Nanotherapeutics to Modulate the Compromised Micro-Environment for Lung Cancers and Chronic Obstructive Pulmonary Disease

The use of nanomaterials to modulate the tumor microenvironment has great potential to advance outcomes in patients with lung cancer. Nanomaterials can be used to prolong the delivery time of therapeutics enabling their specific targeting to tumors while minimizing and potentially eliminating cytotoxic effects. Using nanomaterials to deliver small-molecule inhibitors for oncogene targeted therapy and cancer immunotherapy while concurrently enabling regeneration of the extracellular matrix could enhance our therapeutic reach and improve outcomes for patients with non-small cell lung cancer (NSCLC) and chronic obstructive pulmonary disease (COPD). The objective of this review is to highlight the role nanomedicines play in improving and reversing adverse outcomes in the tumor microenvironment for advancing treatments for targeting both diseases

Alterations in phenotype and gene expression of adult human aneurysmal smooth muscle cells by exogenous nitric oxide

International audienceAbdominal aortic aneurysms (AAA) are characterized by matrix remodeling, elastin degradation, absence of nitric oxide (NO) signaling, and inflammation, influencing smooth muscle cell (SMC) phenotype and gene expression. Little is known about the biomolecular release and intrinsic biomechanics of human AAA-SMCs. NO delivery could be an attractive therapeutic strategy to restore lost functionality of AAA-SMCs by inhibiting inflammation and cell stiffening. We aim to establish the differences in phenotype and gene expression of adult human AAA-SMCs from healthy SMCs. Based on our previous study which showed benefits of optimal NO dosage delivered via S-Nitrosoglutathione (GSNO) to healthy aortic SMCs, we tested whether such benefits would occur in AAA-SMCs. The mRNA expression of three genes involved in matrix degradation (ACE, ADAMTS5 and ADAMTS8) was significantly downregulated in AAA-SMCs. Total protein and glycosaminoglycans synthesis were higher in AAA-SMCs than healthy-SMCs (p < 0.05 for AAA-vs. healthy-SMC cultures) and was enhanced by GSNO and 3D cultures (p < 0.05 for 3D vs. 2D cultures; p < 0.05 for GSNO vs. non-GSNO cases). Elastin gene expression, synthesis and deposition, desmosine crosslinker levels, and lysyl oxidase (LOX) functional activity were lower, while cell proliferation, iNOS, LOX and fibrillin-1 gene expressions were higher in AAA-SMCs (p < 0.05 between respective cases), with differential benefits from GSNO exposure. GSNO and 3D cultures reduced MMPs −2, −9, and increased TIMP-1 release in AAA-SMC cultures (p < 0.05 for GSNO vs. non-GSNO cultures). AAA-SMCs were inherently stiffer and had smoother surface than healthy SMCs (p < 0.01 in both cases), but GSNO reduced stiffness (~25%; p < 0.01) and increased roughness (p < 0.05) of both cell types. In conclusion, exogenously-delivered NO offers an attractive strategy by providing therapeutic benefits to AAA-SMCs

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Benefits of Concurrent Delivery of Hyaluronan and IGF-1 Cues to Regeneration of Crosslinked Elastin Matrices by Adult Rat Vascular Cells

Elastin, a major component of vascular matrices, critically determines vascular mechanics and maintains the quiescence of smooth muscle cells (SMCs). Attempts to regenerate elastin in elastincompromised blood vessels using tissue-engineering approaches is limited by the unavailability of elastogenic cues to upregulate poor elastin output and matrix assembly by adult vascular cells. We previously showed that hyaluronan (HA) elastogenically stimulates aortic SMCs, although these effects are highly specific to HA fragment size. The elastogenic response of SMCs can also be modulated with growth factors such as insulin-like growth factor (IGF-1). Here, we evaluate the benefits of concurrent delivery of HA fragments (0.76-2000 kDa) and IGF-1 (500 ng/ml) to elastin synthesis, organization and crosslinking. The study outcomes show that, relative to supplement-free cultures, IGF-1 and long-chain HA/large HA fragments, but not HA oligomers, together induce multifold increases in the synthesis of elastin precursors, structural elastin matrix yields and crosslink densities within cell layers, and encourage elastic fibre formation. These outcomes are not all obtained when either of the cues is provided separately. IGF-1 and large HA fragments (\u3e20 kDa) also together inhibit cell proliferation, a concern in elastin-compromised vessels, where SMC hyperproliferation is common. The results will benefit efforts to provide exogenous or scaffold-based elastogenic cues (IGF-1 + HMW HA/large HA fragments) to enable robust and faithful regeneration of elastin matrix structures in vivo or in vitro. The present outcomes may be used to restore elastin matrix homeostasis in de-elasticized vessels and tissue-engineered constructs that may be grafted as a substitute. Copyright © 2008 John Wiley & Sons, Ltd

Biomimetic Regeneration of Elastin Matrices Using Hyaluronan and Copper Ion Cues

Current efforts to tissue engineer elastin-rich vascular constructs and grafts are limited because of the poor elastogenesis of adult vascular smooth muscle cells (SMCs) and the unavailability of appropriate cues to upregulate and enhance cross-linking of elastin precursors (tropoelastin) into organized, mature elastin fibers. We earlier showed that hyaluronan (HA) fragments greatly enhance tropo- and matrix-elastin synthesis by SMCs, although the yield of matrix elastin is low. To improve matrix yields, here we investigate the benefits of adding copper (Cu2+) ions (0.01 M and 0.1 M), concurrent with HA (756-2000 kDa), to enhance lysyl oxidase (LOX)-mediated elastin cross-linking machinery. Although absolute elastin amounts in test groups were not different from those in controls, on a per-cell basis, 0.1 M of Cu 2+ ions slowed cell proliferation (5.6±2.3-fold increase over 21 days vs 22.9±4.2-fold for non-additive controls), stimulated synthesis of collagen (4.1±0.4-fold), tropoelastin (4.1±0.05-fold) and cross-linked matrix elastin (4.2±0.7-fold). LOX protein synthesis increased 2.5 times in the presence of 0.1 M of Cu2+ ions, and these trends were maintained even in the presence of HA fragments, although LOX functional activity remained unchanged in all cases. The abundance of elastin and LOX in cell layers cultured with 0.1 M of Cu2+ ions and HA fragments was qualitatively confirmed using immunoflourescence. Scanning electron microscopy images showed that SMC cultures supplemented with 0.1 M of Cu2+ ions and HA oligomers and large fragments exhibited better deposition of mature elastic fibers (∼1 μm diameter). However, 0.01 M of Cu2+ ions did not have any beneficial effect on elastin regeneration. In conclusion, the results suggest that supplying 0.1 M of Cu2+ ions to SMCs to concurrently (a) enhance per-cell yield of elastin matrix while allowing cells to remain viable and synthetic and not density-arrested in long-term culture because of their moderating effects on otherwise rapid cell proliferation and (b) provide additional benefits of enhanced elastin fiber formation and cross-linking within these tissue-engineered constructs. © Copyright 2009, Mary Ann Liebert, Inc