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The Progression to Interstitial Lung Disease

Vicarious Facts About Visceral Fat
      FOR RELATED ARTICLE, SEE PAGE 582
      The burden of morbidity that accompanies interstitial lung disease (ILD) is frequently overwhelming and often occurs in conjunction with quality-of-life impairment, progressive lung function decline, incapacitating dyspnea, and recurrent exacerbations that necessitate hospitalization.
      • Wijsenbeek M.
      • Cottin V.
      Spectrum of fibrotic lung diseases.
      The gravity of these debilitating conditions has resulted in an intense push to improve our understanding of the complex pathophysiology underlying ILD susceptibility. As available treatment options are presently limited and typically demonstrate variable efficacies, much emphasis is placed on primary preventive measures such as avoiding pneumotoxic agents and environmental triggers. Given the high mortality associated with ILD, immunosuppressive and antifibrotic therapies are now commonly administered early in the clinical course to blunt disease progression.
      • Adegunsoye A.
      • Strek M.E.
      Therapeutic approach to adult fibrotic lung diseases.
      In parallel, the past decade has witnessed an amplification of research endeavors devoted to searching for novel biomarkers and therapeutic targets with meaningful impact in patient care. Of prime importance among these is the recognition of interstitial lung abnormalities (ILAs) as a risk factor for progression to ILD.
      • Walsh S.L.F.
      • Richeldi L.
      Subclinical interstitial lung abnormalities: lumping and splitting revisited.
      More than 40% of adults are currently classified as obese in the United States, an epidemic that continues on a worrisome upward surge.
      • Ward Z.J.
      • Bleich S.N.
      • Cradock A.L.
      • et al.
      Projected U.S. state-level prevalence of adult obesity and severe obesity.
      Numerous studies have identified obesity as a risk factor for asthma, sleep apnea, obesity hypoventilation syndrome, pulmonary hypertension, and ARDS, incontrovertibly linking obesity to lung disease.
      • Suratt B.T.
      • Ubags N.D.J.
      • Rastogi D.
      • et al.
      An official American Thoracic Society workshop report: obesity and metabolism: an emerging frontier in lung health and disease.
      This multifaceted relationship is partly driven by metabolic, inflammatory, and dietary components, several of which are being investigated as potentially modifiable risk factors for pulmonary disease.
      • Suratt B.T.
      • Ubags N.D.J.
      • Rastogi D.
      • et al.
      An official American Thoracic Society workshop report: obesity and metabolism: an emerging frontier in lung health and disease.
      Nevertheless, studies seeking to establish an association between BMI and early parenchymal lung injury have been inconsistent, prompting the argument that BMI is a poor surrogate for adiposity and more direct metrics for adiposity need to be identified.
      Thoracic visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) measured by CT imaging have emerged as favorable surrogates for determining pulmonary hypertension risk and frailty.
      • Anderson M.R.
      • Kolaitis N.A.
      • Gao Y.
      • et al.
      A nonlinear relationship between visceral adipose tissue and frailty in adult lung transplant candidates.
      ,
      • Al-Naamani N.
      • Pan H.M.
      • Anderson M.R.
      • et al.
      Thoracic visceral adipose tissue area and pulmonary hypertension in lung transplant candidates: the Lung Transplant Body Composition Study.
      VAT is also associated with an increase in proinflammatory cytokines critical to the pathogenesis of lung injury.
      • Lyngso D.
      • Simonsen L.
      • Bulow J.
      Interleukin-6 production in human subcutaneous abdominal adipose tissue: the effect of exercise.
      Further, dysregulated lipid metabolism and accumulation of lipid-laden macrophages within the alveoli have been linked to the onset of pulmonary fibrosis. In these models, reducing pulmonary lipid clearance increased the formation of foam cells and worsened propagation of fibrosis,
      • Romero F.
      • Shah D.
      • Duong M.
      • et al.
      A pneumocyte-macrophage paracrine lipid axis drives the lung toward fibrosis.
      strongly suggesting a pivotal role for adiposity in the development of ILD. The plethora of evidence supporting this notion includes the observation of elevated levels of palmitate, a saturated fatty acid directly toxic to pulmonary epithelial cells, within the lungs of patients with idiopathic pulmonary fibrosis (IPF).
      • Chu S.G.
      • Villalba J.A.
      • Liang X.
      • et al.
      Palmitic acid-rich high-fat diet exacerbates experimental pulmonary fibrosis by modulating endoplasmic reticulum stress.
      This lipotoxic effect is demonstrated in murine models, which show that consuming a diet rich in saturated fat increases susceptibility to developing lung fibrosis.
      • Chu S.G.
      • Villalba J.A.
      • Liang X.
      • et al.
      Palmitic acid-rich high-fat diet exacerbates experimental pulmonary fibrosis by modulating endoplasmic reticulum stress.
      Moreover, lipid-lowering agents effectively reduced pulmonary fibrosis in mice and decreased the differentiation of IPF fibroblasts to myofibroblasts.
      • Summer R.
      • Mora A.L.
      Lipid metabolism: a new player in the conundrum of lung fibrosis.
      ,
      • Oruqaj G.
      • Karnati S.
      • Vijayan V.
      • et al.
      Compromised peroxisomes in idiopathic pulmonary fibrosis, a vicious cycle inducing a higher fibrotic response via TGF-β signaling.
      In this issue of CHEST, Anderson et al
      • Anderson M.R.
      • Kim J.S.
      • Allison M.
      • et al.
      Adiposity and interstitial lung abnormalities in community-dwelling adults: the MESA cohort study.
      sought to establish this relationship further. The authors leveraged data obtained from participants enrolled in a large multicenter prospective cohort, the Multi-Ethnic Study of Atherosclerosis (MESA). They evaluated 6,814 adults between the ages of 45 and 84 years without any clinical evidence of cardiovascular disease and measured pericardial adipose tissue (PAT), VAT, and SAT. They hypothesized that increased PAT, abdominal VAT, and abdominal SAT would be correlated with increased high-attenuation areas (HAAs) and ILA on CT imaging, which they had previously linked to hospitalizations and mortality. Of the 1,923 subjects with available CT scans, Anderson et al found that every doubling in PAT and abdominal VAT volume was associated with a 41.5-unit increase in HAA. The abdominal SAT area was strongly associated with BMI and with HAA in adjusted models. Similarly, PAT demonstrated a strong association with both HAA and ILA, as did abdominal VAT with ILA.
      • Anderson M.R.
      • Kim J.S.
      • Allison M.
      • et al.
      Adiposity and interstitial lung abnormalities in community-dwelling adults: the MESA cohort study.
      Participant sex was found to modify these associations, as the relationship between PAT and ILA was greatest among men, possibly suggesting a role for the interplay between sex hormones and adiposity in disease pathogenesis. Interestingly, there was no effect modification by age.
      Unsurprisingly, the authors found that abdominal VAT and SAT were associated with significantly lower lung function, likely driven by the well-recognized mechanical effects of adipose tissues on the lungs. In contrast, their finding of lower FVC with PAT doubling was intriguing, as PAT is not conclusively known to exert mechanical effects on the lungs directly. The strength of this association between PAT and lung function decline argues strongly for a mechanism of obesity-related lung injury that lies outside of mechanical effects (Fig 1). Hence, weight loss as a means to achieve lower total body lipids and diminish the effect of lipotoxicity might seem appealing and perhaps even intuitive. However, the beneficial value of lipid reduction appears at a minimum to be nuanced, given increasing evidence indicating that weight loss in IPF portends worse outcomes, thus raising the need for caution.
      • Pugashetti J.
      • Graham J.
      • Boctor N.
      • et al.
      Weight loss as a predictor of mortality in patients with interstitial lung disease.
      In their study, the authors also postulated that proinflammatory biomarkers associated with adipocyte hypertrophy could provide an alternative explanation for lung injury through direct drainage of pericardial adipose into the pulmonary circulation. This idea was bolstered by finding a moderate correlation between PAT and IL-6 and a similar relationship between abdominal VAT and IL-6, whereas abdominal VAT was only weakly correlated with CRP.
      Figure thumbnail gr1
      Figure 1Proposed mechanisms contributing to the development and progression of interstitial lung abnormalities in obesity. Increased pericardial adipose tissue (AT), abdominal visceral AT, and abdominal subcutaneous AT exert lipotoxic effects (red arrows) on the lungs, resulting in obesity-related lung injury and the development of interstitial lung abnormalities with lower FVC. The lipotoxic effect of saturated free fatty acids (eg, palmitate) increases IL-6 and other proinflammatory mediators, promoting early senescence of alveolar epithelial cells and lung fibrosis.
      Anderson et al should be congratulated for the many strengths of their study, including the unique coupling of radiographic and biological data to lung function outcomes in a large multicenter, multiethnic cohort that allows for the generalizability of their findings. In addition, the use of multiple indexes of early lung injury that can be adopted in clinical practice is highly laudable. The consistency with which distinct regions of VAT are associated with HAA and ILA as measures of early lung injury is highly refreshing and makes these indexes more broadly appealing as radiologic biomarkers of clinical significance. The study was not without limitations, as the authors readily acknowledge. Inconsistencies between the time epochs for ILA measurement and lung function and adipose tissue assessment could have impacted the results. The lack of association between SAT and HAA in unadjusted models suggests effect modification and the need for caution to avoid overinterpretation of the data. Further, the lack of a separate replication cohort for their findings presents the opportunity to validate these results in future larger clinical datasets, with well-curated radiologic, clinical, and biorepository data.
      Overall, this work by Anderson et al
      • Anderson M.R.
      • Kolaitis N.A.
      • Gao Y.
      • et al.
      A nonlinear relationship between visceral adipose tissue and frailty in adult lung transplant candidates.
      further raises the curtain, providing additional insight into the mechanisms that underlie ILD susceptibility. These hypothesis-generating findings present visceral fat as a potentially modifiable risk factor in the development of ILD. Moreover, the association between PAT, VAT, and IL-6 is undoubtedly deserving of further investigation, as elucidating these proinflammatory pathways may lead to the identification of novel pharmacotherapeutic targets that could blunt progression to overt ILD.

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