<i>Has2</i> deficiency enhances OVA‐induced airway inflammation and hyperresponsiveness in mice

Tsunoda, Yoshiya; Sherpa, Mingma T.; Kiwamoto, Takumi; Matsuyama, Masashi; Osawa, Hajime; Sakurai, Hirofumi; Hayashi, Shigen; Matsuno, Yosuke; Morishima, Yuko; Ishii, Yukio; Hizawa, Nobuyuki

doi:10.1111/all.14715

Cited by 2 publications

(10 citation statements)

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“…Because Has2 homozygous deficient mice are embryonic lethal with severe cardiac and vascular abnormality (9), 6-to 8-weekold female Balb/c mice wild type (WT) and Has2 heterozygous (Has +/− ) were used in the experiments. Breeding sets of Has2 +/− mice (Jackson Laboratory, Bar Harbor, ME, USA) were backcrossed to Balb/c background for at least eight generations (5,9). All animal studies were approved by the Institutional Review Board of the University of Tsukuba (approval number: 19-159, 20-125, and 21-028).…”

Section: Animalsmentioning

confidence: 99%

“…mRNA expression levels were quantified by the 7500 FAST real-time PCR system (Thermo Fisher Scientific, Waltham, MA, USA). The sequences for the Has2 +/− mice-specific TaqMan ® -MGB probes and primers (Thermo Fisher Scientific) were as follows: Has2F 5′-TGCTTG ACCCTGCCTCATC-3′, Has2R 5′-CCCATGAATTCCTGA TTGTACCA-3′, MGB probe 5′-TGTCCAGATTTTAAACAAG-3′ (5). Mouse primers and probes were purchased pre-mixed from Thermo Fisher Scientific: CD44 (Cd44; Mm01277163_m1), TLR4 (Tlr4; Mm00445273_m1), TGF-b1 (Tgfb1; Mm01178820_m1), Hsp40 (Dnajb1; Mm00444519_m1), Hsp70 (Hspa1a; Mm01159846_s1), Herp (Herpud1; Mm00445600_m1), PERK (Eif2ak3; Mm00438700_m1), ATF4 (Atf4; Mm00515325_g1), and GAPDH (Gapdh; Mm99999915_g1).…”

Section: Experimental Protocolsmentioning

confidence: 99%

“…HA size was analyzed as previously described (5,10). Briefly, right whole lung tissues were digested by incubation in proteinase K (MilliporeSigma, Burlington, MA, USA) at 1 mg/ml in 100 mM ammonium acetate (1 ml/25 mg tissue weight).…”

Section: Ha Size Analysismentioning

confidence: 99%

“…Mouse lungs were lavaged using five repeated instillations of 0.6 ml of saline each through the tracheal cannula. The first 1.2 ml of bronchoalveolar lavage fluid (BALF) was centrifuged, and the supernatant was used for the measurements of various cytokines and chemokines as described (5,11). Centrifuged cells were redissolved in the remaining BALF sample.…”

Section: Bronchoalveolar Lavage Fluid Cell Countingmentioning

confidence: 99%

“…Because highmolecular-weight hyaluronan (HMW-HA) is thought to have an anti-inflammatory function, HAS2 dysfunction was thought to exacerbate asthma. Based on these backgrounds, mouse HAS2 gene (Has2) attenuation was recently reported to worsen acute eosinophilic airway inflammation and increase airway hyperresponsiveness (AHR) using Has2 heterozygous-deficient (Has2 +/− ) mice (5). However, the severity of chronic eosinophilic airway inflammation, airway remodeling, and underlying pathogenesis in Has2 +/− mice remains unclear.…”

Section: Introductionmentioning

confidence: 99%

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Has2 Regulates the Development of Ovalbumin-Induced Airway Remodeling and Steroid Insensitivity in Mice

et al. 2022

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HAS2 is a member of the gene family encoding the hyaluronan synthase 2, which can generate high-molecular-weight hyaluronan (HMW-HA). Our previous study identified HAS2 as a candidate gene for increased susceptibility to adult asthma. However, whether HAS2 dysfunction affects airway remodeling and steroid insensitivity is still limited. Therefore, this study aimed to clarify the Has2 dysfunction, triggering severe airway remodeling and steroid insensitivity in a murine model of asthma. Has2 heterozygous-deficient (Has2+/−) mice and their wild-type littermates have been evaluated in a model of chronic ovalbumin (OVA) sensitization and challenge. Mice present a higher sensitivity to OVA and higher IL-17 release as well as eosinophilic infiltration. RNA sequencing demonstrated the downregulation of EIF2 signaling pathways, TGF-β signaling pathways, and heat shock proteins with Th17 bias in Has2+/−-OVA mice. The combined treatment with anti-IL-17A antibody and dexamethasone reduces steroid insensitivity in Has2+/−-OVA mice. Has2 attenuation worsens eosinophilic airway inflammation, airway remodeling, and steroid insensitivity. These data highlight that HAS2 and HMW-HA are important for controlling intractable eosinophilic airway inflammation and remodeling and could potentially be exploited for their therapeutic benefits in patients with asthma.

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Section: Animalsmentioning

confidence: 99%

Section: Experimental Protocolsmentioning

confidence: 99%

Section: Ha Size Analysismentioning

confidence: 99%

Section: Bronchoalveolar Lavage Fluid Cell Countingmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Has2 Regulates the Development of Ovalbumin-Induced Airway Remodeling and Steroid Insensitivity in Mice

et al. 2022

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Common Pathogeneses Underlying Asthma and Chronic Obstructive Pulmonary Disease -Insights from Genetic Studies

Hizawa

2024

COPD

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Neither asthma nor chronic obstructive pulmonary disease (COPD) is a single disease consisting of a uniform pathogenesis; rather, they are both syndromes that result from a variety of basic distinct pathogeneses. Many of the basic pathogeneses overlap between the two diseases, and multiple basic pathogeneses are simultaneously involved at varying proportions in individual patients. The specific combination of different basic pathogeneses in each patient determines the phenotype of the patient, and it varies widely from patient to patient. For example, type 2 airway inflammation and neutrophilic airway inflammation may coexist in the same patient, and quite a few patients have clinical characteristics of both asthma and COPD. Even in the same patient, the contribution of each pathogenesis is expected to differ at different life stages (eg, childhood, adolescence, middle age, and older), during different seasons (eg, high seasons for hay fever and rhinovirus infection), and depending on the nature of treatments. This review describes several basic pathogeneses commonly involved in both asthma and COPD, including chronic non-type 2 inflammation, type 2 inflammation, viral infections, and lung development. Understanding of the basic molecular pathogeneses in individual patients, rather than the use of clinical diagnosis, such as asthma, COPD, or even asthma COPD overlap, will enable us to better deal with the diversity seen in disease states, and lead to optimal treatment practices tailored for each patient with less disease burden, such as druginduced side effects, and improved prognosis. Furthermore, we can expect to focus on these molecular pathways as new drug discovery targets.

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Has2 deficiency enhances OVA‐induced airway inflammation and hyperresponsiveness in mice

Cited by 2 publications

References 6 publications

Has2 Regulates the Development of Ovalbumin-Induced Airway Remodeling and Steroid Insensitivity in Mice

Has2 Regulates the Development of Ovalbumin-Induced Airway Remodeling and Steroid Insensitivity in Mice

Common Pathogeneses Underlying Asthma and Chronic Obstructive Pulmonary Disease -Insights from Genetic Studies

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