Lack of response to all-<i>trans</i>retinoic acid supplementation in adult dogs following left pneumonectomy

Xiao, Yan; Bellotto, Dennis J.; Dane, D. Merrill; Elmore, R.G.; Johnson, Robert L.; Estrera, Aaron S.; Hsia, Connie C. W.

doi:10.1152/japplphysiol.00553.2005

Cited by 18 publications

(12 citation statements)

References 41 publications

(59 reference statements)

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“…These data are supported by the findings of TEPPER et al [43] that 2 weeks of supplementation with ATRA had no effect on compliance, forced flows or diffusing capacity of the lung for carbon monoxide in the rat elastase-model of emphysema, although there was a slight, albeit insignificant increase in computed tomography scan lung tissue density. Notably, ATRA-supplementation had no effect on lung function, alveolar structure, or septal ultrastructure after left-sided pneumonectomy in dogs, which suggests that ATRA does not induce compensatory lung growth in the absence of existing cellular growth activities initiated by other primary signals [44]. Hence, the discrepant results of a number of studies may indicate that additional, yet unknown stimuli are necessary to induce and drive regeneration along a pathway leading to a regular architecture of regenerated alveolar septa.…”

Section: Discussionmentioning

confidence: 96%

All-trans retinoic acid results in irregular repair of septa and fails to inhibit proinflammatory macrophages

Seifart

Muyal

Plagens

et al. 2011

European Respiratory Journal

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All-trans retinoic acid (ATRA) is controversially discussed in emphysema therapy. We re-evaluated ATRA in the elastase model and hypothesised that beneficial effects should be reflected by increased alveolar surface area, elastin expression and downregulation of inflammatory mediators and matrix metalloproteinases (MMPs).Emphysema was induced by porcine pancreatic elastase versus saline in Sprague-Dawley rats. On days 26-37, rats received daily intraperitoneal injections with ATRA (500 mg?kg -1 body weight)versus olive oil. Lungs were removed at day 38. Rat alveolar epithelial L2 cells were incubated with/without elastase followed by ATRA-or vehicle-treatment, respectively. ATRA only partially ameliorated structural defects. Alveolar walls exhibited irregular architecture: increased arithmetic mean thickness, reduction in surface coverage by alveolar epithelial cells type II. ATRA only partially restored reduced soluble elastin. It tended to increase the ratio of ED1 + :ED2 + macrophages. Bronchoalveolar lavage (BAL) cells exhibited a proinflammatory state and high expression of interleukin-1b, cytokine-induced neutrophil chemoattractant-1, tumour necrosis factor-a, nuclear factor-kB, MMP-2, MMP-9, MMP-12, tissue inhibitor of metalloproteinase (TIMP)-1 and TIMP-2 in emphysema, with ATRA exerting only few effects. MMP-7 was highly induced by ATRA in healthy but not in emphysematous lungs. ATRA reduced both MMP-2 and TIMP-1 activity in BAL fluid of emphysematous lungs. ATRA-therapy may bear the risk of unwanted side-effects on alveolar septal architecture in emphysematous lungs.

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Section: Discussionmentioning

confidence: 96%

All-trans retinoic acid results in irregular repair of septa and fails to inhibit proinflammatory macrophages

Seifart

Muyal

Plagens

et al. 2011

European Respiratory Journal

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“…Both pneumonectomy and alveolar hypoxia induce long-term acinar remodeling including (i) variable changes in the volume fractions of alveolar ducts and sacs, which at least partly reflect changes in airway smooth muscle tone, and (ii) reduction in the harmonic mean tissue-plasma-erythrocyte barrier which minimizes the resistance to O 2 transfer (175,180,295,411). Because the harmonic mean barrier thickness is proportional to the reciprocal of local absolute thicknesses, gas flux normally occurs predominantly through the “ thin side ” of the septum.…”

Section: Induced Structural Adaptation and Its Functional Consequencesmentioning

confidence: 99%

Lung Structure and the Intrinsic Challenges of Gas Exchange

Hsia

Hyde

Weibel

2016

Comprehensive Physiology

158

137

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Structural and functional complexities of the mammalian lung evolved to meet a unique set of challenges, namely, the provision of efficient delivery of inspired air to all lung units within a confined thoracic space, to build a large gas exchange surface associated with minimal barrier thickness and a microvascular network to accommodate the entire right ventricular cardiac output while withstanding cyclic mechanical stresses that increase several folds from rest to exercise. Intricate regulatory mechanisms at every level ensure that the dynamic capacities of ventilation, perfusion, diffusion, and chemical binding to hemoglobin are commensurate with usual metabolic demands and periodic extreme needs for activity and survival. This article reviews the structural design of mammalian and human lung, its functional challenges, limitations, and potential for adaptation. We discuss (i) the evolutionary origin of alveolar lungs and its advantages and compromises, (ii) structural determinants of alveolar gas exchange, including architecture of conducting bronchovascular trees that converge in gas exchange units, (iii) the challenges of matching ventilation, perfusion, and diffusion and tissue-erythrocyte and thoracopulmonary interactions. The notion of erythrocytes as an integral component of the gas exchanger is emphasized. We further discuss the signals, sources, and limits of structural plasticity of the lung in alveolar hypoxia and following a loss of lung units, and the promise and caveats of interventions aimed at augmenting endogenous adaptive responses. Our objective is to understand how individual components are matched at multiple levels to optimize organ function in the face of physiological demands or pathological constraints.

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“…Experimental pneumonectomy (PNX) is the most robust and extensively characterized model of CLG mimicking the consequences of anatomical loss of lung units. Mechanical stress has emerged as the major stimulus for the de novo re-initiation of growth in the mature lung (Hsia, 2004b, Wirtz and Dobbs, 2000) while exogenous growth factors (Ravikumar, et al, 2011, Yan, et al, 2005) and ambient hypoxia (Burri and Weibel, 1971, Hsia, et al, 2005) modify the activated growth pathways. As lung units are lost due to surgery or disease, re-direction of air and blood flow to the remaining lung units cause air space expansion, tissue stretch, capillary distention and flow shear, which provide mechanical stimuli for adaptation.…”

Section: Mechanical Signals In Compensatory Lung Growthmentioning

confidence: 99%

Comparative analysis of the mechanical signals in lung development and compensatory growth

Hsia

2017

Cell Tissue Res

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This review compares the manner in which physical stress imposed on the parenchyma, vasculature and thorax, and the thoraco-pulmonary interactions, drive both developmental and compensatory lung growth. Re-initiation of anatomical lung growth in the mature lung is possible when the loss of functioning lung units renders the existing physiologic-structural reserves insufficient for maintaining adequate function and physical stress on the remaining units exceeds a critical threshold. The appropriate spatial and temporal mechanical interrelationships, and the availability of intra-thoracic space, are crucial to growth initiation, follow-on remodeling and physiological outcome. While the endogenous potential for compensatory lung growth is retained and may be pharmacologically augmented, supra-optimal mechanical stimulation, unbalanced structural growth, or inadequate remodeling, may limit functional gain. Finding ways to optimize the signal-response relationships and resolve structure-function discrepancies are major challenges that must be overcome before the innate compensatory ability could be fully realized. Partial pneumonectomy reproducibly removes a known fraction of functioning lung units and remains the most robust model for examining the adaptive mechanisms, structure-function consequences, and plasticity of the remaining functioning lung units capable of regeneration. Fundamental mechanical stimulus-response relationships established in the pneumonectomy model directly inform the exploration of effective approaches to maximize compensatory growth and function in chronic destructive lung diseases, transplantation and bioengineered lungs.

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Lack of response to all-transretinoic acid supplementation in adult dogs following left pneumonectomy

Abstract: . Lack of response to all-trans retinoic acid supplementation in adult dogs following left pneumonectomy.

Cited by 18 publications

References 41 publications

All-trans retinoic acid results in irregular repair of septa and fails to inhibit proinflammatory macrophages

All-trans retinoic acid results in irregular repair of septa and fails to inhibit proinflammatory macrophages

Lung Structure and the Intrinsic Challenges of Gas Exchange

Comparative analysis of the mechanical signals in lung development and compensatory growth

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