Abstract:Obesity is an important risk factor for asthma. Obese individuals have decreased circulating adiponectin, an adipose-derived hormone with anti-inflammatory properties. We hypothesized that transgenic overexpression of adiponectin would attenuate allergic airways inflammation and mucous hyperplasia in mice. To test this hypothesis, we used mice overexpressing adiponectin (Adipo Tg). Adipo Tg mice had marked increases in both serum adiponectin and bronchoalveolar lavage (BAL) fluid adiponectin. Both acute and ch… Show more
“…For example, adiponectin, an antiinflammatory mediator that is decreased in obesity, functions in lean mice to inhibit allergic airway inflammation and airway reactivity (45,46), an activity that appears to be related to its serum levels (47). Conversely, leptin, an adipokine that is elevated in obesity, can increase airway reactivity and serum IgE in an allergic mouse model (48).…”
Section: Pre-existing Asthma Complicated By Obesitymentioning
The majority of patients with severe or difficult-to-control asthma in the United States are obese. Epidemiological studies have clearly established that obese patients tend to have worse asthma control and increased hospitalizations and do not respond to standard controller therapy as well as lean patients with asthma. Less clear are the mechanistic underpinnings for the striking clinical differences between lean and obese patients with asthma. Because obesity is principally a disorder of metabolism and energy regulation, processes fundamental to the function of every cell and system within the body, it is not surprising that it affects the respiratory system; it is perhaps surprising that it has taken so long to appreciate how dysfunctional metabolism and energy regulation lead to severe airway disease. Although early investigations focused on identifying a common factor in obesity that could promote airway disease, an appreciation has emerged that the asthma of obesity is a manifestation of multiple anomalies related to obesity affecting all the different pathways that cause asthma, and likely also to de novo airway dysfunction. Consequently, all the phenotypes of asthma currently recognized in lean patients (which are profoundly modified by obesity), as well as those unique to one's obesity endotype, likely contribute to obese asthma in a particular individual. This perspective reviews what we have learned from clinical studies and animal models about the phenotypes of asthma in obesity, which show how specific aspects of obesity and altered metabolism might lead to de novo airway disease and profoundly modify existing airway disease.
“…For example, adiponectin, an antiinflammatory mediator that is decreased in obesity, functions in lean mice to inhibit allergic airway inflammation and airway reactivity (45,46), an activity that appears to be related to its serum levels (47). Conversely, leptin, an adipokine that is elevated in obesity, can increase airway reactivity and serum IgE in an allergic mouse model (48).…”
Section: Pre-existing Asthma Complicated By Obesitymentioning
The majority of patients with severe or difficult-to-control asthma in the United States are obese. Epidemiological studies have clearly established that obese patients tend to have worse asthma control and increased hospitalizations and do not respond to standard controller therapy as well as lean patients with asthma. Less clear are the mechanistic underpinnings for the striking clinical differences between lean and obese patients with asthma. Because obesity is principally a disorder of metabolism and energy regulation, processes fundamental to the function of every cell and system within the body, it is not surprising that it affects the respiratory system; it is perhaps surprising that it has taken so long to appreciate how dysfunctional metabolism and energy regulation lead to severe airway disease. Although early investigations focused on identifying a common factor in obesity that could promote airway disease, an appreciation has emerged that the asthma of obesity is a manifestation of multiple anomalies related to obesity affecting all the different pathways that cause asthma, and likely also to de novo airway dysfunction. Consequently, all the phenotypes of asthma currently recognized in lean patients (which are profoundly modified by obesity), as well as those unique to one's obesity endotype, likely contribute to obese asthma in a particular individual. This perspective reviews what we have learned from clinical studies and animal models about the phenotypes of asthma in obesity, which show how specific aspects of obesity and altered metabolism might lead to de novo airway disease and profoundly modify existing airway disease.
“…Starting on day 12, mice were challenged weekly for 4 weeks by i.n. instillation of either sterile PBS or OVA (20 lg in 30 lL PBS) as previously described [24]. Mice were studied 24 h after the last OVA or PBS challenge.…”
Section: Allergen Sensitization and Challengementioning
confidence: 99%
“…We used real-time PCR and SYBR Green (Applied Biosystems, Foster City, CA, USA) to assess mRNA expression for each of the following genes: Retnla (resistinlike 1 alpha), Itln1 (intelectin 1), Muc5ac, and Clca3 (Gob5). Primers have been previously described [24]. Gene expression values were normalized to 18 s and expressed relative to WT PBS values, using the DDC t method [35].…”
Section: Rna Extraction and Real-time Pcrmentioning
Background
Major features of allergic asthma include airway hyperresponsiveness (AHR), eosinophilic inflammation, and goblet cell metaplasia. Rho kinase (ROCK) is a serine/threonine protein kinase that regulates the actin cytoskeleton. By doing so, it can modulate airway smooth muscle cell contraction and leukocyte migration and proliferation. This study was designed to determine the contributions of the two ROCK isoforms, ROCK1 and ROCK2, to AHR, inflammation and goblet cell metaplasia in a mast-cell dependent model of allergic airways disease.
Methods and Results
Repeated intranasal challenges with OVA caused AHR, eosinophilic inflammation, and goblet cell hyperplasia in wildtype (WT) mice. OVA-induced AHR was partially or completely abrogated in mice haploinsufficient for ROCK2 (ROCK2+/−) or ROCK1 (ROCK1+/−), respectively. In contrast, there was no effect of ROCK insufficiency on allergic airways inflammation, although both ROCK1 and ROCK2 insufficiency attenuated mast cell degranulation. Goblet cell hyperplasia, as indicated by PAS staining, was not different in ROCK1+/− versus WT mice. However, in ROCK2+/− mice, goblet cell hyperplasia was reduced in medium but not large airways. Maximal acetylcholine-induced force generation was reduced in tracheal rings from ROCK1+/− and ROCK2+/− versus WT mice. The ROCK inhibitor, fasudil, also reduced airway responsiveness in OVA-challenged mice, without affecting inflammatory responses.
Conclusion
In a mast cell model of allergic airways disease, ROCK1 and ROCK2 both contribute to AHR, likely through direct effects on smooth muscle cell and effects on mast-cell degranulation. In addition, ROCK2 but not ROCK1 plays a role in allergen-induced goblet cell hyperplasia.
“…In the first cohort, four‐ to five‐week‐old WT and ROCK2 +/− mice were sensitized to ovalbumin (OVA, Grade V; Sigma‐Aldrich Co., St. Louis, MO, USA) by i.p. injection with alum (Imject; Pierce‐Thermo Fisher Scientific, Rockford, Il, USA) on days 0 and 14 as previously described (see Fig. a for schematic).…”
Section: Methodsmentioning
confidence: 99%
“…The left lung was harvested and RNA prepared and reverse‐transcribed for real‐time PCR as previously described . Primers for murine Muc5ac and 18S ribosomal RNA were previously described . Muc5ac mRNA abundance relative to 18S was calculated based on the ΔΔCT method.…”
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.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.