Pharmacol Rep. 2021 Apr 21. doi: 10.1007/s43440-021-00255-x. Online ahead of print.

ABSTRACT

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes pulmonary injury or multiple-organ injury by various pathological pathways. Transforming growth factor-beta (TGF-β) is a key factor that is released during SARS-CoV-2 infection. TGF-β, by internalization of the epithelial sodium channel (ENaC), suppresses the anti-oxidant system, downregulates the cystic fibrosis transmembrane conductance regulator (CFTR), and activates the plasminogen activator inhibitor 1 (PAI-1) and nuclear factor-kappa-light-chain-enhancer of activated B cells (NF-kB). These changes cause inflammation and lung injury along with coagulopathy. Moreover, reactive oxygen species play a significant role in lung injury, which levels up during SARS-CoV-2 infection.

DRUG SUGGESTION: Pirfenidone is an anti-fibrotic drug with an anti-oxidant activity that can prevent lung injury during SARS-CoV-2 infection by blocking the maturation process of transforming growth factor-beta (TGF-β) and enhancing the protective role of peroxisome proliferator-activated receptors (PPARs). Pirfenidone is a safe drug for patients with hypertension or diabetes and its side effect tolerated well.

CONCLUSION: The drug as a theoretical perspective may be an effective and safe choice for suppressing the inflammatory response during COVID-19. The recommendation would be a combination of pirfenidone and N-acetylcysteine to achieve maximum benefit during SARS-CoV-2 treatment.

PMID:33880743 | DOI:10.1007/s43440-021-00255-x

Case Rep Infect Dis. 2021 Apr 4;2021:6615722. doi: 10.1155/2021/6615722. eCollection 2021.

ABSTRACT

Pulmonary infection due to Mycobacterium abscessus occurs in patients with cystic fibrosis, but rarely in immunocompetent children without underlying lung pathology. Treatment is complicated by frequent resistance to many antibiotics. We present a case report of a 4-month-old female infant with 2 months of cough, difficulty feeding, and failure to thrive, with extensive culture-confirmed M. abscessus pulmonary infection without identified immunodeficiency or underlying lung pathology following multidisciplinary evaluation. We describe our complete evaluation including immunodeficiency evaluation incorporating whole-exome sequencing, describe our antibiotic selection and treatment duration given complicated susceptibility pattern of the M. abscessus isolate, and review literature for nontuberculous mycobacterial pulmonary disease in immunocompetent children. A complete multidisciplinary evaluation for underlying lung disease and primary and acquired immunodeficiency should be undertaken in pediatric patients with M. abscessus pneumonia. Confirming macrolide susceptibility through erm(41) gene evaluation is clinically important for isolates with complicated susceptibility pattern.

PMID:33880194 | PMC:PMC8046554 | DOI:10.1155/2021/6615722

Medicine (Baltimore). 2021 Apr 23;100(16):e25246. doi: 10.1097/MD.0000000000025246.

ABSTRACT

Lung adenocarcinoma (LUAD) is a lethal malignancy worldwide and a major public health concern. We explored the potential clinical significance for LUAD of ATP-binding cassette (ABC), sub-family C, consisting of ABCC1-6, 8-12, and cystic fibrosis transmembrane conductance regulator (CFTR).Five hundred LUAD patients from The Cancer Genome Atlas database were used for analysis, including differential expression and diagnostic and prognostic significance. Oncomine and MERAV databases were used to validate differential expression and diagnostic significance. A risk score model was constructed using prognosis-related ABCC members. Prognosis-related genes were further explored to correlate their expression with tumor stage progression. Interaction networks, including biological processes and metabolic pathways, were constructed using Cytoscape software and STRING website.ABCC1-3 consistently showed high expression in tumor tissues (all P ≤ 0.05). Most datasets indicated that ABCC5, 10, and 11 were highly expressed in tumor tissues whereas ABCC6, 9, and CFTR were highly expressed in nontumor tissues (all P ≤ 0.05). Diagnostic significance of ABCC3 and ABCC5 was consistently assessed and validated in three datasets (all area under the curve > 0.700) whereas ABCC6, 8, 10, 11, and CFTR were assessed in The Cancer Genome Atlas dataset and validated in one dataset (all area under the curve > 0.700). Prognostic analysis indicated that ABCC2, 6, and 8 mRNA expression was associated with survival of LUAD (all adjusted P ≤ .037). The risk score model constructed using ABCC2, 6, and 8 suggested prognostic significance for survival predictions. ABCC2 expression was associated with tumor stage, whereas ABCC6 and 8 were not. Interaction networks indicated that they were involved in establishment of localization, ion transport, plasma membrane, apical plasma membrane, adenylyl nucleotide binding, ABC transporters, ABC transporter disorders, ABC-family-protein-mediated transport, and bile secretion.Differentially expressed ABCC2 and ABCC5 might be diagnostic whereas ABCC2, 6, and 8 may be prognostic biomarkers for LUAD, possibly through ABC-family-mediated transporter disorders.

PMID:33879658 | DOI:10.1097/MD.0000000000025246

J Cyst Fibros. 2021 Apr 17:S1569-1993(21)00108-9. doi: 10.1016/j.jcf.2021.03.026. Online ahead of print.

NO ABSTRACT

PMID:33879418 | DOI:10.1016/j.jcf.2021.03.026

Trials. 2021 Apr 20;22(1):292. doi: 10.1186/s13063-021-05224-6.

ABSTRACT

BACKGROUND: Cystic fibrosis (CF) is a genetic disorder, which is caused by the CFTR protein defects. Along with CFTR dysfunction, inflammation plays a key role in the disease outcomes. Inflammation may develop due to the internal dysfunction of the CFTR protein or external factors. Curcumin affects the CFTR protein function primarily as a corrector and potentiator and secondary as an anti-inflammatory and antimicrobial agent. The present study aims to assess the impact of nano-curcumin on clinical and inflammatory markers in children with CF.

METHODS: This prospective, double blind control trial will be conducted at the Akbar Children's Hospital in Mashhad, Iran. Children with CF will be enrolled based on the eligibility criteria. Placebo and curcumin with the maximum dose of 80 mg considering the body surface of the patients will be administrated for 3 months. The primary outcome is to evaluate inflammation based on serum interleukin-6, interleukin-10, and hs-CRP, stool calprotectin, and neutrophil count of nasopharyngeal swab. The secondary outcome involved clinical assessment via spirometry, anthropometrics, and quality of life. They will be assessed before and after 3 months.

DISCUSSION: Due to the multifarious effects of curcumin on CF disease, it could be proposed as a nutritional strategy in the treatment of cystic fibrosis.

TRIAL REGISTRATION: Iranian Registry of Clinical Trials IRCT20200705048018N1 . Registered on July 10, 2020.

PMID:33879218 | DOI:10.1186/s13063-021-05224-6

Int J Infect Dis. 2021 Apr 17:S1201-9712(21)00362-3. doi: 10.1016/j.ijid.2021.04.051. Online ahead of print.

ABSTRACT

We evaluated the activities of dalbavancin and comparator agents against Staphylococcus aureus isolated from the lower respiratory tract of cystic fibrosis (CF) and non-CF patients with pneumonia. Bacterial isolates (n = 357) were collected from CF patients in 36 medical centers worldwide (2018-2019) and susceptibility tested by reference broth microdilution method. Susceptibility results from these isolates were compared to 725 S. aureus isolates consecutively collected from non-CF patients with pneumonia from the same medical centers during the same period. Only isolates determined to be the probable cause of pneumonia were included in the study. Susceptibility profiles were very similar among isolates from CF and non-CF patients. Dalbavancin exhibited potent activity (MIC50/90, 0.03/0.03 mg/L) and complete coverage (100.0% susceptibility) against isolates from CF and non-CF patients. Ceftaroline (MIC50/90, 0.25/1 mg/L) was active against 97.8% and 98.1% of isolates from CF and non-CF patients, respectively. Oxacillin resistance (MRSA) rates were 27.7% among CF and 28.7% among non-CF patients. Among MRSA isolates from CF/non-CF patients (n = 99/208), susceptibility to ceftaroline, clindamycin, levofloxacin, and tetracycline were 91.9%/93.3%, 58.6%/64.4%, 40.4%/29.3%, 83.8%/89.4%, respectively. Dalbavancin demonstrated high potency against S. aureus from CF and non-CF patients and may represent a valuable treatment option for CF patients with MRSA pulmonary infection.

PMID:33878463 | DOI:10.1016/j.ijid.2021.04.051

Chest. 2021 Apr 17:S0012-3692(21)00697-8. doi: 10.1016/j.chest.2021.04.010. Online ahead of print.

ABSTRACT

BACKGROUND: Understanding how health outcomes differ for cystic fibrosis (CF) patients with advanced lung disease in the United States (US) compared to Canada has health policy implications.

RESEARCH QUESTION: What are rates of lung transplant (LTx) and rates of death without LTx in the US and Canada among individuals with forced expiratory volume in 1 second (FEV1) <40% predicted?

STUDY DESIGN: and Methods: Retrospective population-based cohort study, 2005-2016, using the US CF Foundation, United Network for Organ Sharing, and Canadian CF registries. Individuals with CF and ≥2 FEV1 measurements <40% predicted within a 5-year period, age ≥6 years, without prior LTx were included. Multivariable competing risk regression for time to death without LTx (LTx as a competing risk) and time to LTx (death as a competing risk) was performed.

RESULTS: There were 5,899 (53% male) and 905 (54% male) CF patients with FEV1 <40% predicted in the US and Canada, respectively. Multivariable competing risk regression models identified an increased risk of death without LTx (HR 1.79, 95% CI 1.52-2.1) and decreased LTx (HR 0.66, 95% CI 0.58-0.74) among individuals in the US compared to Canada. More pronounced differences were seen in the patients in the US with Medicaid/Medicare insurance compared to Canadians (multivariable HR for death without LTx 2.24, 95% CI 1.89-2.64; multivariable HR for LTx 0.54, 95% CI 0.47-0.61). Patients with non-White race were also disadvantaged (multivariable HR for death without LTx 1.56, 95% CI 1.32-1.84; multivariable HR for LTx 0.47, 95% CI 0.36-0.62).

INTERPRETATION: There are lower rates of LTx and an increased risk of death without LTx for CF patients with FEV1 <40% predicted in the US compared to Canada. Findings are more striking among US CF patients with Medicaid/Medicare health insurance, and non-White patients in both countries, raising concerns about underutilization of LTx among vulnerable populations.

PMID:33878343 | DOI:10.1016/j.chest.2021.04.010

Methods Mol Biol. 2021;2302:49-67. doi: 10.1007/978-1-0716-1394-8_4.

ABSTRACT

Ion channels play crucial roles in cell physiology, and are a major class of targets for clinically relevant pharmaceuticals. Because they carry ionic current, the function and pharmacology of ion channels can be studied using electrophysiological approaches that range in resolution from the single molecule to many millions of molecules. This chapter describes electrophysiological approaches for the study of one representative ion channel that is defective in a genetic disease, and that is the target of so-called highly effective modulator therapies now used in the clinic: the cystic fibrosis transmembrane conductance regulator (CFTR). Protocols are provided for studying CFTR expressed heterologously, for CFTR expressed in situ in airway epithelial cells, and for purified or partially purified CFTR protein reconstituted into planar lipid bilayers.

PMID:33877622 | DOI:10.1007/978-1-0716-1394-8_4

Methods Mol Biol. 2021;2302:21-35. doi: 10.1007/978-1-0716-1394-8_2.

ABSTRACT

Reconstitution of detergent-solubilized membrane proteins into phospholipid bilayers allows for functional and structural studies under close-to-native conditions that greatly support protein stability and function. Here we outline the detailed steps for membrane protein reconstitution to result in proteoliposomes and nanodiscs. Reconstitution can be achieved via a number of different strategies. The protocols for preparation of proteoliposomes use detergent removal via dialysis or via nonpolar polystyrene beads, or a mixture of the two methods. In this chapter, the protocols for nanodiscs apply polystyrene beads only. Proteoliposome preparation methods allow for substantial control of the lipid-to-protein ratio, from minimal amounts of phospholipid to high concentrations, type of phospholipid, and mixtures of phospholipids. In addition, dialysis affords a fairly large degree of control and variation of parameters such as rate of reconstitution, temperature, buffer conditions, and proteoliposome size. For the nanodisc approach, which is highly advantageous for ensuring equal access to both membrane sides of the protein as well as fast reconstitution of only a single membrane protein into a well-defined bilayer environment in each nanodisc, the protocols outline how a number of these parameters are more restricted in comparison to the proteoliposome protocols.

PMID:33877620 | DOI:10.1007/978-1-0716-1394-8_2

Antimicrob Agents Chemother. 2021 Apr 19:AAC.02318-20. doi: 10.1128/AAC.02318-20. Online ahead of print.

ABSTRACT

Ceftolozane-tazobactam (C/T) is a new fifth-generation cephalosporin/β-lactamase inhibitor combination approved by the Food and Drug Administration and the European Medicines Agency for treatment of complicated intra-abdominal infections, complicated urinary tract infections, and hospital-acquired pneumonia in adult patients. This review will briefly describe the pharmacology of C/T and focus on the emerging clinical trial and real-world data supporting its current utilization. Additionally, our synthesis of this data over time has set our current usage of C/T at Barnes-Jewish Hospital (BJH). C/T is primarily employed as directed monotherapy at BJH when P. aeruginosa isolates are identified with resistance to other beta-lactams. C/T can also be used empirically at BJH prior to microbiologic detection of an antibiotic-resistant P. aeruginosa isolate in specific clinical situations. These situations include critically ill patients in the ICU setting where there is a high likelihood of infection with multidrug-resistant (MDR) P. aeruginosa including patients failing therapy with a carbapenem, specific patient populations known to be at high risk for infection with MDR P. aeruginosa (e.g., lung transplant and cystic fibrosis patients), and patients know to have previous infection or colonization with MDR P. aeruginosa.

PMID:33875428 | DOI:10.1128/AAC.02318-20

J Cyst Fibros. 2021 Apr 16:S1569-1993(21)00109-0. doi: 10.1016/j.jcf.2021.03.027. Online ahead of print.

ABSTRACT

BACKGROUND: Trial participation can allow people with CF early access to CFTR modulator therapies, with high potential for clinical benefit. Therefore, the number of people wishing to participate can substantially exceed the number of slots available. We aimed to understand how the CF community thinks slots to competitive trials should be allocated across the UK and whether this should be driven by clinical need, patients' engagement/adherence or be random. For the latter, we explored site-level versus registry-based, national randomisation processes.

METHODS: We developed an online survey, recruiting UK-based stakeholders through social media, newsletters and personal contacts. Closed questions were analysed for frequencies and percentages of responses. Free-text questions were analysed using thematic analysis.

RESULTS: We received 203 eligible responses. Overall, 75% of stakeholders favoured allocation of slots to individual sites based on patient population size, although pharma favoured allocation based on previous metrics. Currently, few centres have defined strategies for allocating slots locally. At face-value, stakeholders believe all eligible participants should have an equal chance of getting a slot. However, further questioning reveals preference for prioritisation strategies, primarily perceived treatment adherence, although healthcare professionals were less likely to favour this strategy than other stakeholder groups. The majority of stakeholders would prefer to allocate slots and participate in trials locally but 80% said if necessary, they would engage in a system of national allocation.

CONCLUSIONS: Fair allocation to highly competitive trials does not appear to have a universally acceptable solution. Therefore, transparency and empathy remain critical to negotiate this uncertain territory.

PMID:33875366 | DOI:10.1016/j.jcf.2021.03.027

Paediatr Respir Rev. 2021 Mar 11:S1526-0542(21)00022-1. doi: 10.1016/j.prrv.2021.03.001. Online ahead of print.

NO ABSTRACT

PMID:33875358 | DOI:10.1016/j.prrv.2021.03.001

J Card Fail. 2021 Apr 16:S1071-9164(21)00122-6. doi: 10.1016/j.cardfail.2021.04.001. Online ahead of print.

ABSTRACT

BACKGROUND: Angiopoietin-1 and 2 (Ang1, Ang2) are important mediators of angiogenesis. Angiopoietin levels are perturbed in cardiovascular disease, but it is unclear whether angiopoietin signaling is causative, an adaptive response, or merely epiphenomenon of disease activity.

METHODS AND RESULTS: In a cohort free of cardiovascular disease at baseline (MESA), relationships between angiopoietins, cardiac morphology, and subsequent incidence of heart failure or cardiovascular death were evaluated. In cohorts with pulmonary arterial hypertension (PAH) or left heart disease (LHD), associations between angiopoietins, invasive hemodynamics, and adverse clinical outcomes were evaluated. In MESA, Ang2 was associated with a higher incidence of heart failure or cardiovascular death (HR 1.21 per standard deviation, P<0.001). Ang2 was associated with increased right atrial pressure (PAH cohort) and increased wedge pressure and right atrial pressure (LHD cohort). Elevated Ang2 was associated with mortality in the PAH cohort.

CONCLUSION: Ang2 was associated with incident heart failure or death among adults without cardiovascular disease at baseline and with disease severity in individuals with existing heart failure. Our findings that Ang2 is elevated prior to disease onset and that elevations reflect disease severity, suggest Ang2 may contribute to heart failure pathogenesis.

PMID:33872759 | DOI:10.1016/j.cardfail.2021.04.001

ACS Infect Dis. 2021 Apr 19. doi: 10.1021/acsinfecdis.1c00045. Online ahead of print.

ABSTRACT

Pseudomonas aeruginosa is a Gram-negative opportunistic pathogen that is frequently found in the airways of cystic fibrosis (CF) patients due to the dehydrated mucus that collapses the underlying cilia and prevents mucociliary clearance. During this life-long chronic infection, P. aeruginosa cell accumulates mutations that lead to inactivation of the mucA gene that results in the constitutive expression of algD-algA operon and the production of alginate exopolysaccharide. The viscous alginate polysaccharide further occludes the airways of CF patients and serves as a protective matrix to shield P. aeruginosa from host immune cells and antibiotic therapy. Development of inhibitors of alginate production by P. aeruginosa would reduce the negative impact from this viscous polysaccharide. In addition to transcriptional regulation, alginate biosynthesis requires allosteric activation by bis (3'-5')-cyclic dimeric guanosine monophosphate (c-di-GMP) binding to an Alg44 protein. Previously, we found that ebselen (Eb) and ebselen oxide (EbO) inhibited diguanylate cyclase from synthesizing c-di-GMP. In this study, we show that EbO, Eb, ebsulfur (EbS), and their analogues inhibit alginate production. Eb and EbS can covalently modify the cysteine 98 (C98) residue of Alg44 and prevent its ability to bind c-di-GMP. However, P. aeruginosa with Alg44 C98 substituted with alanine or serine was still inhibited for alginate production by Eb and EbS. Our results indicate that EbO, Eb, and EbS are lead compounds for reducing alginate production by P. aeruginosa. Future development of these inhibitors could provide a potential treatment for CF patients infected with mucoid P. aeruginosa.

PMID:33871968 | DOI:10.1021/acsinfecdis.1c00045

Front Pediatr. 2021 Apr 1;9:663228. doi: 10.3389/fped.2021.663228. eCollection 2021.

ABSTRACT

Drug desensitization can be achieved successfully by gradual drug dose increases in different protocols. Most protocols are designed to obtain temporal tolerance. The data on long-term maintenance of drug tolerance is scarce. Based on an IgE-mediated colomycin allergy we describe the maintenance of drug tolerance to nebulized drug for the period of 10 years in a 15-year-old cystic fibrosis patient, proceeded by successful rush intravenous desensitization protocol. The mechanism of drug tolerance is largely speculative; however, long-term maintenance of it seems achievable by continuous local drug application.

PMID:33869120 | PMC:PMC8049140 | DOI:10.3389/fped.2021.663228

Front Pediatr. 2021 Mar 31;9:640184. doi: 10.3389/fped.2021.640184. eCollection 2021.

ABSTRACT

Cystic Fibrosis (CF) lung damage begins early in life. Lung function decline is associated with pulmonary infections, neutrophil infiltration and inflammation. In CF, neutrophils have an altered phenotype. In this pilot study, we aimed to determine if signals of dysfunctional neutrophil responses were evident early in life and whether these signals may be associated with lung damage in later childhood. We examined the pulmonary protein profiles of 14 clinical stable infants and pre-school children with CF employing the aptamer-based affinity platform, SOMAscan®. High resolution computed tomography (HRCT) was performed on all children after age 6 years and Brody score calculated. A Spearman's rank order correlation analysis and Benjamini-Hochberg adjustment was used to correlate protein concentrations in early life to Brody scores in later childhood. Early life concentrations of azurocidin and myeloperoxidase, were positively correlated with Brody score after age 6 (p = 0.0041 and p = 0.0182, respectively). Four other neutrophil associated proteins; Complement C3 (p = 0.0026), X-ray repair CCP 6 (p = 0.0059), C3a anaphylatoxin des Arginine (p = 0.0129) and cytokine receptor common subunit gamma (p = 0.0214) were all negatively correlated with Brody scores. Interestingly, patients with more severe lung damage after age 6 had significantly lower levels of IL-22 in early years of life (p = 0.0243). IL-22 has scarcely been reported to have implications in CF. Identification of early biomarkers that may predict more severe disease progression is particularly important for the future development of early therapeutic interventions in CF disease. We recommend further corroboration of these findings in prospective validation studies.

PMID:33869115 | PMC:PMC8044422 | DOI:10.3389/fped.2021.640184

Front Cell Infect Microbiol. 2021 Apr 1;11:656984. doi: 10.3389/fcimb.2021.656984. eCollection 2021.

ABSTRACT

Biogenic silver nanoparticles (bio-AgNPs) are increasingly recognized as an antibiofilm and antivirulence strategy against P. aeruginosa, a bacterium that causes chronic infections in immunocompromised and cystic fibrosis patients. This study aimed to investigate the effects of subinhibitory concentrations of bio-AgNPs on motility and biofilm formation in P. aeruginosa. Bio-AgNPs were synthesized via reduction of ionic silver catalyzed by cell-free culture filtrate from Fusarium oxysporum. A total of 17 P. aeruginosa isolates and strains were evaluated for swarming, swimming, and twitching motility in the presence and absence (control) of bio-AgNPs, including 10 clinical isolates from patients with and without cystic fibrosis, 5 environmental isolates obtained from the public water supply system, and 2 reference strains (PAO1 and PA14). Isolates were identified by biochemical and molecular methods. Minimum inhibitory concentrations (MICs) were determined by the broth microdilution method. Swarming, swimming, and twitching motility assays were performed in Petri dishes. Biofilm formation capacity was assessed quantitatively by the crystal violet method. MIC values ranged from 15.62 to 62.50 µM. The results showed that subinhibitory concentrations of bio-AgNPs (½ MIC, 7.81-31.25 µM) significantly increased (p < 0.05) swarming, swimming, and twitching motility in 40.0, 40.0, and 46.7% of isolates, respectively. Subinhibitory bio-AgNP treatment enhanced (p < 0.05) biofilm formation capacity in PA14 and a cystic fibrosis isolate (P11). It is concluded that subinhibitory concentrations of bio-AgNPs increased biofilm formation and swarming, swimming, and twitching motility in PA14 and some P. aeruginosa isolates. These virulence factors are directly involved with quorum-sensing systems. Further research should investigate the effects of AgNPs on P. aeruginosa quorum sensing to help elucidate their mechanism of action at subinhibitory concentrations.

PMID:33869087 | PMC:PMC8047417 | DOI:10.3389/fcimb.2021.656984

Front Immunol. 2021 Mar 31;12:654649. doi: 10.3389/fimmu.2021.654649. eCollection 2021.

ABSTRACT

Extracellular traps released by neutrophils (NETs) are essential for the clearance of Pseudomonas aeruginosa. Alkaline protease (AprA) secreted by P. aeruginosa negatively correlates with clinical improvement. Moreover, anti-AprA in patients with cystic fibrosis (CF) can help identify patients with aggressive forms of chronic infection. However, the mechanism underlying the clinical outcomes remains unclear. We demonstrated that aprA deficiency in P. aeruginosa decreased the bacterial burden and reduced lung infection. AprA degraded NET components in vitro and in vivo but did not affect NET formation. Importantly, antibodies induced by AprA acted as an agonist and directly enhanced the degrading activities of AprA. Moreover, antisera from patients with P. aeruginosa infection exhibited antibody-dependent enhancement (ADE) similar to that of the antibodies we prepared. Our further investigations showed that the interaction between AprA and the specific antibodies might make the enzyme active sites better exposed, and subsequently enhance the recognition of substrates and accelerate the degradation. Our findings revealed that AprA secreted by P. aeruginosa may aggravate infection by destroying formed NETs, an effect that was further enhanced by its antibodies.

PMID:33868297 | PMC:PMC8044376 | DOI:10.3389/fimmu.2021.654649

Front Immunol. 2021 Mar 24;12:653969. doi: 10.3389/fimmu.2021.653969. eCollection 2021.

ABSTRACT

Under normal physiological conditions, the lung remains an oxygen rich environment. However, prominent regions of hypoxia are a common feature of infected and inflamed tissues and many chronic inflammatory respiratory diseases are associated with mucosal and systemic hypoxia. The airway epithelium represents a key interface with the external environment and is the first line of defense against potentially harmful agents including respiratory pathogens. The protective arsenal of the airway epithelium is provided in the form of physical barriers, and the production of an array of antimicrobial host defense molecules, proinflammatory cytokines and chemokines, in response to activation by receptors. Dysregulation of the airway epithelial innate immune response is associated with a compromised immunity and chronic inflammation of the lung. An increasing body of evidence indicates a distinct role for hypoxia in the dysfunction of the airway epithelium and in the responses of both innate immunity and of respiratory pathogens. Here we review the current evidence around the role of tissue hypoxia in modulating the host-pathogen interaction at the airway epithelium. Furthermore, we highlight the work needed to delineate the role of tissue hypoxia in the pathophysiology of chronic inflammatory lung diseases such as asthma, cystic fibrosis, and chronic obstructive pulmonary disease in addition to novel respiratory diseases such as COVID-19. Elucidating the molecular mechanisms underlying the epithelial-pathogen interactions in the setting of hypoxia will enable better understanding of persistent infections and complex disease processes in chronic inflammatory lung diseases and may aid the identification of novel therapeutic targets and strategies.

PMID:33868294 | PMC:PMC8044850 | DOI:10.3389/fimmu.2021.653969

Acta Paediatr. 2021 Apr 18. doi: 10.1111/apa.15880. Online ahead of print.

ABSTRACT

Cystic fibrosis (CF) is an orphan disease with increased morbidity and mortality, mainly due to chronic pulmonary infections. The symptoms and treatment are complex, and patients are followed at specialised CF centres. The exact treatment, and the segregation policies to avoid cross-infection from airway pathogens, vary between CF centres, including those in Scandinavian countries.

PMID:33866605 | DOI:10.1111/apa.15880