Effects of Rho-kinase inhibition in lung tissue with chronic inflammation

Righetti, Renato Fraga; Pigati, Patricia Angeli da Silva; Possa, Samantha Souza; Habrum, Fábio Cetinic; Xisto, Débora G.; Antunes, Mariana A.; Leick, Edna Aparecida; Prado, Carla M.; Martins, Mílton de Arruda; Rocco, Patrícia Rieken Macêdo; Tibério, Iolanda de Fátima Lopes Calvo

doi:10.1016/j.resp.2013.12.012

Cited by 48 publications

(93 citation statements)

References 62 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Our data indicate an important role for ROCK2 in allergic airways disease: OVA-induced cellular inflammation, type 2 cytokine production, mucous hypersecretion, and AHR were each substantially reduced in ROCK2 +/À vs. WT mice treated with saline (Figs 2,4 and 5), consistent with previous reports [13,17]. The pan ROCK inhibitors, fasudil and Y-27632, also attenuate these outcomes in allergen-challenged mice [16,17,53]. Together, the data indicate a key role for ROCK2 in allergen-induced eosinophil recruitment, mucous cell hyperplasia, and AHR.…”

Section: Discussionsupporting

confidence: 90%

Role of ROCK2 in CD4⁺ cells in allergic airways responses in mice

Kasahara¹,

Mathews²,

Ninin³

et al. 2017

Clin Experimental Allergy

View full text Add to dashboard Cite

Background Rho kinases (ROCKs) contribute to allergic airways disease. ROCKs also play a role in lymphocyte proliferation and migration. Objective To determine the role of ROCK2 acting within CD4+ cells in allergic airways responses. Methods ROCK2 haploinsufficient (ROCK2+/-) and wildtype mice were sensitized with ovalbumin (OVA). ROCK2+/- mice then received either CD4+ cells from ROCK2 sufficient OVA TCR transgenic (OT-II) mice or saline i.v. 48 hours before challenge with aerosolized OVA. Wildtype mice received saline before challenge. Allergic airway responses were measured 48 hours after the last challenge. Allergic airways responses were also assessed in mice lacking ROCK2 only in CD4+ cells (ROCK2CD4Cre mice) versus control (CD4-Cre and ROCK2flox/flox) mice. Results OVA-induced increases in bronchoalveolar lavage lymphocytes, eosinophils, IL-13, IL-5, and eotaxin were reduced in ROCK2+/- versus wildtype mice, as were airway hyperresponsiveness and mucous hypersecretion. In ROCK2+/- mice, adoptive transfer with CD4+ cells from OT-II mice restored effects of OVA on lymphocytes, eosinophils, IL-13, IL-5, and mucous hypersecretion to wildtype levels, whereas eotaxin and airway hyperrresponsiveness were not affected. ROCK2 inhibitors reduced IL-13-induced release of eotaxin from airway smooth muscle (ASM), similar to effects of these inhibitors on ASM contractility. Despite the ability of adoptive transfer to restore allergic airways inflammation in ROCK2 insufficient mice, allergic inflammation was not different in ROCK2CD4Cre versus control mice. Conclusion ROCK2 contributes to allergic airways responses likely via effects within ASM cells and within non lymphocyte cells involved in lymphocyte activation and migration into the airways.

show abstract

Section: Discussionsupporting

confidence: 90%

Role of ROCK2 in CD4⁺ cells in allergic airways responses in mice

Kasahara¹,

Mathews²,

Ninin³

et al. 2017

Clin Experimental Allergy

View full text Add to dashboard Cite

show abstract

“…The slides sections were counterstained with Harris hematoxylin (Merck, Darmstadt, Germany) and mounted using Entellan microscopy resin (Merck). Cells that stained positive as neutrophils or for MMP-9, MMP-12, TIMP-1, iNOS, eNOS, TNF-α, 8- iso -PGF2α and MUC-5AC were evaluated by the point-counting technique [38]. The positive cells in the alveolar walls and airways were with the conventional morphometric analysis using a reticule of known area (50 lines and 100 points) coupled in a microscope (CH30, Olympus, Tokyo, Japan).…”

Section: Methodsmentioning

confidence: 99%

“…As the reticule should be placed in 10 random fields in the distal lung and 3–5 airway wall per animal at a magnification of 1000× and the number of positive cells was determined as the number of positive cells in each field divided by the number contacting the alveolar wall or airway area (10 4 μm 2 ). The researcher who performed the measurements was unaware of the study groups [38,39,40]. …”

Section: Methodsmentioning

confidence: 99%

A Plant Proteinase Inhibitor from Enterolobium contortisiliquum Attenuates Pulmonary Mechanics, Inflammation and Remodeling Induced by Elastase in Mice

Theodoro-Junior

Righetti

Almeida-Reis

et al. 2017

IJMS

View full text Add to dashboard Cite

Proteinase inhibitors have been associated with anti-inflammatory and antioxidant activities and may represent a potential therapeutic treatment for emphysema. Our aim was to evaluate the effects of a plant Kunitz proteinase inhibitor, Enterolobium contortisiliquum trypsin inhibitor (EcTI), on several aspects of experimental elastase-induced pulmonary inflammation in mice. C57/Bl6 mice were intratracheally administered elastase (ELA) or saline (SAL) and were treated intraperitoneally with EcTI (ELA-EcTI, SAL-EcTI) on days 1, 14 and 21. On day 28, pulmonary mechanics, exhaled nitric oxide (ENO) and number leucocytes in the bronchoalveolar lavage fluid (BALF) were evaluated. Subsequently, lung immunohistochemical staining was submitted to morphometry. EcTI treatment reduced responses of the mechanical respiratory system, number of cells in the BALF, and reduced tumor necrosis factor-α (TNF-α), matrix metalloproteinase-9 (MMP-9), matrix metalloproteinase-12 (MMP-12), tissue inhibitor of matrix metalloproteinase (TIMP-1), endothelial nitric oxide synthase (eNOS) and inducible nitric oxide synthase (iNOS)-positive cells and volume proportion of isoprostane, collagen and elastic fibers in the airways and alveolar walls compared with the ELA group. EcTI treatment reduced elastase induced pulmonary inflammation, remodeling, oxidative stress and mechanical alterations, suggesting that this inhibitor may be a potential therapeutic tool for chronic obstructive pulmonary disease (COPD) management.

show abstract

“…The ROCK inhibitor Y-27632 administered by inhalation inhibits eosinophilic inflammation, AHR, and airway remodeling after chronic allergen exposure in sensitized guinea pigs (Schaafsma et al, 2008a;Possa et al, 2012;Righetti et al, 2014). This drug inhibits AHR, bronchoconstriction, and eosinophilic inflammation in a mouse model of acute allergic inflammation (Henry et al, 2005).…”

Section: A Rho-associated Protein Kinase Inhibitionmentioning

confidence: 99%