenchymal lung tissue, contributing to emphysema development in COPD patients . Repeated injury leads to fibroblast activation, which causes excessive extracellular matrix deposition and remodeling of the small airways in COPD. However, fibroblasts appear unable to provide adequate tissue repair after smoke-induced damage in the parenchyma of COPD lungs (Osei et al Eur Respir J 2015; 46:807-18).

Asthma

Asthma is a complex heterogeneous disease associated with local tissue chronic inflammation of the airway and is characterized by variable and recurring symptoms (including wheezing, coughing, chest tightness, and shortness of breath), reversible airflow obstruction, airway remodeling, and airway hyper-responsiveness. Asthma is ranked as the 14th most important chronic disease worldwide regarding the prevalence, extent, and duration of disability and affects 334 million individuals of all ages, resulting in 90 and 170 deaths per million in female and male individuals, respectively. Asthma is caused by a complex and incompletely understood combination of genetic (polymorphisms of multiple genes) and environmental (such as respiratory infections and particulates PM2.5) factors, which induce an immune response via the infiltration of inflammatory cells into the airway and consequent cytokine release. Emerging evidence shows that Toll-like receptors (TLRs) are associated with the inflammatory response and chronic airway inflammation in asthma. TLRs are a subgroup of pattern recognition receptors (PRRs) that are expressed by cells of the innate immune system and that sense two classes of molecules such as pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs), which then initiates the downstream immune cascades (Dong et al. Mediators Inflamm. 2016).