Manual Lung Biology in Health & Disease Volume 177 Therapeutic Targets in Airway Inflammation

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A variety of chemokines and immune cells are involved in the dys-regulation of immune responses in CF airway pathology. However, overexpression of IL-8 and infiltration of neutrophils are the two major markers representing hyperinflammation in CF airways and associated with the clinical status of CF patients. IL-8 is produced by macrophages, epithelial cells, airway smooth muscle cells, endothelial cells, etc. The gene of IL-8 is located at chromosome 4qq21 in human [ 27 ].

It is initially produced as a precursor peptide of 99 amino acids which undergoes cleavage to create several active IL-8 isoforms [ 28 ]. Multiple stimulators such as P. However the redundancy of the phosphoproteins and transcription factors involved in IL-8 expression indicates that no single step can completely inhibit IL-8 gene transcription. The airway epithelial cells AECs , together with mucins secreted by intraepithelial goblet cells, form a physical barrier.

They also express pattern recognition receptors PRRs which recognize pathogen associated molecular patterns PAMPs , resulting in the production of proinflammatory cytokines and chemokines, as well as activation and recruitment of immune cells, such as granulocytes and lymphocytes to the site of infection. Airway surface dehydration and inefficient mucociliary clearance resulting from abnormal CFTR function disable the physical barrier of airway, which predisposes the airway to chronic infection with pathogens, such as S. The factors contributing to the inflammatory progression in CF airways still remain elusive.

Some evidence suggests that the hyper-inflammation of the airway is triggered by the infection of bacteria and viruses [ 52 , 53 ], whereas others argue that the intrinsic deficiency of CFTR functions is the primary factor which causes the CF airway prone to inflammation even in the absence of appreciable colonization of bacteria [ 54 , 55 ].

AECs are one of the major sources of chemokines including IL-8 in the airway during inflammatory response. Many clinical data shows that airway inflammation occurred at the early age of CF patients in the absence of appreciable colonization of bacteria [ 55 ].


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This phenomenon substantially supports the argument that the intrinsic deficiency of CFTR functions might be the primary factor which makes the CF airway prone to inflammation [ 54 ]. In vitro experiments also prove that the basal expression or secretion of IL-8 is upregulated without any stimulation of pathogens or cytokines in AECs with mutated CFTR [ 55 ]. CF patients are often infected with certain opportunistic bacteria, and bronchoalveolar lavage BAL samples from different loci of airway show different features [ 57 ].

Those factors should be considered when the infection status and inflammatory conditions are evaluated. Moreover, multiple biological factors or chemicals in the air could challenge the airways of the infants with CF. Atmospheric pollutants such as ozone can cause increased IL-8 production in CF airway epithelial cell lines [ 58 ]. Multiple factors such as cell type, genetic manipulation, culturing medium and materials might affect the cell signaling involved in the proinflammatory responses including the secretion of IL-8 [ 62 — 64 ].

Cells from CF patients might have been pre-activated by some pathogens and the effects might still persist, at least partially, even after the samples are cultured in the medium for a period of time. CF disease is a genetic disorder which has been acquired since embryogenesis [ 2 ]. Some studies demonstrated that CFTR is critical to the development of lung during embryogenesis [ 65 ], and CFTR functions as more than just an ion channel [ 66 ].

But the possible off-target, non-specific effects of CFTRinh should also be considered when interpreting the results [ 68 ]. CF lung disease is characterized by chronic infection especially by some opportunistic pathogens in airways. The TLRs are expressed on various immune and non-immune cells including B lymphocytes, natural killer NK cells, macro-phages, dendritic cells, fibroblast cells, epithelial cells, and endothelial cells [ 72 ]. The expression of TLRs in airway epithelial cells is important in inflammation and immunity in response to inhaled pathogens.

However, the uncontrolled or deregulated immune response mediated by TLRs might be the critical trigger for the exaggerated inflammatory responses and lung fibrosis in CF. Roussel et al. Antigny et al. The regulated production of proinflammatory and antiinflammatory cytokines is important for the efficient immune response against infection and wound healing. The enhanced expression of proinflammatory cytokines and insufficient production of anti-inflammatory cytokines such as IL lead to the exaggerated inflammatory responses in CF lung disease.

Positive feedback serves to amplify inflammatory signals. The low levels of the anti-inflammatory cytokine IL has been observed in CF cells [ , ]. It functions as a potent and pleiotropic transcriptional activator in the signal-transducing pathways activated by a wide variety of pathogenic signals and cytokines [ ]. The production of cytokines is predominantly regulated by the transcription rates of cytokine genes instead of secretion in response to the inflammatory stimuli. Therefore transcription factors are critical in regulating inflammation mediated by cytokines and chemokines [ ].

Hunter et al. Weber et al. Schmidt et al. These findings provide insight into the regulatory mechanism involved in the cytokine-induced specific and temporal gene expression [ ].

Leukotriene receptors as potential therapeutic targets

Hoffmann et al. In addition, the formation of functional A20 ubiquitin editing complex is also abnormal. Hence, the aberrant expression and function of A20 might be one of the reasons for the persistent nuclear expression of P65 and overexpression of IL-8 in CF airway cells [ ]. Neutrophil recruitment to sites of infection or injury is a crucial step in the inflammatory response of the innate immune system, protecting the host from invading bacteria. However, uncontrolled neutrophil infiltration often leads to tissue dysfunction and damage [ ].

Therefore, blocking neutrophil transmigration across cellular barriers such as mucosal or airway epithelium represents an effective approach to prevent excessive inflammation in many diseases including cystic fibrosis. The chemokine receptor CXCR2 is a major receptor regulating recruitment of neutrophils in acute and chronic inflamed tissues [ ]. Activation of CXCR2 by its cognate ligands such as IL-8 induces intracellular signals associated with chemotaxis, recruitment and infiltration of leukocytes especially neutrophils from the bloodstream during inflammation [ ].

CXCR2 signaling must be tightly regulated to provide both effective immune protection and avoid inflammation-induced pathology.

Dysregulated Chemokine Signaling in Cystic Fibrosis Lung Disease: A Potential Therapeutic Target

Thus, the mechanisms that fine-tune the CXCR2-mediated inflammatory response are of particular importance. Investigations focused on identifying CXCR2 molecular pathways involved in cellular dysfunctions in CF may help identify new therapeutic targets that, in combination with current treatments, could improve the life expectancy for CF patients.

In a recent clinical trial, an oral and well-tolerated CXCR2 antagonist, SB, was administrated into adult subjects with cystic fibrosis, who showed trends for improvement in sputum inflammatory biomarkers, although with an increase in systemic inflammatory markers [ ].

Inflammation in cystic fibrosis: An update

Therefore, CXCR2 biological axis appears to represent an attractive potential therapeutic target [ ]. However, targeting CXCR2 receptor alone may lead to undesired global effects as CXCR2 has also been reported in many other vital cellular functions, such as in preservation of oligodendrocyte function and myelinization of neural tissues[ ]. Therefore, it is important to identify selective therapeutic targets that might be specific for neutrophil-dominated inflammation as in CF lung disease.

A variety of PDZ scaffold proteins have been documented to mediate the formation of compartmentalized multi-protein complexes critical for efficient and specific signaling in cells [ — ]. Recently, we have demonstrated that the PDZ motif of CXCR2 plays an important role in regulating neutrophil functions as disrupting this interaction mediated by PDZ motif via using an exogenous peptide mimic mapping CXCR2 PDZ motif potently and significantly inhibited CXCR2-mediated calcium mobilization and neutrophil chemotaxis and transepithelial migration, suggesting that CXCR2 signaling complex could be a potential therapeutic target for neutrophil dominant inflammatory diseases, such as cystic fibrosis [ ].

Bhattacharyya et al. Especially, the expression of miR was found more than 5-fold elevated in CF lung epithelial cells in culture, compared with control cells. MiR was also increased in lung epithelial cells and circulating neutrophils collected from CF patients, as compared with non-CF samples.

Another study by Fabbri et al. Multiple cytokines and chemokines are involved in the pathophysiologic process of CF lung disease. Targeting one cytokine or chemokine might not achieve significant and long-term clinical effects. Considering that a single miR can target several mRNAs [ ], miRs might be an optimal candidate for treatment of hyper-inflammatory conditions of CF lung disease if the association between specific miRs and the pathophysiology of cystic fibrosis lung disease has been well established.

The discovery of CFTR gene 25 years ago has led to the much clearer understanding of the molecular and cellular pathogenesis of CF. However, the processes that initiate and perpetuate CF lung disease still remain incompletely understood.

Review Series

The mechanisms and pathways responsible for lung inflammation in CF are still under debate. The hallmarks of CF lung disease are respiratory infections by opportunistic pathogens and the deregulated inflammatory responses. Multiple defective inflammatory responses have been linked to the deficiency of CFTR, including dysregulated innate and acquired immunity, abnormal lipid metabolism, defective molecular signaling, etc.

Diverse therapeutic strategies have been developed to disrupt pathophysiologic cascade in CF lung disease, such as CFTR potentiators and correctors [ ], dornase alpha [ ], and antibiotics [ ], which may indirectly promote the resolution of over-inflammation in CF airway.

Drugs directly targeting the inflammatory mediators, such as leukotriene B4, have been shown to slow the decline in lung function and improve survival [ , ]. Clinical trials using anti-inflammatory drugs in CF patients have been conducted for more than 30 years. Although the outcome shows promise but the progress is still relatively small. Ibuprofen has been the only anti-inflammatory drug currently recommended for the long-term treatment of CF airway inflammation [ ]. Therefore, there is still a relatively long way to go before safe, effective, and affordable therapies emerge.

The author s confirm that this article content has no conflict of interest.

Small Airway-on-a-Chip: Modeling COPD and Asthma

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