Inflammatory responses to acute exercise during pulmonary rehabilitation in patients with COPD

Objective Pulmonary rehabilitation is a cornerstone treatment in the management of chronic obstructive pulmonary disease (COPD). Acute bouts of exercise can lead to short bursts of inflammation in healthy individuals. However, it is unclear how COPD patients respond to acute bouts of exercise. This study assessed inflammatory responses to exercise in COPD patients at the start (phase 1) and end (phase 2) of pulmonary rehabilitation. Methods Blood samples were collected before and after an acute exercise bout at the start (phase 1, n = 40) and end (phase 2, n = 27) of pulmonary rehabilitation. The primary outcome was change in fibrinogen concentrations. Secondary outcomes were changes in CRP concentrations, total/differential leukocyte counts, markers of neutrophil activation (CD11b, CD62L and CD66b), and neutrophil subsets (mature, suppressive, immature, progenitor). Results Acute exercise (phase 1) did not induce significant changes in fibrinogen (p = 0.242) or CRP (p = 0.476). Total leukocyte count [mean difference (MD), 0.5 ± 1.1 (109 L−1); p = 0.004], neutrophil count [MD, 0.4 ± 0.8 (109 L−1); p < 0.001], and immature neutrophils (MD, 0.6 ± 0.8%; p < 0.001) increased post-exercise. Neutrophil activation markers, CD11b (p = 0.470), CD66b (p = 0.334), and CD62L (p = 0.352) were not significantly altered post-exercise. In comparison to the start of pulmonary rehabilitation (phase 2), acute exercise at the end of pulmonary rehabilitation led to a greater fibrinogen response (MD, 84 mg/dL (95% CI − 14, 182); p = 0.045). Conclusion An acute bout of exercise does not appear to induce significant alterations in the concentrations of inflammatory mediators but can increase white blood cell subsets post-exercise. A greater fibrinogen response to acute exercise is seen at the end of pulmonary rehabilitation when compared to the start. Further research is required to understand the clinical context of these acute inflammatory responses to exercise

Neutrophil Extracellular Traps in Respiratory Disease: guided anti-microbial traps or toxic webs?

Neutrophil recruitment to the airways and lungs is a major hallmark of many respiratory diseases. One of the more recently discovered unique innate immune effector mechanisms of neutrophils is the formation of neutrophil extracellular traps (NETs), consisting of an extracellular network of DNA fibers studded with nuclear and granule proteins. Although in the respiratory system NETs contribute to capture and inactivation of bacteria, fungi and viruses, there is a delicate 'balance' between aid and damage to the host. Accumulating evidence now suggests that NETs can have direct cytotoxic effects to lung epithelial and endothelial cells and can contribute to airway obstruction. As such, NETs may play an important role in the pathogenesis of respiratory diseases. The purpose of this review is to give an up-to-date overview of the current status of NETs in respiratory diseases. We examine both experimental and clinical data concerning the role of NETs in host defence as well as immunopathology, with special attention paid to the literature relevant for the paediatric pulmonology community. Finally, we discuss future treatment strategies that may target the formation of NETs in the airways and lung

Broadly Reactive Anti-Respiratory Syncytial Virus G Antibodies from Exposed Individuals Effectively Inhibit Infection of Primary Airway Epithelial Cells

Respiratory syncytial virus (RSV) causes severe respiratory disease in young children. Antibodies specific for the RSV prefusion F protein have guided RSV vaccine research, and in human serum, these antibodies contribute to >90% of the neutralization response; however, detailed insight into the composition of the human B cell repertoire against RSV is still largely unknown. In order to study the B cell repertoire of three healthy donors for specificity against RSV, CD27(+) memory B cells were isolated and immortalized using BCL6 and Bcl-xL. Of the circulating memory B cells, 0.35% recognized RSV-A2-infected cells, of which 59% were IgA-expressing cells and 41% were IgG-expressing cells. When we generated monoclonal B cells selected for high binding to RSV-infected cells, 44.5% of IgG-expressing B cells and 56% of IgA-expressing B cells reacted to the F protein, while, unexpectedly, 41.5% of IgG-expressing B cells and 44% of IgA expressing B cells reacted to the G protein. Analysis of the G-specific antibodies revealed that 4 different domains on the G protein were recognized. These epitopes predicted cross-reactivity between RSV strain A (RSV-A) and RSV-B and matched the potency of antibodies to neutralize RSV in HEp-2 cells and in primary epithelial cell cultures. G-specific antibodies were also able to induce antibody-dependent cellular cytotoxicity and antibody-dependent cellular phagocytosis of RSV-A2-infected cells. However, these processes did not seem to depend on a specific epitope. In conclusion, healthy adults harbor a diverse repertoire of RSV glycoprotein-specific antibodies with a broad range of effector functions that likely play an important role in antiviral immunity.IMPORTANCE Human RSV remains the most common cause of severe lower respiratory tract disease in premature babies, young infants, the elderly, and immunocompromised patients and plays an important role in asthma exacerbations. In developing countries, RSV lower respiratory tract disease has a high mortality. Without an effective vaccine, only passive immunization with palivizumab is approved for prophylactic treatment. However, highly potent RSV-specific monoclonal antibodies could potentially serve as a therapeutic treatment and contribute to disease control and mortality reduction. In addition, these antibodies could guide further vaccine development. In this study, we isolated and characterized several novel antibodies directed at the RSV G protein. This information can add to our understanding and treatment of RSV diseas

Human respiratory syncytial virus infection in the pre-clinical calf model

Human respiratory syncytial virus (hRSV) is the most important respiratory pathogen in young children worldwide. Experimental modelling of hRSV disease by bovine RSV (bRSV) infection in calves provides an important tool for developing new strategies for prevention and treatment. Depending on the scientific hypothesis under investigation, this cognate host-virus model might have the disadvantage of using a highly related but not genetically identical virus. In this study, we aim to describe viral kinetics and (clinical) disease characteristics in calves inoculated with hRSV. Our results show that hRSV infects the upper and, to a lesser extent, the lower respiratory tract of calves. Infection causes upper airway clinical disease symptoms and neutrophilic infiltration of the lower airways. We conclude that a hRSV model in calves may aid future research involving distinct scientific questions related to hRSV disease in children.</p

Human respiratory syncytial virus infection in the pre-clinical calf model

Human respiratory syncytial virus (hRSV) is the most important respiratory pathogen in young children worldwide. Experimental modelling of hRSV disease by bovine RSV (bRSV) infection in calves provides an important tool for developing new strategies for prevention and treatment. Depending on the scientific hypothesis under investigation, this cognate host-virus model might have the disadvantage of using a highly related but not genetically identical virus. In this study, we aim to describe viral kinetics and (clinical) disease characteristics in calves inoculated with hRSV. Our results show that hRSV infects the upper and, to a lesser extent, the lower respiratory tract of calves. Infection causes upper airway clinical disease symptoms and neutrophilic infiltration of the lower airways. We conclude that a hRSV model in calves may aid future research involving distinct scientific questions related to hRSV disease in children

Viral load and lung permeability.

(A) Viral loads in viral copies per 109 GAPDH copies in C57Bl6 (day 8) and BALBc mice (day 7), no significant differences between 1A8 mAb treated (grey circles, N = 6/group) or isotype control treated animals (white circles, N = 6/group). (B) Lung permeability as measured by IgM (ng/mL) in BAL of C57Bl6 (non-infected and PVM infected, day 8) and PVM infected BALBc mice (day 7). Increased IgM levels after PVM infection, with a significant increase in isotype control treated (white circles, N = 6/group) BALBc mice, compared to 1A8 mAb treated (grey circles, N = 6/group) BALBc mice (* p = 0.03). Data are shown as individual values and median with bars depicting IQR.</p

NET production.

<p><b>(A)</b> Citrullinated histone H3 staining of a non-infected lung tissue section, no NETs are visible (magnification 200×). <b>(B,C)</b> Citrullinated histone H3 staining of PVM infected C57Bl6 (day 8) and BALBc (day 7) mice (non-lavaged lung sections, magnification 200×) shows scarce NET formation (insets, magnification 1200×) without airway occlusion (asterisk).</p

Lung histopathology.

<p><b>(A,C)</b> Representative image of HE-staining of C57Bl6 mice (day 8), showing interstitial cellular infiltrates and proteinacious debris <b>(B,D)</b> HE-staining of BALBc mice (day 7), showing hemorrhaging and proteinacious debris (magnification 400×).</p

Neutrophil subset responses in infants with severe viral respiratory infection

Neutrophils are the predominant inflammatory cells recruited to the respiratory tract as part of the innate immune response to viral infections. Recent reports indicate the existence of distinct functional neutrophil subsets in the circulatory compartment of adults, following severe inflammatory conditions. Here, we evaluated the occurrence of neutrophil subsets in blood and broncho-alveolar lavage fluid during severe viral respiratory infection in infants based on CD16/CD62L expression. We show that during the course of severe respiratory infection infants may develop four heterogeneous neutrophil subsets in blood (mature, immature, progenitor, and suppressive neutrophils), each with distinct activation states. However, while isolated viral respiratory infection was characterized by a relative absence of suppressive neutrophils in both blood and lungs, only patients with bacterial co-infection were shown to produce suppressive neutrophils. These data suggest the occurrence of distinct and unique neutrophil subset responses during severe viral and (secondary) bacterial respiratory infection in infant