Inflammation plays a central role in the development of asthma, which is considered an allergic disease with a classic Th2 inflammatory profile. However, cytokine IL-17 has been examined to better understand the pathophysiology of this disease. Severe asthmatic patients experience frequent exacerbations, leading to infection, and subsequently show altered levels of inflammation that are unlikely to be due to the Th2 immune response alone. This study estimates the effects of anti-IL-17 therapy in the pulmonary parenchyma in a murine asthma model exacerbated by LPS. BALB/c mice were sensitized with intraperitoneal ovalbumin and repeatedly exposed to inhalation with ovalbumin, followed by treatment with or without anti-IL-17. Twenty-four hours prior to the end of the 29-day experimental protocol, the two groups received LPS (0.1 mg/ml intratracheal OVA-LPS and OVA-LPS IL-17). We subsequently evaluated bronchoalveolar lavage fluid, performed a lung tissue morphometric analysis, and measured IL-6 gene expression. OVA-LPS-treated animals treated with anti-IL-17 showed decreased pulmonary inflammation, edema, oxidative stress, and extracellular matrix remodeling compared to the non-treated OVA and OVA-LPS groups (p < 0.05). The anti-IL-17 treatment also decreased the numbers of dendritic cells, FOXP3, NF-κB, and Rho kinase 1- and 2-positive cells compared to the non-treated OVA and OVA-LPS groups (p < 0.05). In conclusion, these data suggest that inhibition of IL-17 is a promising therapeutic avenue, even in exacerbated asthmatic patients, and significantly contributes to the control of Th1/Th2/Th17 inflammation, chemokine expression, extracellular matrix remodeling, and oxidative stress in a murine experimental asthma model exacerbated by LPS.

Several studies have demonstrated the importance of Rho-kinase in the modulation of smooth muscle contraction, airway hyperresponsiveness, and inflammation. However, the effects of repeated treatment with a specific inhibitor of this pathway have not been previously investigated. We evaluated the effects of repeated treatment with Y-27632, a highly selective Rho-kinase inhibitor, on airway hyperresponsiveness, oxidative stress activation, extracellular matrix remodeling, eosinophilic inflammation, and cytokine expression in an animal model of chronic airway inflammation. Guinea pigs were subjected to seven ovalbumin or saline exposures. The treatment with Y-27632 (1 mM) started at the fifth inhalation. Seventy-two hours after the seventh inhalation, the animals' pulmonary mechanics were evaluated, and exhaled nitric oxide (E(NO)) was collected. The lungs were removed, and histological analysis was performed using morphometry. Treatment with Y-27632 in sensitized animals reduced E(NO) concentrations, maximal responses of resistance, elastance of the respiratory system, eosinophil counts, collagen and elastic fiber contents, the numbers of cells positive for IL-2, IL-4, IL-5, IL-13, inducible nitric oxide synthase, matrix metalloproteinase-9, tissue inhibitor of metalloproteinase-1, transforming growth factor-β, NF-κB, IFN-γ, and 8-iso-prostaglandin F2α contents compared with the untreated group (P < 0.05). We observed positive correlations among the functional responses and inflammation, remodeling, and oxidative stress pathway activation markers evaluated. In conclusion, Rho-kinase pathway activation contributes to the potentiation of the hyperresponsiveness, inflammation, the extracellular matrix remodeling process, and oxidative stress activation. These results suggest that Rho-kinase inhibitors represent potential pharmacological tools for the control of asthma.

Background: Intensive care patients commonly develop muscle wasting and functional impairment. However, the role of severe COVID-19 in the magnitude of muscle wasting and functionality in the acute critical disease is unknown.Objective: To perform a prospective characterization to evaluate the skeletal muscle mass and functional performance in intensive care patients with severe COVID-19.Methods: Thirty-two critically ill patients (93.8% male; age: 64.1 ± 12.6 years) with the diagnosis of the severe COVID-19 were prospectively recruited within 24 to 72 h following intensive care unit (ICU) admission, from April 2020 to October 2020, at Hospital Sírio-Libanês in Brazil. Patients were recruited if older than 18 years old, diagnosis of severe COVID-19 confirmed by RT-PCR, ICU stay and absence of limb amputation. Muscle wasting was determined through an ultrasound measurement of the rectus femoris cross-sectional area, the thickness of the anterior compartment of the quadriceps muscle (rectus femoris and vastus intermedius), and echogenicity. The peripheral muscle strength was assessed with a handgrip test. The functionality parameter was determined through the ICU mobility scale (IMS) and the International Classification of Functioning, Disability and Health (ICF). All evaluations were performed on days 1 and 10.Results: There were significant reductions in the rectus femoris cross-section area (−30.1% [95% IC, −26.0% to −34.1%]; P &lt; 0.05), thickness of the anterior compartment of the quadriceps muscle (−18.6% [95% IC, −14.6% to 22.5%]; P &lt; 0.05) and handgrip strength (−22.3% [95% IC, 4.7% to 39.9%]; P &lt; 0.05) from days 1 to 10. Patients showed increased mobility (0 [0–5] vs 4.5 [0–8]; P &lt; 0.05), improvement in respiratory function (3 [3–3] vs 2 [1–3]; P &lt; 0.05) and structure respiratory system (3 [3–3] vs 2 [1–3]; P &lt; 0.05), but none of the patients returned to normal levels.Conclusion: In intensive care patients with severe COVID-19, muscle wasting and decreased muscle strength occurred early and rapidly during 10 days of ICU stay with improved mobility and respiratory functions, although they remained below normal levels. These findings may provide insights into skeletal muscle wasting and function in patients with severe COVID-19.

Changes in extracellular matrix (ECM) components in the lungs are associated with the progression of respiratory diseases, such as asthma, chronic obstructive pulmonary disease (COPD), and acute respiratory distress syndrome (ARDS). Experimental and clinical studies have revealed that structural changes in ECM components occur under chronic inflammatory conditions, and these changes are associated with impaired lung function. In bronchial asthma, elastic and collagen fiber remodeling, mostly in the airway walls, is associated with an increase in mucus secretion, leading to airway hyperreactivity. In COPD, changes in collagen subtypes I and III and elastin, interfere with the mechanical properties of the lungs, and are believed to play a pivotal role in decreased lung elasticity, during emphysema progression. In ARDS, interstitial edema is often accompanied by excessive deposition of fibronectin and collagen subtypes I and III, which can lead to respiratory failure in the intensive care unit. This review uses experimental models and human studies to describe how inflammatory conditions and ECM remodeling contribute to the loss of lung function in these respiratory diseases.