Pulmonary Hypertension: 236 (Lung Biology in Health and Disease)

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The pathogenesis of COPD involves aberrant inflammatory and dysregulated cellular responses of the lung to cigarette smoke CS exposure.

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Loss of acetyl-CoA and the Krebs cycle intermediate succinate is observed in basal cells of smokers PH is characterized by obstruction of small pulmonary arteries, increased pulmonary arterial pressure, and lung vasculopathy. Vascular obstruction occurs as a consequence of excessive proliferation and apoptosis resistance of vascular cells.

Chronic repression of mitochondrial metabolism, including decreased mitochondrial FA oxidation and transport 24 , is associated with metabolic switching from mitochondrial-derived glucose oxidation to cytoplasmic-derived anaerobic glycolysis The metabolic shift to anaerobic glycolysis contributes mechanistically to the apoptosis-resistant, proliferative phenotype of PH.

Oxygen-associated alterations in complex II and I in response to hyperoxia are also observed in models of bronchopulmonary dysplasia BPD , a chronic lung disorder of infants and children who receive prolonged mechanical ventilation to treat respiratory distress syndrome RDS 28 , Similarly, asthma, a heterogeneous chronic inflammatory disease characterized by variable airway obstruction, airway remodeling, and bronchial hyperresponsiveness, is also associated with a reduction in OXPHOS, specifically decreased expression and activity of COX in bronchial epithelium 30 , and increased Krebs cycle enzymatic activity in platelets Absence of the lung-specific isoform of COX, COX4i2, results in reduced airway responsiveness and a lung pathology that worsens over time, thus highlighting the potential importance of COX4i2 in the pathogenesis of asthma 7.

Changes in bioenergetic processes, such as those observed in the lung diseases described above, may alter mitochondrial shape, movement, and cellular interactions. Mitochondria form a dynamic interconnected intracellular network, changing cellular location via cytoskeletal motors and altering size and shape in response to the metabolic needs of the cell. Mitochondria undergo membrane remodeling through cycles of fusion and division 35 ; the balance of these processes controls mitochondrial structure and metabolism as well as the cell cycle and results in the intermixing of the mitochondrial population in the cell both during normal mitochondrial turnover in homeostatic physiology and in response to mitochondrial or cellular stress Increased fusion or reduced fission promotes the formation of elongated mitochondrial networks, whereas increased fission or reduced fusion causes mitochondrial fragmentation.

Hyperfusion has been documented in COPD and in lung cancer 17 , 18 , 37 , 38 , whereas loss of fusion, specifically loss of MFN2, has been associated with lung cancer 38 and PH The role of mitochondrial fission and fusion in lung cancer may be microenvironment specific; increased fission may allow cancer cells to proliferate rapidly and invade the surrounding tissue, while increased fusion may allow for cell survival during times of stress or drug toxicity Similarly, mitochondrial distribution within lung endothelial cells influences mitochondrial signaling in PH with the perinuclear clustering of mitochondria associated with the regulation of hypoxia-sensitive genes Mitochondrial fission, fusion, mitophagy, and cell death.

Mitochondrial biogenesis and mitophagy allow cells to quickly replace metabolically dysfunctional mitochondria with fresh, undamaged organelles.

CRC Press Online - Series: Lung Biology in Health and Disease

D Mitochondrial-derived second messengers trigger a series of stress response pathways that provide both short-term and long-term benefits in increased stress resistance and longevity. However, excessive activation of these pathways may ultimately become detrimental to the cell, leading to the activation of programmed cell death pathways, including apoptosis, necroptosis, and pyroptosis.

Fission and fusion are intimately linked to the formation of new mitochondria and allow the cell to maintain a healthy pool of mitochondria. Mitochondria are not formed de novo, but mitochondrial biogenesis results from the growth and division of preexisting mitochondria Mitochondrial biogenesis can occur in distal lung cells, including type II AECs 42 , in small blood vessel SMCs, and in inflammatory cells of the alveolar region 9 and is thought to arise during growth, conditions of high-energy demand, or cellular stress.

Medical Therapy for Heart Failure Associated With Pulmonary Hypertension

In the parenchyma, type II AECs initiate mitochondrial biogenesis during acute lung injury ALI , pneumonia, hyperoxic lung injury 43 , and Staphylococcus aureus —associated sepsis ALI, acute respiratory distress syndrome ARDS , and sepsis remain significant sources of morbidity and mortality in the critically ill patient population ALI and ARDS result from the inflammatory response of the lung to both direct and indirect insults and are characterized by severe hypoxemia, hypercapnia, diffuse infiltration visible in the chest x-ray, and a substantial reduction in pulmonary compliance Mitochondrial biogenesis is increased in bronchial smooth muscle remodeling in asthma 46 and in lung cancer; however, in lung cancer, it is unclear whether these alterations contribute to tumorigenesis or are a consequence of carcinogenesis In contrast, loss of mitochondrial biogenesis is associated with COPD, which may be associated with a significantly lower body mass index and lower muscle mass ref.

Metabolically active cells, such as type II AECs, have developed robust programs of mitochondrial quality control consisting of mitochondrial biogenesis and mitochondrial removal. Damaged or defective mitochondria are removed by selective encapsulation into double-membraned autophagosomes that are delivered to the lysosome for degradation, a process called mitophagy Mitochondrial biogenesis and mitophagy allow cells to quickly replace metabolically dysfunctional mitochondria before energy failure The role of mitophagy in lung disease is complex.

In some cases, mitophagy-related processes appear to be pathogenic, whereas in others, these processes are protective. Specifically, COPD patients have increased mitochondrial fission and increased mitophagy Conversely, defective mitophagy leads to CS-induced cellular senescence in human lung fibroblasts and small AECs 53 , and loss of PINK1 and defective mitophagy promote pulmonary fibrosis PF in animal models and in human idiopathic pulmonary fibrosis IPF 54 , PF is characterized by irreversible destruction of lung architecture, abnormal wound healing, and deposition of extracellular matrix ECM proteins, leading to disruption of gas exchange and death from respiratory failure.

Lung fibrosis is either idiopathic 54 or arises from exposure to environmental toxins, such as fibers, asbestos, metals, pesticides, chemotherapeutic drugs, viruses, or radiotherapy. While the pathogenic role of mitophagy in lung disease is perplexing, the differential role of mitophagy in specific cell types in the lung and in diseases such as COPD and IPF may help to explain the differences in obvious clinical, radiological, and pathologic features and may offer novel routes for therapeutic intervention or biomarker development.

Mitochondrial biogenesis and mitophagy also allow cells to quickly replace or segregate mitochondria with pathogenic damaged mitochondrial DNA mtDNA away from the rest of the cell. However, with the arrival of deep sequencing, it has become clear that low-level heteroplasmy in mtDNA is present in most tissues, including the lung 56 , where a portion is maternally inherited and another portion is presumed to arise from de novo acquired mutations Asthma is not considered a mitochondrial syndrome per se; however, maternal inheritance is a risk factor for asthma and other atopic diseases 62 , and mitochondrial haplogroups are associated with increased serum IgE levels 63 , Recent technological advances have identified hundreds of mitochondrial proteins that vary in a cell-specific and tissue-dependent manner; however, the biochemical functions of the majority of these proteins remain unknown 1.

With the other 1, or so proteins that make up the mitochondrion encoded by the nucleus, mitochondria have developed a symbiotic codependency on the nuclear genome and must signal to it in a retrograde fashion to ensure survival and adaptation. The best example of such signaling is the generation of mROS where, under normal physiological conditions, basal ROS released from the mitochondria acts as a second messenger to maintain cellular homeostasis Genetic ablation of Nrf2 enhances susceptibility to CS-induced emphysema 67 and bleomycin-induced PF 68 in mice.

However, there are many variables yet to be explored that may increase epithelial, interstitial, or pulmonary vascular engraftment with circulating or donor-derived cells. More vigorous injury regimens, such as serial naphthalene administration to deplete airway epithelial cells, coupled with busulfan to suppress endogenous bone marrow, appear to have increased engraftment of exogenously administered bone marrow cells Comparably, several reports suggest that chronic or progressive lung injury may result in more substantial engraftment of AECII cells and of interstitial and pulmonary vascular cells with donor-derived cells in mouse or rat models , However, not all chronic lung injury models result in more substantial engraftment The effect of age of either donor cells or of recipients is also less well-explored; although transplantation of whole marrow into 1-day-old mouse pups, using a variety of conditioning regimens, did not increase the number of bone marrow-derived cells over those observed after administration of total marrow to adult mice The route of administration of donor-derived cells is also less well-characterized, as most studies have investigated engraftment after systemic administration of donor cells.

Direct intratracheal administration of MSCs or other marrow-derived cells appears to result in apparent epithelial engraftment. However, levels of apparent engraftment are variable, and when initial engraftment is observed, it is not sustained , In addition to existing studies of HSCs, MSCs of bone marrow, cord blood, and placental tissues origin , EPCs, and fibrocytes, the possibility remains that there may be other cell populations that could be recruited to the lung or that localize to the lung after systemic or other route of administration.

For example, two different populations of cells isolated from human amniotic tissue—human amniotic epithelial cells hAECs and a population of multipotent cells termed human amniotic fluid stem cells hAFSCs —have both been described to apparently engraft in limited amounts in mouse lungs , The hAFSCs localized to distal airway where they expressed thyroid transcription factor 1 TTF1 and surfactant protein C SPC , whereas the hAECs localized to both distal airway and to areas of lung injury where they expressed a range of surfactant proteins.

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Notably, administration of hAECs to bleomycin-injured immunocompetent mice resulted in abrogation of lung injury without apparent host response to the cells Comparably, hAECs administered to rats with experimentally induced myocardial infarction were able to reduce the extent of infarction and also apparently acquired phenotypic characteristics of cardiomyocytes This suggests that these cells may be used in other xenogeneic models of lung injury and may also exhibit paracrine effects that modulate lung injury, a topic discussed further in the section on mesenchymal stromal cells below.

A recent report has also described a population of CCSP-expressing adult marrow cells that appear to more robustly lodge and engraft in lung after either systemic or intratracheal administration Figure 2 Other sources of stem or progenitor cells, such as adipose tissues, also have not been extensively characterized for their ability to engraft as lung tissue as have bone marrow and cord blood origin cells , However, the ability to structurally engraft in adult lung may not solely be a property of stem or progenitor cells.

Intratracheal administration of neonatal mouse lung fibroblasts resulted in apparent alveolar and interstitial engraftment, and engraftment was higher in areas of elastase-induced lung injury Intratacheal administration of fibroblasts, transduced to express angiopoietin-1, mitigated acute lung injury and inflammation in mice Comparably, intratracheal administration of AECII cells results in rare engraftment in areas of injured lung after administering bleomycin to rats Notably, bleomycin-injured rats that received the AECII cells had less histologic injury and decreased hydroxyproline content.

Most recently, AECII cells, derived in vitro from human embryonic stem cells, were able to both engraft and to mitigate bleomycin-induced lung injury in mice These results suggest that lung injuries might be amenable to a variety of cell therapy approaches. Figure 2. B Isotype staining of lung from bone marrow transplant recipient.

C—E Bone marrow transplant recipients had a wild-type background. C Low-power image. D and E High-power images. F Low-power image. G and H High-power image. I and K Thirty days after bone marrow transplant with naphthalene injury. I Low-power image. J and K High-power image. Reprinted with permission from Reference For those studies in which more robust evidence of engraftment has been suggested, the potential role of fusion is still not fully elucidated.

Bone marrow-derived cells can be induced to fuse with lung epithelial cells in vitro , but in vivo investigations suggest that fusion is a rare occurrence , One study suggests that fusion of donor-derived marrow cells with AECII cells can occur in mouse lungs but that the Y chromosome may be lost from the resulting heterokaryon cells Nonetheless, fusion of exogenously administered cells with resident lung cells is thought to be a rare occurrence of uncertain physiologic significance.

Mechanisms by which circulating or systemically administered stem or progenitor cells might be recruited to the lung remain poorly understood. Whether this represents formation of cell emboli in the lung or a specific adherence to pulmonary vascular adhesion or other molecules remains unclear.

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In another study, embolization of systemically administered MSCs in lung was felt to result in secretion of an anti-inflammatory protein, TSG-6 The timing of cell administration after lung injury can also influence recruitment and phenotypic conversion. Systemic administration of MSCs 4 hours after lung irradiation resulted in apparent engraftment of cells as epithelial and vascular endothelial cells However, MSCs administered at later time points appeared to engraft as interstitial cells and participate in the development of fibrosis , Recipient immune responses also play significant yet poorly characterized roles in retention of cells in lung Commonly used approaches of sex-mismatched transplantation or cell administration may also result in clearance of cells The range and identity of chemotactic soluble mediators released by injured lung cells and the role of up-regulation of adhesion molecules with which circulating cells might interact remains poorly understood reviewed in 1 and 2 , , — As with engraftment, a number of factors including age of donor or recipient, type of cell administered, route of administration, and so forth, might affect recruitment of cells to the lung.

Comparably, the mechanisms by which stem or progenitor cells isolated from adult tissues might be induced to acquire the phenotype of lung epithelial, interstitial, or vascular endothelial cells, remain poorly understood. Comparably, coculture of embryonic stem cells with fetal pulmonary mesenchyme can promote the development of cells expressing phenotypic markers of lung epithelial cells One novel mechanism of inducing phenotypic change might involve the release of membrane-derived microvesicles, a recently appreciated means of intercellular communication that involves horizontal transfer of mRNA and proteins between cells , Nonetheless, despite continuing interest in the possibilities of engraftment of exogenous cells in the lung, emphasis has moved to other areas, notably immumomodulatory effects of administered cells and ex vivo tissue engineering.

In the past decade, circulating bone marrow—derived cells putatively similar to embryonal angioblasts have been identified , Increasing evidence demonstrates that EPCs play a role in pathogenesis of a wide variety of lung diseases including pulmonary hypertension, pulmonary fibrosis, airway diseases, including asthma, COPD, acute lung injury, lung cancer, and most recently bronchopulmonary dysplasia and obstructive sleep apnea in children — However, studies of EPCs in lung diseases have been hampered by a lack of consensus regarding identification of these cells Early investigations relied almost exclusively on the use of flow cytometry in conjunction with immunostaining to identify and enumerate these cells in bone marrow as well as in the circulation.

Furthermore, when similar techniques were used in different studies, a different group of markers were used. The lack of a unique cell surface maker to identify an EPC continues to complicate comparative assessments for similar disease processes. As a result, a growing consensus in the field encourages the use of functional assays both in vitro and in vivo in conjunction with the use of flow cytometry and immunohistochemistry IHC to not only enumerate EPCs, but to better characterize their true ability to form functional endothelium. A critical area for future study remains to develop a consensus-based approach to definition and use of EPCs with particular emphasis on functional capabilities of these cells.

At present, there appear to be two major types of EPCs that can be isolated from human peripheral blood by differential culture, an approach that avoids having to have prior certainty of surface selection markers for EPCs , These cells are now known to be derivatives of the hematopoietic lineage differentiating along the myeloid lineage in response to certain cytokines and chemokines. Each of these cell types may have a unique potential in lung microvascular repair, with early EPCs having a role as paracrine cells, and late EPCs functioning more specifically in restoring vascular structures of the lung.

Intravenous infusion of each type of cell in an animal model has demonstrated their ability to preferentially localize to lung The two EPC types may have a synergistic role in restoring vascular structure and function when infused together Further characterization of these two EPC types, including methods to enhance their numbers ex vivo could have implications for the development of therapy specific to the phenotypic abnormalities of a given lung disease. In addition, the source of EPCs, for example adult peripheral blood versus umbilical cord blood, may also influence the differentiation potential of EPCs , A schematic and summary of current classification and characterization of human EPCs is depicted in Figure 3.

Figure 3. Schematics depicting current thinking in isolation and identification of endothelial progenitor cells. The number of circulating EPCs has been correlated with a variety of clinical variables in several lung disease states, demonstrating the potential utility of EPCs as biomarkers. For example, an decrease in the number of circulating EPCs in patients with COPD was associated with more abnormal spirometry , although a different study showed that levels of circulating EPCs were inversely correlated with COPD disease severity Increased numbers of circulating EPCs also portended worse survival among those with non—small cell lung cancer , , In asthma, numbers of circulating EPCs were increased compared with nonasthmatic control subjects, but this did not correlate with clinical outcomes Several clinical factors have been implicated in the mobilization of EPCs, and mechanisms for their effects have begun to be elucidated Hypoxia appears to be a stimulus for EPC mobilization and recruitment, whereas hyperoxia is correlated with decreased circulating EPCs, particularly in preterm EPCs , , These features may play a role in bronchopulmonary dysplasia in premature infants and neonates exposed to high oxygen levels , They also suggest that EPCs could contribute to lung repair after acute lung injury.


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A recent study demonstrated that systemic administration of a population of bone marrow—derived angiogenic cells improved lung alveolar architecture after neonatal hyperoxia exposure in rats Some degree of engraftment was observed, but it is unclear if structural contribution of the engrafted cells, or rather paracrine or other growth stimulating effects, were responsible. Defective lung development or defective lung repair in the setting of protracted inflammation and injury may result in part from an inadequate contribution of local or circulating EPCs.

Age has been previously reported to be inversely correlated both with EPC number and also in the ability of EPCs to home to ischemic tissues based on age , Hypoxia-induced release of insulin-like growth factor 2 may also play a prominent role in EPC homing Goals of increasing numbers of EPCs, or developing methods to enhance their mobilization may not be appropriate for all diseases that affect the lung, particularly for lung cancers , Although levels of circulating EPCs may serve as biomarkers for disease progression or severity , , , EPCs may have an effect on the development of lung tumor vasculature and homing to sites of lung metastases as well as in other cancers , , , , , Because neovascularization involves the recruitment of EPCs from the bone marrow, these cells are a logical target for antiangiogenesis therapy.

For example, an investigational drug, TK 1—2 the kringle domain of tissue-type plasminogen activator , was demonstrated to be useful in blocking adhesion, differentiation, and migration of ex vivo human EPCs in vitro and also in decreasing tumor growth and vascularity in a SCID mouse tumor model These findings suggest that blocking EPCs could be an important therapy in the prevention of cancer progression. Additionally, after systemic injection, EPCs localize to the lung and appear to home to metastatic tumors in the lung through as yet poorly understood mechanisms , This suggests that modification of EPCs to express suicide genes or other therapeutic molecules could be potentially used in cell-based therapy approaches for lung cancer , Mechanisms controlling mobilization and homing of EPCs to the lung remain poorly understood and are the subject for more intense investigation.

A number of studies in mice and dogs have demonstrated a role for exogenously administered EPCs in vasculogenesis and vascular repair in experimental models of pulmonary hypertension 44 , , , , , , — Furthermore, EPCs can be transduced to express proangiogenic factors such as endothelial nitric oxide synthetase eNOS or inhibitors of smooth muscle cell proliferation such as calcitonin gene-related peptide and appear to home to sites of endothelial damage and lung injury EPCs can also preferentially localize to areas of injured lung after systemic administration and may also have paracrine effects to decrease inflammation , , As such, two pilot trials of autologous EPC administration for primary pulmonary hypertension conducted at Zhejiang University in Hangzhou, China in adult and pediatric patients demonstrated increased 6-minute walk capacity and improved hemodynamic variables, including mean pulmonary artery pressure, pulmonary vascular resistance, and cardiac output, 12 weeks after systemic administration of autologous EPCs with conventional therapy when compared with patients receiving conventional therapy alone , Importantly, no adverse effects of EPC administration were noted, although long-term follow-up is pending.

As of March , the PHACeT trial has completed enrollment of the first two dose-panels with three patients receiving a total of 7 million early growth EPCs transfected to overexpress human eNOS in panel 1 and three more patients receiving 23 million cells in panel 2 information courtesy of Duncan Stewart, M. The cell delivery procedure was well tolerated and there were no safety concerns. Notably, the first six patients showed a remarkable reduction in total pulmonary vascular resistance PVR over the course of the 3-day delivery period, which might represent the effect of increased NO release by the engineered EPCs within the pulmonary microcirculation.

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Pulmonary Hypertension / Edition 1

The trial's Data Safety Monitoring Board has approved moving to panel 3, which calls for a total of 50 million cells, in three divided doses over 3 days. Completion of the third dose panel will be followed by enrollment of an additional three patients at the highest tolerated cell dose, which should provide sufficient support to move forward with the design of a randomized controlled trial that can assess potential efficacy of this cell therapy approach in pulmonary arterial hypertension PAH.

Going forward, clarification of the specific cell types involved in the process of neoangiogenesis will result in less confusion surrounding the term EPC. It is apparent that the early outgrowth cells are hematopoietic derivatives that can be identified by their classic cell surface markers, morphology, and in vitro hematopoietic colony-forming activity or in vivo reconstitution of the blood lineages in immunodeficient mice. In contrast, the ECFC or OEC are rare endothelial cells that display clonal proliferative capacity and in vivo vessel forming ability that can be discriminated by several cell surface antigens from the hematopoietic subsets.

Circulating fibrocytes were first described as a subset of circulating leukocytes that produced collagen and homed to sites of inflammation , The identity and phenotypic characterization of circulating fibrocytes is more firmly established and these cells are described by the cell surface markers CD34, CD45, CD13, and MHC II and also express type 1 collagen and fibronectin. Circulating fibrocytes have been implicated in the pathogenesis of several lung diseases including both mouse and clinical models of pulmonary fibrosis, pulmonary hypertension, the subepithelial fibrosis that can develop in severe asthma, and in clinical bronchiolitis obliterans in patients with lung and bone marrow transplants 4 , 8 , — Further levels of circulating fibrocytes may be an indicator of worse prognosis in IPF , Interestingly, numbers of circulating fibrocytes were highest in patients experiencing an acute exacerbation and the numbers returned to baseline with recovery Several chemokines including stromal derived factor-1 SDF-1 and the CCR2 and CCR5 axes have been implicated in recruitment of circulating fibrocytes to fibrotic lungs but overall mechanisms of fibrocyte recruitment to lung are poorly understood , — Matrix metalloproteinase expression may also be involved in recruiting fibrocytes to injured or post-transplant lungs Similarly the mechanisms by which fibrocytes are induced to undergo phenotypic transformation into fibroblasts and myofibroblasts and contribute to fibrogenesis in lung are poorly understood although both haptoglobin and cysteinyl leukotrienes have been implicated , Hypoxia is a potent stimulus for release of a variety of factors by pulmonary vascular endothelium that both serve to recruit fibrocytes as well as induce phenotypic conversion to fibroblasts or myofibroblasts Notably, depletion of circulating fibrocytes abrogated hypoxia-induced perivascular remodeling in rats Circulating fibroblasts may also be important in lung cancer development or metastasis.

Circulating fibrocyte precursors found in blood of lung cancer patients contributed to tumor development when systemically administered to NOD SCID mice engrafted with human lung cancer xenografts Bone marrow-derived cells may also contribute to fibroblasts and myofibroblasts in tumor stromal tissue These results suggest that specific inhibition of fibrocytes or their use as drug delivery vehicles may also be important therapeutic targets in pulmonary vascular disease. MSCs were first described in 1, as an adherent, clonogenic, non-phagocytic, and fibroblastic-like population of bone marrow cells The nomenclature has changed over the years as MSCs were initially termed fibroblastic colony forming units , subsequently as marrow stromal cells, then as mesenchymal stem cells , and most recently as multipotent mesenchymal stromal cells or MSCs MSCs have now been isolated from a wide variety of tissues including umbilical cord blood, Wharton's jelly, placenta, and adipose tissue — More recently cells with characteristics suggesting identity as MSCs have been isolated from adult mouse lungs — , human nasal mucosa and from lungs of both human neonates and human lung transplant recipients — Human lung MSCs appear to have some immunomodulatory capabilities similar to those of bone marrow-derived MSCs whereas ovalbumin sensitization and challenge increase the number of lung MSCs in mice This suggests that the lung MSCs may be involved in regulation of local inflammatory immune responses.

However, the exact identity and physiologic role of putative lung MSCs is not yet clear.