The simultaneous measurement of various parameters related to lung function and structure, pro- and anti-inflammatory factors and fibrotic factors in the present study showed that the systemic immune response in the older adults participants with MS was associated with the worsening of lung function. Both pulmonary and systemic inflammatory and fibrotic factors showed alterations in those with MS compared to their without counterparts. While the hand grip, a measure of general strength was preserved in both MS and without MS, there was a significant deterioration in respiratory muscle strength in the older adults with MS. The functional and structural alterations observed in the lungs (airways and parenchyma), in the older adults with MS suggest that the role of lungs as a potential target organ in the older adults in the setting of MS. The increases in airway and tissue resistance in the lungs, suggesting the process of remodeling, is characterized by the accumulation of extracellular matrix proteins (collagen, elastin, proteoglycans, laminins) and reflect the structural and functional alterations in the lungs (Aquino-Junior et al.,2018) The alterations of the inflammatory milieu in the lungs is considered a causative factor in its remodeling process (Aquino-Junior et al., 2018, Mirhafez et al.,2015)
Metabolic syndrome leads to immune hyperactivation mainly characterized by increased levels of pro-inflammatory cytokines (i.e. IL-1beta, IL-6, IL-8, TNF-alpha, etc), pro-inflammatory adipokine (leptin) and pro-fibrotic growth factors (i.e. VEGF, TGF-beta, etc) (Aquino-Junior et al., 2018, Mirhafez et al.,2015). The increased levels of proinflammatory mediators can disrupt the release of anti-inflammatory cytokines such as IL-1ra, IL-10, and anti-inflammatory adipokines such as adiponectin, accounting for impairment of the normal immune function, alter normal lung function and may perpetuate the development and progression of chronic diseases (Aquino-Junior et al.,2018, Andersen et al.,2016). Previous reports have showed robust correlations of MS with structural and functional alterations in the heart (Sherling et al.,2017), blood vessels (Sherling et al.,2017) and kidneys (Sherling et al.,2017). The present study showed that concomitant with the systemic responses, there were strong pro-inflammatory and pro-fibrotic responses in the lungs in the participants with MS. We also observed a reduction in anti-inflammatory response in the lungs of older adults with MS.
Metabolic alterations and impairments are classic features of aging, and they are typically mediated by a compromised immune response leading to inflammaging and immunosenescence (Wong et al.,2019, Salminen 2020) Although inflammaging and immunosenescence are well characterized in humans, the contribution of MS towards its development and/or progression is less understood (Wong et al.,2019; Salminen 2020). The present study highlights that MS in the older adults is associated with substantially increased release of systemic pro-inflammatory mediators such as IL-1beta, IL-8, TNF-alpha, leptin, and the pro-fibrotic mediator, VEGF, when compared to older adults with without MS.. More importantly, the study also showed for the first time that anti-inflammatory mediators such as IL-1ra, IL-10, and adiponectin, and anti-fibrotic mediators such as Klotho, Relaxin 1, Relaxin 3 (Buendia-Roldan et al.,2019, Samuel et al.,2017) are reduced in the older adults with MS. Such effects observed in the older adults with MS may accelerate the process of senescence increasing the risk for CVD (Andersen et al., 2016, Guarner and Rubio,2015). A previous study demonstrated that in patients with idiopathic interstitial lung diseases, reduced serum levels of klotho were associated with reduced lung function (Buendia-Roldan et al.,2019). This is similar to the data in the present study with reduced levels of klotho in serum related to impaired lung function in the older adults with MS.
Further, in the current study, there was a positive correlation between impaired pulmonary immune response (increased levels of pro-inflammatory and pro-fibrotic and reduction of anti-inflammatory and antifibrotic mediators) and impaired pulmonary and mechanical function. The presentation of an amplified inflammatory state in the lungs and systemically, in the older adults with MS is interesting, particularly considering the lack of data in this population. While the underlying mechanisms remain unclear, the present study showed that such pro-inflammatory and pro-fibrotic responses in the lungs were associated with increased resistance of the respiratory system (R5Hz), proximal airways (R20Hz), distal airway (R5Hz-R20Hz) and proximal (RCentral) and distal (RPeripheral) pulmonary tissue, in addition to increases in the deepest resistance of the distal airways (X5Hz). In fact, the impairment of pulmonary mechanics observed in the present study (as described above) reflects structural changes in different pulmonary compartments (Brashier,2015), similar to the detrimental changes that chronic subclinical inflammation and pro-fibrotic mediators provoke in the cardiovascular system, both structure and function (Bartekova et al.,2018).
Increased levels of VEGF have been associated with different pulmonary diseases, such as asthma, chronic obstructive pulmonary disease, and idiopathic pulmonary fibrosis, with altered established fibrotic processes (Lee et al., 2004, Westergren-Thorsson et al.,2018, Barrat et al.,2018). VEGF induces fibrosis via fibroblast and smooth muscle proliferation and activation, leading to synthesis and release of larger amounts of extracellular matrix proteins, such as collagen and elastic fibers, proteoglycans and laminins. (Lee et al., 2004, Westergren-Thorsson et al.,2018, Barrat et al.,2018). The present study revealed that older adults with MS presents higher levels of VEGF compared with NMS, in circulation (systemic response) as well as in the breath condensate (pulmonary response). Thus, the airway obstruction found in older adults with MS could be the result of central airway remodeling due to pro-inflammatory and pro-fibrotic pulmonary processes (Arimura et al.,2012, Park et al.,2018). For the distal airways, it can be due to a decrease in the retraction capacity of the lung tissue, induced by accumulation of elastic fibers that may result in increased lung elastance, as observed in the present study through the increases in RPeripheral values (Fehrenbach et al.,2017).
Beyond the impairment of lung function and mechanics, and of systemic and pulmonary immune response, the present study also showed a reduction in the respiratory muscle strength, while the general muscle strength remained stable, in older adults with MS compared to without MS. This is a clinically significant finding with respect to the impairment of lung function and mechanics, since the number of cardiorespiratory events in older adults is typically higher than in younger population. These are even at higher magnitude in the older adults with MS (Rodgers et al.,2019). Likewise, during the cardiorespiratory events, the need for intubation following mechanical ventilation is higher among the older adults and the impaired lung function and reduced diaphragm muscle mass may adversely affect the prognosis (Who et al.,2019). Thus, the reduced respiratory muscle strength in older adults with MS observed in this study should be carefully considered in critically ill older adults, as these patients are more susceptible and may stay longer under mechanical ventilation.
The present study has a few limitations worth noting. The blood glucose levels were not measured, since all MS older adults were diagnosed with diabetes, but well-controlled and stable under standard medication provided by the Brazilian government for at least 24 months. The lack of computerized tomography (CT) measurement of structural changes in the lungs is also a limitation and the related data should be considered with caution. Further, we did not determine the impact of each component of the MS separately in the derangement of lung structure and function.
In conclusion, MS affects lung mechanics, function, and immunological response in the older adults individuals. Given the wide prevalence of MS in the general older adults population, it is crucial that we continue to further understand the underlying mechanisms of how the metabolic derangements in the older adults impact the lung and how to prevent complications. In fact, the present study highlights the clinical relevance of assessing not only systemic inflammation but also pulmonary inflammation along with lung mechanics in the older adults with MS. Such an approach will enable the development of more directed therapeutic interventions to improve the outcomes in older adults people with MS. Future research should also address if optimally controlling the components of MS early in its clinical course will have a protective effect and/or contribute to the amelioration of the path towards inflammaging and/or immunosenescence of the lungs via attenuation of the inflammatory pathways, both systemically and in the respiratory system.