Heart Failure With Preserved Ejection Fraction: JACC Scientific Statement
How Diabetes Impacts Pulmonary Vascular Dysfunction And Fibrosis
Type 2 diabetes and prediabetes can both significantly impact pulmonary health, highlighting the need for early detection and intervention.
A new paper has highlighted the significant impact of type 2 diabetes on pulmonary health, particularly pulmonary vascular dysfunction and fibrosis.
According to the review published in Frontiers in Endocrinology, this intricate relationship between prediabetes, type 2 diabetes, and pulmonary disorders underscores the urgent need for extensive research into prediabetes and its underlying mechanisms to prevent progression to diabetes.1
Pulmonary complications, such as vascular dysfunction and fibrotic lung disease, significantly increase morbidity and mortality, while also diminishing the quality of life for individuals with type 2 diabetes. Early detection and management of prediabetes with a focus on preventing pulmonary complications may help reduce the risk of developing type 2 diabetes. Understanding and treating pulmonary disorders in these patients can also improve patient outcomes and alleviate the burden of metabolic disorders, making it even more important to target both prediabetes and pulmonary health at the same time.
Research has also suggested a potential link between prediabetes and pulmonary functionImage credit: peopleimages.Com – stock.Adobe.Com
The review authors found that diabetes, which is traditionally linked to cardiovascular and microvascular complications, can also lead to pulmonary complications through mechanisms such as oxidative stress, dysregulated fibrotic signaling, and chronic inflammation.
Type 2 diabetes is a chronic metabolic condition characterized by insulin resistance and impaired glucose metabolism that affects multiple organs, including the lungs. Research has underscored a significant link between type 2 diabetes and pulmonary vascular disorders, such as pulmonary arterial stiffness and hypertension.
This relationship is marked by problems such as:
These issues make it harder for the lungs to get enough oxygen into the blood, and high blood sugar levels in diabetes can make these problems worse by causing increased stress, inflammation, and changes in how insulin works in the body. These changes lead to the growth of smooth muscle in blood vessels, remodeling of lung tissues, and damage from substances called oxidants. Together, these factors make it harder for the lungs to function properly, which can cause symptoms like difficulty exercising and feeling short of breath, similar to what happens in pulmonary hypertension.
Research has also suggested a potential link between prediabetes and pulmonary function, with studies linking prediabetes and breathing problems, showing how diabetes-related changes in body chemistry affect lung function. Prediabetes is characterized by insulin resistance, unhealthy lipid levels, and chronic low-grade inflammation, and it may adversely affect the lungs, similar to how it impacts other organ systems.
These metabolic disturbances can damage the blood vessels in the lungs and the lung tissue itself, potentially leading to conditions such as pulmonary fibrosis. Additionally, elevated blood sugar and lipid levels in prediabetes can increase oxidative stress and inflammation in lung cells, which activate pathways that cause tissue scarring and remodeling. This damage is further exacerbated by disrupted lipid metabolism and the accumulation of harmful compounds, leading to more severe lung damage.
Prediabetes can also disturb the production and availability of nitric oxide (NO)—a critical molecule for maintaining healthy blood vessels—by impairing the activity of enzymes involved in NO production. This leads to blood vessel dysfunction, increased vessel constriction, and reduced vascular relaxation, all of which contribute to cardiovascular complications like hypertension and atherosclerosis. The imbalance in NO levels, alongside the increase of inflammatory and fibrotic signaling molecules, underscores the importance of early detection and intervention in prediabetes to prevent both cardiovascular and pulmonary complications.
While prediabetes has mainly been connected to heart and small blood vessel problems in the past, understanding how it affects lung health is now seen as very important, the review authors emphasized.
"The transition from prediabetes to overt T2DM [type 2 diabetes mellitus] may further intensify these pulmonary complications, highlighting the importance of early intervention and preventive measures," the authors said. "However, the precise mechanisms linking prediabetes to pulmonary pathology remain incompletely understood. Hence, more research is needed to look at the relationship between prediabetes and pulmonary dysfunction, including reduced pulmonary function, an elevated risk of respiratory infections, and maybe the onset of pulmonary fibrosis."
Outside of this review, other research published in the International Journal of Chronic Obstructive Pulmonary Disease found that patients who have both type 2 diabetes and chronic obstructive pulmonary disease (COPD) face higher rates of both all-cause and respiratory-cause mortality compared with those without COPD.2 The study revealed that diabetes and COPD share an inflammatory nature and similar risk factors, leading to significant overlap and interaction between these 2 conditions.
The all-cause mortality rate was significantly higher in individuals with COPD (448.7 per 1000 person-years) compared with those without COPD (296.6 per 1000 person-years). Similarly, the respiratory mortality rate was 3.03 times higher for those with COPD (129.0 per 1000 person-years) than for those without COPD (26.6 per 1000 person-years). By the end of the study, the all-cause mortality survival probability was approximately 25% for those with COPD and 40% for those without COPD; the respiratory mortality survival probability was about 75% for those with COPD, compared with nearly 100% for those without COPD. The study also found that while COPD was associated with moderately increased cardiovascular mortality rates, this association was not significant after adjusting for preexisting cardiovascular disease.
Together, these findings underscore the importance of further research into the interplay between diabetes and respiratory conditions like COPD and pulmonary fibrosis.
References
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Let-7 Is A Key Guardian Of Healthy Lungs That Keeps Pulmonary Fibrosis In Check
Researchers at Baylor College of Medicine and collaborating institutions have uncovered a key molecular player that is involved in lung repair and in the development of pulmonary fibrosis, a common and severe class of adult lung diseases linked to respiratory failure.
Published in Nature Communications, the study shows that a small gene named let-7 functions as a guardian of the lungs' health and healing processes. When the gene is absent in mice, injured lungs are not able to repair themselves properly – they develop pulmonary fibrosis, or scarring and severe inflammation. The researchers uncovered molecular pathways by which let-7 fulfills its functions, which can provide opportunities for new drugs and interventions to prevent or slow the progression of this devastating disease.
"Pulmonary fibrosis refers to a group of incurable interstitial lung diseases that usually affect people over 50 years old," said corresponding author Dr. Antony Rodríguez, associate professor of medicine, section of immunology, allergy and rheumatology at Baylor. "The lungs of affected individuals become stiff due to improper healing that makes it difficult to breathe. In our lab we focus on lung injury and regeneration and the healing processes that go wrong in pulmonary fibrosis."
The lungs are very resilient. During a person's life, the lungs can heal after repeated injuries, such as severe flu or COVID-19 infections. But as people age, the healing capacity of the lung declines. "Progenitor stem cells called AT2 are in charge of lung repair and healing," Rodriguez said. "Lung injuries activate AT2 stem cells, which then orchestrate the healing process by producing AT1 cells. As people age, AT2 cells become dysfunctional – instead of repairing the lungs, they create scars, which is what we see in pulmonary fibrosis."
To better understand the process that transforms healthy AT2 into fibrosis-promoting AT2 cells, Rodríguez and his colleagues investigated the involvement of the let-7 gene, whose expression is reduced in human pulmonary fibrosis. Previous studies showed that let-7 is a tumor suppressor gene involved in malignancy, cell growth and metastasis of epithelial cells in various cancers.
"Using a combination of molecular, biochemistry and microscopy techniques in mouse models, 3D lung organoids and tissue samples of pulmonary fibrosis, we examined the molecular mechanisms that promote the formation of AT2 cells that lead to scarring and inflammation in the lung," Rodríguez said.
They discovered that let-7 is downregulated in mouse models of the condition. When the researchers knocked out the gene in mice, the animals spontaneously developed fibrosis, strongly suggesting that let-7 is key to maintaining the lungs healthy and keeping fibrosis in check. But, how does it do it?
Digging deeper into the mechanism revealed that let-7 prevents the inappropriate expression of genes associated with cancer and organ fibrosis.
"We showed that these cancer-associated genes become more active as the AT2 cells were being reprogrammed into fibrotic scar-forming cells," Rodríguez said. "Probing further showed that let-7 also plays an integral role in modulating tumor-like pathways epigenetically via modifications in histones or DNA-associated proteins, in scar-forming AT2 cells."
Organ fibrosis is common in all different organs, including kidneys, liver and heart. "Let-7 is expressed in all the organs. Our findings support exploring whether the mechanism we have discovered also plays a role other organ fibrosis," Rodríguez said.
Other contributors to this work include Matthew J. Seasock, Md Shafiquzzaman, Maria E. Ruiz-Echartea, Rupa S. Kanchi, Brandon T. Tran, Lukas M. Simon, Matthew D. Meyer, Phillip A. Erice, Shivani L. Lotlikar, Stephanie C. Wenlock, Scott A. Ochsner, Anton Enright, Alex F. Carisey, Freddy Romero, Ivan O. Rosas, Katherine Y. King, Neil J. McKenna and Cristian Coarfa. The authors are affiliated with one or more of the following institutions: Baylor College of Medicine, Texas Children's Hospital, Rice University, University of Cambridge and St. Jude Children's Research Hospital in Memphis.
This work was supported by grants from the NHLBI (R01HL140398, HL167814, HL155672, F31 HL164287), and NIGMS (grant T32 GM136554). Partial support was provided by the Cancer Prevention Institute of Texas (CPRIT grants RP210227 and 829 RP200504) and NIEHS grants (P30 ES030285 and P42 ES027725).
Pulmonary Fibrosis: Study Targets Proteins To Reverse Lung Scarring
A discovery at Duke-NUS Medical School offers new hope in the battle against pulmonary fibrosis, a debilitating lung condition that progressively makes it harder for patients to breathe. Scientists have pinpointed proteins in immune cells that, when blocked, could significantly reduce lung tissue scarring.
Current treatments primarily manage symptoms and improving quality of life, without addressing the underlying cause of pulmonary fibrosis.
Although macrophages, a type of immune cell, had previously been known to contribute to inflammation and scarring in pulmonary fibrosis, the underlying mechanisms remained unclear. After discovering that two proteins in macrophages -- YAP and TAZ -- are involved in heart scarring, researchers from the School sought to determine whether these proteins play a similar role in the lungs and to better understand how their activity influences disease progression.
YAP and TAZ are part of a critical molecular pathway that usually helps cells grow and repair. However, in a preclinical model of pulmonary fibrosis, the researchers discovered that these proteins can also contribute to harmful scarring.
In their study, published in the European Respiratory Journal, the researchers found that blocking YAP and TAZ can curb scar formation and restore the immediate environment to one that encourages regeneration in three ways:
Dampening a loud call to arms: YAP and TAZ drive inflammation by amplifying the effect of a molecule called CCL2. Like a homing beacon, this signalling molecule attracts various immune cells to the affected areas of the lungs during injuries. However, when recruited to the lungs in excess, these immune cells can harm the organs by causing uncontrolled inflammation, leading to tissue scarring. Disrupting the connection between the two proteins and CCL2 reduces the number of immune cells recruited, impeding tissue scarring.
Maintaining a healthy immune cell ratio: YAP and TAZ can harm the lungs by increasing inflammatory immune cell levels, amplifying tissue inflammation. When these proteins are removed, immune cells that help to repair and regenerate damaged tissue outnumber their inflammatory counterparts, reducing lung inflammation and allowing the organ to heal more effectively.
Disrupting the proteins' communication with a nearby pathway: These proteins can also exacerbate pulmonary fibrosis by influencing macrophages' interaction with fibroblasts, which are nearby cells that are key to repairing damaged tissue and maintaining organ structure. Unregulated macrophage activity excessively signals fibroblasts to respond to an injury in the lungs, leading to tissue scarring. Inhibiting YAP and TAZ interrupts the communication between macrophages and fibroblasts, reducing damage to the lungs.
Principal Research Scientist Dr Md Masum Mia from Duke-NUS' Cardiovascular and Metabolic Disorders Programme, the study's first author, said of the findings:
"This breakthrough not only deepens our understanding of the specific molecular mechanisms responsible for pulmonary fibrosis, but could also lead to treatments that halt or even reverse lung scarring in the disease."
Paving the way for new treatment options for pulmonary fibrosis
Global early-phase clinical trials for novel therapies that target YAP and TAZ in cancers, which are characterised by immune-driven inflammation and scarring, are underway, and the research team is exploring if such therapies are viable for treating patients with pulmonary fibrosis.
Associate Professor Manvendra Kumar Singh from Duke-NUS' Cardiovascular and Metabolic Disorders Programme, the study's senior author, said of the next steps for the project:
"Pulmonary fibrosis is strongly linked to the unregulated activity of immune and connective tissue cells as well as the loss of epithelial cells. By delving into these interactions that drive tissue scarring, we can gain deeper insights and uncover potential therapeutic targets for treatment. Next, we will further validate the roles of YAP and TAZ in the disease and confirm the effectiveness of therapies that inhibit these proteins, offering patients better outcomes."
In addition to pulmonary fibrosis, YAP and TAZ are also implicated in heart, liver and kidney fibrosis, suggesting that therapies targeting these proteins could offer broader therapeutic potential for a range of fibrotic diseases.
Professor Patrick Tan, Senior Vice-Dean for Research at Duke-NUS, commented:
"By focusing on the root causes of fibrosis, our novel therapeutic approach offers the potential not just to manage but to significantly halt or reverse the progression of pulmonary fibrosis. This breakthrough could dramatically improve patient outcomes, reduce long-term healthcare costs, and ultimately enhance life expectancy and quality for sufferers globally."
This new research, part of Duke-NUS' efforts to develop biomedical solutions that improve the lives of patients, is supported by the National Research Foundation, Singapore under the National Medical Research Council (NMRC) Open Fund-Individual Research Grant (MOH-001625) and the Open Fund-Young Individual Research Grant (MOH-001130) and administered by the Singapore Ministry of Health through the NMRC Office, MOH Holdings Pte Ltd.
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