Excessive host inflammatory responses negatively impact disease outcomes in respiratory infection. Host-pathogen interactions during the infective phase of influenza are well studied, but little is ...known about the host’s response during the repair stage. Here, we show that influenza infection stimulated the expression of angiopoietin-like 4 (ANGPTL4) via a direct IL6-STAT3-mediated mechanism. ANGPTL4 enhanced pulmonary tissue leakiness and exacerbated inflammation-induced lung damage. Treatment of infected mice with neutralizing anti-ANGPTL4 antibodies significantly accelerated lung recovery and improved lung tissue integrity. ANGPTL4-deficient mice also showed reduced lung damage and recovered faster from influenza infection when compared to their wild-type counterparts. Retrospective examination of human lung biopsy specimens from infection-induced pneumonia with tissue damage showed elevated expression of ANGPTL4 when compared to normal lung samples. These observations underscore the important role that ANGPTL4 plays in lung infection and damage and may facilitate future therapeutic strategies for the treatment of influenza pneumonia.
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•ANGPTL4 is upregulated by a STAT3-mediated mechanism during influenza pneumonia•ANGPTL4-deficient mice show reduced lung damage and accelerated lung recovery•Antibodies targeting ANGPTL4 reduce pulmonary tissue leakiness and damage•ANGPTL4 is a potential biomarker for respiratory infection and pneumonia
Li et al. show that influenza infection stimulates the expression of ANGPTL4 through a STAT3-mediated mechanism. Host ANGPTL4 enhances pulmonary tissue leakiness and exacerbates inflammation-induced lung damage. ANGPTL4 deficiency improves pulmonary tissue integrity and accelerates lung tissue recovery.
A Man With Pleural Effusion and Ascites Li, Andrew, MBBS; Poon, Limei, MBBS; Khoo, Kay-Leong, MD, FCCP ...
Chest,
06/2015, Volume:
147, Issue:
6
Journal Article
Peer reviewed
Open access
A male lifelong nonsmoker aged 58 years with no prior asbestos exposure complained of gradual worsening breathlessness over 3 months. This was associated with abdominal and leg swelling and a 2-kg ...weight loss. He had no fever, night sweats, hemoptysis, joint pain, rash, abdominal pain, chest pain, or orthopnea. The patient had no recent travel or contact with pulmonary TB. He had stage I left-side testicular seminoma treated with left-sided radical orchidectomy 10 years previous and recently received a diagnosis of Child's B alcoholic liver cirrhosis. His hepatitis B and C screen result was normal.
Secondary bacterial lung infection by
(
) poses a serious health concern, especially in developing countries. We posit that the emergence of multiantibiotic-resistant strains will jeopardize current ...treatments in these regions. Deaths arising from secondary infections are more often associated with acute lung injury, a common consequence of hypercytokinemia, than with the infection
Given that secondary bacterial pneumonia often has a poor prognosis, newer approaches to improve treatment outcomes are urgently needed to reduce the high levels of morbidity and mortality. Using a sequential dual-infection mouse model of secondary bacterial lung infection, we show that host-directed therapy via immunoneutralization of the angiopoietin-like 4 c-isoform (cANGPTL4) reduced pulmonary edema and damage in infected mice. RNA sequencing analysis revealed that anti-cANGPTL4 treatment improved immune and coagulation functions and reduced internal bleeding and edema. Importantly, anti-cANGPTL4 antibody, when used concurrently with either conventional antibiotics or antipneumolysin antibody, prolonged the median survival of mice compared to monotherapy. Anti-cANGPTL4 treatment enhanced immune cell phagocytosis of bacteria while restricting excessive inflammation. This modification of immune responses improved the disease outcomes of secondary pneumococcal pneumonia. Taken together, our study emphasizes that host-directed therapeutic strategies are viable adjuncts to standard antimicrobial treatments.
Despite extensive global efforts, secondary bacterial pneumonia still represents a major cause of death in developing countries and is an important cause of long-term functional disability arising from lung tissue damage. Newer approaches to improving treatment outcomes are needed to reduce the significant morbidity and mortality caused by infectious diseases. Our study, using an experimental mouse model of secondary
infection, shows that a multimodal treatment that concurrently targets host and pathogen factors improved lung tissue integrity and extended the median survival time of infected mice. The immunoneutralization of host protein cANGPTL4 reduced the severity of pulmonary edema and damage. We show that host-directed therapeutic strategies as well as neutralizing antibodies against pathogen virulence factors are viable adjuncts to standard antimicrobial treatments such as antibiotics. In view of their different modes of action compared to antibiotics, concurrent immunotherapies using antibodies are potentially efficacious against secondary pneumococcal pneumonia caused by antibiotic-resistant pathogens.
Background
The frontal sinus and its drainage pathway are difficult spaces to navigate surgically. The complexity of the frontal recess anatomy as well as inflammatory factors may influence outcomes ...of endoscopic frontal sinusotomy. It is not clear which factors are more important in determining post-operative frontal ostium patency.
Objective
The objective is to investigate whether the distribution of fronto-ethmoidal cells, frontal recess dimensions and sinonasal inflammation predict frontal ostium patency at 1- and 2-years after endoscopic frontal sinusotomy.
Methods
A retrospective review of 94 chronic rhinosinusitis patients (185 sides) who had undergone endoscopic frontal sinusotomies between 2015 and 2019 was conducted. Computed tomography was used to evaluate the type of fronto-ethmoidal cells present and determine the dimensions of the frontal recess. The International Classification of the Radiological Complexity of frontal recess and frontal sinus was used to grade the complexity of frontal recess anatomy. Mucosal inflammation was graded according to a structured histopathology report. Frontal ostium patency at 1- and 2-years post-operatively was recorded.
Results
The frontal ostium patency rates were 80.9% and 73.4% at 1- and 2-years respectively. Eosinophilic predominance (adjusted OR 3.5, 95% CI 1.6–8.0,
p
= 0.003) and mucosal ulceration on histology (adjusted OR 4.5, 95% CI 1.1–17.9,
p
= 0.033) predicted ostial stenosis at 1 year. Smoking (adjusted OR 7.6, 95% CI 2.4–24.7,
p
= 0.001), aspirin exacerbated respiratory disease (AERD) (adjusted OR 7.6, 95% CI 1.9–30.1,
p
= 0.004) and histological findings of severe inflammation (adjusted OR 8.9, 95% CI 1.9–41.2,
p
= 0.005) were independent predictors of ostial stenosis at 2 years. Frontal cell patterns, frontal recess dimensions and frontal recess complexity did not predict frontal ostium stenosis at both 1- and 2-years post-operatively.
Conclusion
Post-operative control of sinonasal inflammation is important in maintaining frontal ostium patency, regardless of frontal cell patterns or frontal recess dimensions.
Invasive aspergillosis (IA) is a major opportunistic fungal infection in patients with haematological malignancies. Morbidity and mortality rates are high despite anti-fungal treatment, as the ...compromised status of immune system prevents the host from responding optimally to conventional therapy. This raises the consideration for immunotherapy as an adjunctive treatment. In this study, we evaluated the utility of expanded human NK cells as treatment against Aspergillus fumigatus infection in vitro and in vivo. The NK cells were expanded and activated by K562 cells genetically modified to express 4-1BB ligand and membrane-bound interleukin-15 (K562-41BBL-mbIL-15) as feeders. The efficacy of these cells was investigated in A. fumigatus killing assays in vitro and as adoptive cellular therapy in vivo. The expanded NK cells possessed potent killing activity at low effector-to-target ratio of 2:1. Fungicidal activity was morphotypal-dependent and most efficacious against A. fumigatus conidia. Fungicidal activity was mediated by dectin-1 receptors on the expanded NK cells leading to augmented release of perforin, resulting in enhanced direct cytolysis. In an immunocompromised mice pulmonary aspergillosis model, we showed that NK cell treatment significantly reduced fungal burden, hence demonstrating the translational potential of expanded NK cells as adjunctive therapy against IA in immunocompromised patients.
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