The complex relationship between inflammation and lung function in severe asthma

Manni, Michelle L.; Trudeau, John B.; Scheller, Erich V.; Mandalapu, Sivanarayana; Elloso, M. Merle; Kolls, Jay K.; Wenzel, Sally E.; Alcorn, John F.

doi:10.1038/mi.2014.8

Cited by 97 publications

(90 citation statements)

References 43 publications

(47 reference statements)

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“…This information allowed us to establish a new animal model of SA in which immune response and poor control by CS resembled that observed in human disease. Using genetically engineered mice subjected to the SA model, IFN-γ but not IL-17 was found to be responsible for heightened airway hyperresponsiveness (AHR), which was in line with findings in a recent human study that failed to associate IL-17 with worse lung function in SA patients (8). In contrast, mice subjected to a Th2-dominated model displayed lower AHR and complete resolution by CS.…”

Section: Introductionsupporting

confidence: 71%

“…Although a previous study showed the ability of IL-17 to cause airway smooth muscle (ASM) contraction using tracheal rings from humans and mice (35), a recent study failed to associate an IL-17 sputum signature with worse lung function in SA subjects (36). The animal model in the former study employed i.p.…”

Section: Regulation Of Ifn-γ Production By C-di-gmp Via Il-12 Inductimentioning

confidence: 99%

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High IFN-γ and low SLPI mark severe asthma in mice and humans

Raundhal¹,

Morse²,

Khare³

et al. 2015

J. Clin. Invest.

311

304

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Results SA subjects harbor more IFN-γ + CD4+ T cells in their airways compared with MMA subjects. A total of 66 subjects, 33 classified with MMA and 33 classified with SA, were included in this study; details of patient characteristics are included in Table 1. Of note, biological samples, such as cells in BAL fluid used for differential cell counts and cytokine expression, were analyzed from a subset of these subjects based on availability, as described in each figure legend. Since the recovery of BAL Severe asthma (SA) is a challenge to control, as patients are not responsive to high doses of systemic corticosteroids (CS). In contrast, mild-moderate asthma (MMA) is responsive to low doses of inhaled CS, indicating that Th2 cells, which are dominant in MMA, do not solely orchestrate SA development. Here, we analyzed broncholalveolar lavage cells isolated from MMA and SA patients and determined that IFN-γ (Th1) immune responses are exacerbated in the airways of individuals with SA, with reduced Th2 and IL-17 responses. We developed a protocol that recapitulates the complex immune response of human SA, including the poor response to CS, in a murine model. Compared with WT animals, Ifng -/-mice subjected to this SA model failed to mount airway hyperresponsiveness (AHR) without appreciable effect on airway inflammation. Conversely, AHR was not reduced in Il17ra -/-mice, although airway inflammation was lower. Computer-assisted pathway analysis tools linked IFN-γ to secretory leukocyte protease inhibitor (SLPI), which is expressed by airway epithelial cells, and IFN-γ inversely correlated with SLPI expression in SA patients and the mouse model. In mice subjected to our SA model, forced SLPI expression decreased AHR in the absence of CS, and it was further reduced when SLPI was combined with CS. Our study identifies a distinct immune response in SA characterized by a dysregulated IFN-γ/SLPI axis that affects lung function.

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Section: Introductionsupporting

confidence: 71%

Section: Regulation Of Ifn-γ Production By C-di-gmp Via Il-12 Inductimentioning

confidence: 99%

High IFN-γ and low SLPI mark severe asthma in mice and humans

Raundhal¹,

Morse²,

Khare³

et al. 2015

J. Clin. Invest.

311

304

View full text Add to dashboard Cite

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“…Pulmonary function was assessed during mechanical ventilation of anesthetized (90 mg/kg pentobarbital intraperitoneally) and tracheotomized mice using a computercontrolled small-animal mechanical ventilator (flexiVent; SCIREQ, Montreal, QC, Canada) as previously described (34,35). Quasistatic compliance, Newtonian resistance, tissue damping, and tissue elastance were calculated as described previously (36,37).…”

Section: Lung Mechanics and Airway Hyperresponsiveness Measurementsmentioning

confidence: 99%

A Novel CD4⁺ T Cell–Dependent Murine Model of Pneumocystis-driven Asthma-like Pathology

Eddens

Campfield

Serody

et al. 2016

Am J Respir Crit Care Med

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Rationale: Infection with Pneumocystis, an opportunistic fungal pathogen, can result in fulminant pneumonia in the clinical setting of patients with immunosuppression. In murine models, Pneumocystis has previously been shown to induce a CD4 1 T cell-dependent eosinophilic response in the lung capable of providing protection.Objectives: We sought to explore the role of Pneumocystis in generating asthma-like lung pathology, given the natural eosinophilic response to infection.Methods: Pneumocystis infection or antigen treatment was used to induce asthma-like pathology in wild-type mice. The roles of CD4 1 T cells and eosinophils were examined using antibody depletion and knockout mice, respectively. The presence of anti-Pneumocystis antibodies in human serum samples was detected by ELISA and Western blotting.Measurements and Main Results: Pneumocystis infection generates a strong type II response in the lung that requires CD4 1 T cells. Pneumocystis infection was capable of priming a Th2 response similar to that of a commonly studied airway allergen, the house dust mite. Pneumocystis antigen treatment was also capable of inducing allergic inflammation in the lung, resulting in anti-Pneumocystis IgE production, goblet cell hyperplasia, and increased airway resistance. In the human population, patients with severe asthma had increased levels of anti-Pneumocystis IgG and IgE compared with healthy control subjects. Patients with severe asthma with elevated antiPneumocystis IgG levels had worsened symptom scores and lung parameters such as decreased forced expiratory volume and increased residual volume compared with patients with severe asthma who had low anti-Pneumocystis IgG.Conclusions: The present study demonstrates for the first time, to our knowledge, that Pneumocystis is an airway allergen capable of inducing asthma-like lung pathology.

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“…Importantly, these patients are consistently found to be largely refractory to steroid treatment, and thus, they have limited treatment options (38,39). Considerable work on mice has suggested a role for IL-17 in this neutrophilic inflammation (87,88), but human data supporting the importance of this pathway, including the minimal efficacy of an anti-IL-17R antibody in moderate-to-severe asthma, is lacking (89,90). Some studies have shown potential benefit with macrolide therapy in these patients, which decreases IL-8 levels and neutrophil activation (91).…”

Section: Type 2 Lo Asthmamentioning

confidence: 99%