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The Periarterial Space in the Lung: Its Important Role in Lung Edema, Transplantation, and Microbial or Allergic Inflammation

The Periarterial Space in the Lung: Its Important Role in Lung Edema, Transplantation, and... Review Received: May 14, 2004 Pathobiology 2004;71:287–294 Accepted: June 23, 2004 DOI: 10.1159/000081723 The Periarterial Space in the Lung: Its Important Role in Lung Edema, Transplantation, and Microbial or Allergic Inflammation R. Pabst Department of Functional and Applied Anatomy, Medical School of Hannover, Hannover, Germany Key Words microscopy of vascular casts [2]. A diagram of this com- Lung W Compartments W Periarterial space W Edema W partment is shown in figure 1. This review will describe Inflammation different aspects of the periarterial space in lung edema and transplantation, models of infections and allergies of the lung and models of other diseases. This compartment Abstract has been found to be involved in a wide range of diseases or In mammal lungs different compartments for leukocytes their models in all species so far studied. Furthermore, the can be identified during health and disease, e.g. lung potential role of adhesion molecules, cytokines and chemo- interstitium, bronchoalveolar space, the epithelium and kines in the accumulations of leukocytes in this space will lamina propria of the air-conducting part. A so far ne- be discussed. In nearly all studies cited in this review, the glected compartment is the space around the branches influx of leukocytes into the periarterial space or edema of the pulmonary arteries, characterized by a unique formation was documented by figures and also mentioned architecture of capillaries running in parallel to the in passing, but never described in the summaries. pulmonary artery. This compartment – the periarterial space – is described and its phyiological and pathophysi- ological role reviewed. The periarterial space is infil- Edema in the Periarterial Space trated by different leukocyte subsets during edema for- mation in the early stages of a lung transplant rejection In many experiments in various species, a prominent and, in particular, during inflammatory and allergic reac- edema around branches of pulmonary arteries is seen tions. The periarterial compartment seems to be of major (fig. 2). There seem to be different forms of pulmonary relevance in all these situations. edema, which was very obvious in the studies of Chetham Copyright © 2004 S. Karger AG, Basel et al. [3] on microsvascular and macrovascular barrier dis- ruption. A thapsigargin-induced edema was mainly found in pre- and postcapillary vessels but not in the alveolar In 2002 a concept was proposed that there is an addi- microcirculation. However, the periarterial capillaries tional compartment in the lung – the periarterial space – had not been studied. The platelet-activating factor can which is characterized by a different capillary bed [1]. In cause pulmonary edema in isolated perfused lungs of rats addition to the alveolar capillaries some capillaries run and in mice in vivo which could be blocked by quinolines parallel to the branches of the pulmonary artery, as [4]. The mechanisms involved in the permeability of lung impressively documented in rats by scanning electron endothelial cells are described in a recent review [5]. The © 2004 S. Karger AG, Basel Prof. Dr. R. Pabst ABC 1015–2008/04/0716–0287$21.00/0 Anatomie II, Medizinische Hochschule Hannover Fax + 41 61 306 12 34 Carl-Neuberg-Strasse 1 E-Mail karger@karger. ch Accessible online at: DE–30625 Hannover (Germany) www. karger.com www. karger.com/pat Tel. +49 511 532 6740, Fax +49 511 532 2948, E-Mail [email protected] molecular mechanism of edema formation in the periarter- Periarterial Inflammation Can Be Induced by Bacteria, Viruses and Fungi ial space of the lung is still unknown. In two recent studies, rats were ventilated with high tidal volumes [6, 7] and this mechanical stress induced a periarterial edema resulting in Despite minor differences, the exposure to different an enlarged periarterial space. It remains to be shown bacteria such as Haemophilus influenzae [15], Streptococ- whether the increased expression of certain genes [7] is cus pyogenes [16] or mycobacterial products [17, 18] all localized in this compartment. The engorged lymphatics resulted in periarterial accumulations, which however, shown by Schraufnagel et al. [6] could be a secondary effect. were often only mentioned in passing. Some examples of After infecting mice with an adenovirus, there was not only virus causing infections are influenza virus [19], respira- an infiltration by leukocytes but also edema formation on tory syncytial virus [20–22], lymphocytic choriomeningi- day 7 and 14 after infection, with a decreased expression of tis virus or murine cytomegalovirus [23]. In these experi- aquaporin 1 and 6 [8]. After experimental ischemia and ments the role of a previous immunization to the specific reperfusion, it was possible to prevent periarterial edema or other viral infections was studied. A heterologous formation by preserving the tubular myelin [9]. immunity was evident for many viruses, but in most cases Many pathobiological aspects remain to be studied ‘periarterial lymphocytic cuffing’ was seen. In Aspergillus before the sequence of edema formation in the periarterial fumigatus-induced airway disease in mice, a massive space can be understood and potential therapeutic ap- periarterial leukocyte accumulation was observed which proaches considered. could be attenuated when RANTES was given from day 5 to 15; later this did not have an effect [24]. The positive effect of RANTES on periarterial infiltration was also The Periarterial Space in Lung Transplantation documented in acute lung allograft rejection [25, 26]. Thus, the effect of the chemokine RANTES is not re- The rejection of transplanted lungs has been classified stricted to reactions in inflammation. However, it is and ranges from acute to chronic vascular rejection (for unclear whether RANTES affects the leukocyte emigra- review see [10]). The principal histological feature of tion via the periarterial capillaries or by other mecha- acute rejection is characterized as ‘periarterial mononu- nisms. Mycoplasma pneumoniae induced not only a peri- clear infiltrates’. The revised working formulation of the bronchial but also a dramatic periarterial cellular inflam- Lung Rejection Study Group [11] graded acute lung rejec- matory response involving neutrophils, mononuclear cells tion from A1 ‘infrequent periarterial infiltrates’ to A4 ‘dif- and alveolar macrophages [27]. In addition to the many fuse periarterial, interstitial and alveolar infiltrates’. microbial agents which cause a leukocyte influx in the However, Tazelaar [12] stressed that the presence of periarterial space, sheep red blood cells (a nonmicrobial periarterial inflammation on transbronchial biopsies after particulate antigen) also produced a prominent accumula- lung transplantation should only be taken as an indicator tion [28]. of rejection if inflammations due to cytomegalovirus and Thus, irrespective of the type of microbial organism, pneumocystis have already been excluded. In recent ex- periarterial inflammatory reactions were seen after instil- periments in rats, the important effect of carbon monox- lation of the organisms into the airspace in a very compa- ide as a cytoprotector in the transplanted lung was docu- rable fashion. mented by modern techniques such as gene array technol- ogy [13]. Ischemia and reperfusion might damage endo- thelial cells; however, it has not been tested whether the Leukocyte Infiltration of the Periarterial Space in Allergy Models capillaries in the periarterial space are more prone to this damage than alveolar capillaries and thus induce the periarterial leukocyte influx. In a recent study the role of There are innumerable studies documenting an influx chemokines CXXL9/CXCR3 has been shown, e.g. an of inflammatory cells into this space usually with a paral- anti-CXCL9 therapy combined with a low-dose cyclospo- lel peribronchial influx (fig. 3). Therefore, only a few rin A treatment resulted in much less leukocyte infiltra- papers will be referred to which show specific aspects. tion in the transplanted lung [14]. Some of the allergens involved were: house dust mite [29, In conclusion, the periarterial space seems to be a sen- 30], Aspergillus fumigatus allergen [31], and protease sitive indicator for early transplant rejection, although allergen extract of Penicillium chrysogenum conidia [32]. many details are still not known. The most widely used antigen is ovalbumin (OVA), which Pathobiology 2004;71:287–294 288 Pabst 1 Fig. 1. Schematic drawing of the compartment around the branch of Fig. 3. A After i.p. sensitization with ovalbumin and an intratracheal a pulmonary artery with the unique pattern of capillaries in the instillation of OVA there is an obvious influx of leukocytes into the lung. peribronchial area but the periarterial space is not affected. B Sec- Fig. 2. Edema in the periarterial space in the lung of a rat in a model tions of a rat lung after the instillation of sheep red blood cells into of edema after the application of the platelet-activating factor (PAF). the trachea. There is a predominant influx of immune cells in the (Tissue sample by courtesy of Prof. S. Uhlig, Borstel, Germany). A = periarterial space and only some inflammatory cells in the peribron- branch of the pulmonary artery; Br = bronchial branch. chial area. A = branch of the pulmonary artery; Br = bronchial branch. is mostly injected intraperitoneally for sensitization in dendritic cells (DC) in the OVA model has been repeated- mice or rats, and the animals are later exposed to OVA by ly shown. Nishida et al. [34] documented by microscop- inhalation or tracheal instillation. In all experiments ical and ultrastructural techniques that DC, eosinophils which localized the leukocyte influx, a periarterial infil- and lymphocytes were next to vessels in a chronic OVA tration was documented. Hamada et al. [33] showed an model at 24 h and lymphocytes emigrated via capillaries. age effect in mice: in very young pups no infiltration was When OVA-pulsed DC were instilled into the trachea of seen. However, after combining OVA with residual oil fly rats and these animals challenged for 3 days, a dramatic ash as a typical air pollutant, it induced the development accumulation of mononuclear cells in the periarterial of airway hypersensitivity in neonatal mice. The role of space was seen [35, 36]. The costimulatory molecules Pathobiology 2004;71:287–294 The Periarterial Space in the Lung 289 CD80 and CD86 seem to play a key role in this respect, as Chemokines and their receptors are increasingly be- mice lacking these molecules did not show periarterial infil- coming more interesting. However, little is known of tration after OVA exposure [37]. A dissociation of hyper- these molecules in lung diseases. The chemokine receptor reactivity and eosinophil influx has also been documented 8 (CCR8) had no effect on leukocyte accumulation in the after the transfer of peptide-pulsed DC [38]. Allergen ef- periarterial space in an OVA mouse model [45]. fects can be increased by the concomitant exposition of diesel exhaust particles with different effects on airway hypersensitivity and cellular influx, which was partly focal Lipopolysaccharide (LPS) in Periarterial in the periarterial space [39]. Side stream cigarette smoke Leukocyte Infiltration exposure of mice after birth also influenced eosinophilic inflammation after OVA exposure [40]. The effects of The proinflammatory glycolipid component of the respiratory syncytial virus infection on mite allergen expo- gram-negative bacterial cell wall lipopolysaccharide (LPS) sition were recently studied, demonstrating a preferential is ubiquitously present in many different airborne parti- eosinophilic infiltration of the periarterial space [41]. Po- cles. When mice were repeatedly challenged over 12 tential therapeutic aspects were the focus of two studies us- weeks (twice weekly) by an intratracheal LPS instillation ing the OVA model. Mice without cyclo-oxygenase-1 and the lungs studied at one and 8 weeks after this expo- (COX-1) had an exaggerated cell influx, which was not the sure period, among several other effects a dense periarte- –/– + case in cyclooxygenase-2 mice [42]. The allergen-induced rial infiltration by lymphocytes (mainly CD4 ) was docu- eosinophil influx into the periarterial space was dramatical- mented [46]. Contamination of the bedding material for ly reduced in mice, when recombinant human platelet acti- laboratory animals by bacterial products also induced vating acetylhydroxylase – an inhibitor of platelet-activat- periarterial infiltrations in rats and this might be of major ing factor – was injected. This might be considered as a relevance when experiments between different laborato- therapeutic strategy to reduce the late effects in asthma. ries are compared [47]. In another study in mice, the role Thus, there seems to be common sequelae after aerosol of the Toll-like receptor 4 after sensitization and intrana- exposure with allergens, resulting in periarterial accumu- sal OVA exposure was described. High levels of LPS with lation of leukocytes. The relevance of this general phe- an antigen resulted in a TH1 response, which was in con- nomenon remains to be elucidated. trast to low doses leading to Th2 responses [48]. However, both high and low doses of LPS resulted in periarterial lymphocyte accumulation. In another study LPS reduced The Role of Adhesion Molecules and the sensitization to inhaled antigen by a reduced TH2 Chemokines in the Influx of Leukocytes into development due to DCs and this phenomenon was inde- the Periarterial Space pendent of IL-12 [49]. One reason for the influx of leuko- cytes after LPS might be the well-documented induction It is generally accepted that a variety of microbial stim- of apoptosis of endothelial cells after LPS, which requires uli and cytokines are involved in the expression of adhe- the generation of ceramide [50]. A flavonoid from plants, sion molecules on endothelial cells to recruit leukocytes luteolin, protected against leukocyte periarterial infiltra- into areas of inflammation. Vascular adhesion protein 1 tion after LPS, which was obviously due to a reduced pro- was expressed on the endothelium of large to medium duction of TNF-· and the adhesion molecule ICAM-1 sized pulmonary vessels, but not in alveolar septae in nor- [51]. Another bacterial product, the staphylococcal ente- mal human and mice lungs [43]. In an inflammatory mod- rotoxin B, a well-known superantigen given intranasally el in these experiments, vascular adhesion protein 1 was to mice resulted in a dose-dependent leukocyte infiltra- positive in inflammatory cells in the periarterial space tion of the periarterial space with hardly any peribron- also. In a bleomycin-induced fibrotic lung the endothelial chial influx [52]. adhesion molecules (ICAM-1) could be seen on the venu- In conclusion, bacterial products such as LPS instilled lar and arteriolar endothelia by real time confocal laser in the airspace of mice resulted in a leukocyte influx into luminescence microscope in rats. ICAM-1 was expressed the periarterial space. It remains to be studied how the along the venular and capillary walls [44]. However, capil- information of LPS instillation is conveyed from the air- laries in the periarterial space have not been checked by space to the periarterial capillaries to open the vessel wall this technique, but they might be tested when this lung for leukocytes. compartment is no longer neglected. Pathobiology 2004;71:287–294 290 Pabst Cytokines in Lung Periarterial Leukocyte Influx tions. In pigs the first sign of edema formation was in the periarterial space [Pabst and Binns, unpubl. observa- Intranasal administration of IL-25 resulted in the pro- tions]. In rhesus monkeys a similar compartment could be duction of other cytokines, airway hyper-reactivity, and seen [Plopper, pers. commun.]. Not surprisingly, much epithelial cell hyperplasia, but also a marked infiltrate less is documented for the human lung. In one study on around the branches of the pulmonary arteries (mainly pulmonary arteries in smokers versus nonsmokers a peri- eosinophils with some macrophages and lymphocytes) arterial space was obvious, but it was not filled with infil- –/– [53]. IL-10 mice showed a periarterial infiltration, but trating leukocytes [61]. In another group of patients with no airway hyper-reactivity [54]. In another study on mice, COPD CD8 , leukocytes were seen in the adventitia of a blockade of IL-13 partially blocked airway hypersensi- the branches of pulmonary arteries [62]. In smoking tivity and goblet cell hyperplasia, but not periarterial patients with severe or mild COPD no differences in leu- accumulation of inflammatory cells [55]. kocyte infiltrates were observed in the adventitial layer These data show a rather constant effect of interleukins [63]. These findings resemble a vasculitis. This is in con- on the periarterial leukocyte influx in contrast to a varied trast to data from laboratory animals, in which the wall of effect on typical characteristics of asthma such as airway the pulmonary artery was not infiltrated by inflammatory hyper-reactivity. cells. In conclusion, the periarterial space of the lung seems to be the site of leukocyte infiltration and edema forma- Matrix Metalloproteinases (MMP) and tion in all mammals studied so far. The strain differences Periarterial Cellular Infiltration in mice are difficult to explain at present. In many inflammatory reactions the matrix metallo- proteinases (MMPs) play a critical role, e.g. by affecting The Effect of Genetic Defects on Leukocyte Accumulations in the Periarterial Space the interstitial matrix. In mice lacking MMP-9, compara- ble numbers of eosinophils were found in the bronchoal- veolar lavage and a similar bronchial hyper-responsive- When lymphotoxin was knocked out, there were no –/– ness was documented. However, there was a drastically lung-draining lymph nodes. However, in naı ¨ve LT· reduced leukocyte influx into the periarterial space [56]. mice there was no sign of peribronchial inflammation but In contrast the lack of MMP-2 reduced the influx of leuko- a mild periarterial infiltration, which was much more pro- cytes into the airway lumen despite a periarterial accumu- nounced and consisted mainly of mononuclear cells after lation [57]. The tissue inhibitor of metalloproteinase 1 OVA sensitization [64]. Interestingly, the allergic sensiti- –/– was markedly increased in the periarterial region on day 4 zation was completely absent in splenectomized LT· after bleomycin [58], indicating that the MMPs and tissue mice. In a more recent study, there was an increased per- –/– inhibitors of metalloproteinase also seem to play a role in iarterial leukocyte accumulation in LT· mice with a periarterial cellular infiltrations, e.g. after instilling bleo- reduced IgE level and reduced airway hypersensitivity, mycin into the airway lumen, which might be due to a thus documenting a heterogenous genetic dependence of modulation of matrix turnover. cellular criteria of allergy [65]. With age a spontaneous cumulative airway inflammation developed. In a recent study of mice in which surfactant protein D was knocked Which Species Show a Periarterial Leukocyte out, there was an increased baseline inflammation includ- Infiltration at Different Stages after Allergen ing the periarterial space, probably caused by a disruption Exposure or Lung Infection? of NO signaling within the innate immune system [66]. As in many other models, it is unclear how a defect in the The species studied most often with this accumulation bronchial surface to the air has effects on the periarterial is the mouse. There were obvious strain differences de- space. In a mouse model for lupus erythromatodes (lpr spite comparable age and breeding conditions (BALB-c mice) not only did lymphosplenomegaly and kidney pa- vs. C57Bl/6) [59] [Singh et al., in preparation]. There was thology develop, but also, an ‘angiocentric’, although not less sensitivity for the late airway inflammation in male peribronchial, pattern of cellular infiltration in the lung compared to female BALB/c mice [60]. As will be de- was obvious. The figures seemed to show this infiltration scribed later, the rat shows similar periarterial accumula- as perivenular and not periarterial in one study [67], but Pathobiology 2004;71:287–294 The Periarterial Space in the Lung 291 in a recent study only periarterial [Neumann et al. 2004, in the periarterial space while the peribronchial area in preparation]. There is a growing number of mice in showed only a tendency to lower numbers [72]. which different genes have been knocked out and differ- Thus, there have been a number of recent, very differ- ent lymphoid organs are undeveloped. However, the lung ent therapeutic approaches with promising results in ani- has rarely been studied in such mice. mal models. These data indicate that the lack of draining lymph nodes results in a (probably) secondary accumulation in the periarterial space due to the blocking of lymphatics Conclusions leaving the lung. A relevant biological role of the periarterial space in the lung can be assumed, as it is involved in central patho- Potential Therapeutic Aspects of Periarterial biological phenomena such as edema formation and leu- Leukocyte Accumulations kocyte influx in many heterogenous inflammatory and allergic models in different species. Future research Recently in studies in which very different therapeutic should not overlook this compartment any longer. The approaches were described, effects on periarterial leuko- basic structural and molecular reasons for the preferential cyte accumulations were reported, although it was not edema formation might be due to a unique wall of the clear whether these were the main or secondary effects; periarterial capillaries. It is unclear how an antigen or even in these studies the periarterial space was not the microbial factors which are inhaled or instilled into the focus of the experiments. In a hypersensitivity pneumoni- airspace can modify the production of cytokines or che- tis model in mice, the inhibition of E and P selectin to mokines, which reach the area beyond the bronchial wall. sialyl-Lewis x suppressed the inflammatory response [68]. One idea is that such particular or soluble antigens are Anti-IL-9 treatment in the OVA model in the mouse taken up in the peripheral air space and this stimulus is resulted in a dramatic reduction of periarterial leukocytes transported to the periarterial capillaries modifying the after OVA challenge. There was also no airway hyper- tightness of their wall or upregulating adhesion molecules reactivity in response to metacholin [69]. Lipoxin, a sepa- as a basis for leukocyte efflux. Lymphatics might also play rate class of eicosanoids, inhibited not only airway hyper- a role in this respect. However, this concept does not responsiveness but also the leukocyte influx into the include a convincing argument why leukocytes emigrate periarterial space [70]. Phosphoinositide 3-kinase might and accumulate in this compartment. This review might be a relevant contributor in the pathogenesis of asthma. stimulate future experiments and stop the long neglect of The fusion protein of a dominant negative form of the this compartment. regulatory subunit P85· blocked the leukocyte accumula- tion in the periarterial space in parallel to other criteria of asthma [71]. In a recently published study simvastatin, a Acknowledgments drug widely used as a serum cholesterol-lowering drug, The author’s experiments have been supported by the Deutsche had an anti-inflammatory effect in the mouse OVA mod- Forschungsgemeinschaft (SFB 587/B1). The meticulous correction of el. The influx of leukocytes was significantly reduced only the English by Sheila Fryk is greatly acknowledged. 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The Periarterial Space in the Lung: Its Important Role in Lung Edema, Transplantation, and Microbial or Allergic Inflammation

Pabst, R.
Pathobiology , Volume 71 (6): 8 – Dec 1, 2004
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Karger
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© 2004 S. Karger AG, Basel
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1015-2008
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1423-0291
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10.1159/000081723
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Abstract

Review Received: May 14, 2004 Pathobiology 2004;71:287–294 Accepted: June 23, 2004 DOI: 10.1159/000081723 The Periarterial Space in the Lung: Its Important Role in Lung Edema, Transplantation, and Microbial or Allergic Inflammation R. Pabst Department of Functional and Applied Anatomy, Medical School of Hannover, Hannover, Germany Key Words microscopy of vascular casts [2]. A diagram of this com- Lung W Compartments W Periarterial space W Edema W partment is shown in figure 1. This review will describe Inflammation different aspects of the periarterial space in lung edema and transplantation, models of infections and allergies of the lung and models of other diseases. This compartment Abstract has been found to be involved in a wide range of diseases or In mammal lungs different compartments for leukocytes their models in all species so far studied. Furthermore, the can be identified during health and disease, e.g. lung potential role of adhesion molecules, cytokines and chemo- interstitium, bronchoalveolar space, the epithelium and kines in the accumulations of leukocytes in this space will lamina propria of the air-conducting part. A so far ne- be discussed. In nearly all studies cited in this review, the glected compartment is the space around the branches influx of leukocytes into the periarterial space or edema of the pulmonary arteries, characterized by a unique formation was documented by figures and also mentioned architecture of capillaries running in parallel to the in passing, but never described in the summaries. pulmonary artery. This compartment – the periarterial space – is described and its phyiological and pathophysi- ological role reviewed. The periarterial space is infil- Edema in the Periarterial Space trated by different leukocyte subsets during edema for- mation in the early stages of a lung transplant rejection In many experiments in various species, a prominent and, in particular, during inflammatory and allergic reac- edema around branches of pulmonary arteries is seen tions. The periarterial compartment seems to be of major (fig. 2). There seem to be different forms of pulmonary relevance in all these situations. edema, which was very obvious in the studies of Chetham Copyright © 2004 S. Karger AG, Basel et al. [3] on microsvascular and macrovascular barrier dis- ruption. A thapsigargin-induced edema was mainly found in pre- and postcapillary vessels but not in the alveolar In 2002 a concept was proposed that there is an addi- microcirculation. However, the periarterial capillaries tional compartment in the lung – the periarterial space – had not been studied. The platelet-activating factor can which is characterized by a different capillary bed [1]. In cause pulmonary edema in isolated perfused lungs of rats addition to the alveolar capillaries some capillaries run and in mice in vivo which could be blocked by quinolines parallel to the branches of the pulmonary artery, as [4]. The mechanisms involved in the permeability of lung impressively documented in rats by scanning electron endothelial cells are described in a recent review [5]. The © 2004 S. Karger AG, Basel Prof. Dr. R. Pabst ABC 1015–2008/04/0716–0287$21.00/0 Anatomie II, Medizinische Hochschule Hannover Fax + 41 61 306 12 34 Carl-Neuberg-Strasse 1 E-Mail karger@karger. ch Accessible online at: DE–30625 Hannover (Germany) www. karger.com www. karger.com/pat Tel. +49 511 532 6740, Fax +49 511 532 2948, E-Mail [email protected] molecular mechanism of edema formation in the periarter- Periarterial Inflammation Can Be Induced by Bacteria, Viruses and Fungi ial space of the lung is still unknown. In two recent studies, rats were ventilated with high tidal volumes [6, 7] and this mechanical stress induced a periarterial edema resulting in Despite minor differences, the exposure to different an enlarged periarterial space. It remains to be shown bacteria such as Haemophilus influenzae [15], Streptococ- whether the increased expression of certain genes [7] is cus pyogenes [16] or mycobacterial products [17, 18] all localized in this compartment. The engorged lymphatics resulted in periarterial accumulations, which however, shown by Schraufnagel et al. [6] could be a secondary effect. were often only mentioned in passing. Some examples of After infecting mice with an adenovirus, there was not only virus causing infections are influenza virus [19], respira- an infiltration by leukocytes but also edema formation on tory syncytial virus [20–22], lymphocytic choriomeningi- day 7 and 14 after infection, with a decreased expression of tis virus or murine cytomegalovirus [23]. In these experi- aquaporin 1 and 6 [8]. After experimental ischemia and ments the role of a previous immunization to the specific reperfusion, it was possible to prevent periarterial edema or other viral infections was studied. A heterologous formation by preserving the tubular myelin [9]. immunity was evident for many viruses, but in most cases Many pathobiological aspects remain to be studied ‘periarterial lymphocytic cuffing’ was seen. In Aspergillus before the sequence of edema formation in the periarterial fumigatus-induced airway disease in mice, a massive space can be understood and potential therapeutic ap- periarterial leukocyte accumulation was observed which proaches considered. could be attenuated when RANTES was given from day 5 to 15; later this did not have an effect [24]. The positive effect of RANTES on periarterial infiltration was also The Periarterial Space in Lung Transplantation documented in acute lung allograft rejection [25, 26]. Thus, the effect of the chemokine RANTES is not re- The rejection of transplanted lungs has been classified stricted to reactions in inflammation. However, it is and ranges from acute to chronic vascular rejection (for unclear whether RANTES affects the leukocyte emigra- review see [10]). The principal histological feature of tion via the periarterial capillaries or by other mecha- acute rejection is characterized as ‘periarterial mononu- nisms. Mycoplasma pneumoniae induced not only a peri- clear infiltrates’. The revised working formulation of the bronchial but also a dramatic periarterial cellular inflam- Lung Rejection Study Group [11] graded acute lung rejec- matory response involving neutrophils, mononuclear cells tion from A1 ‘infrequent periarterial infiltrates’ to A4 ‘dif- and alveolar macrophages [27]. In addition to the many fuse periarterial, interstitial and alveolar infiltrates’. microbial agents which cause a leukocyte influx in the However, Tazelaar [12] stressed that the presence of periarterial space, sheep red blood cells (a nonmicrobial periarterial inflammation on transbronchial biopsies after particulate antigen) also produced a prominent accumula- lung transplantation should only be taken as an indicator tion [28]. of rejection if inflammations due to cytomegalovirus and Thus, irrespective of the type of microbial organism, pneumocystis have already been excluded. In recent ex- periarterial inflammatory reactions were seen after instil- periments in rats, the important effect of carbon monox- lation of the organisms into the airspace in a very compa- ide as a cytoprotector in the transplanted lung was docu- rable fashion. mented by modern techniques such as gene array technol- ogy [13]. Ischemia and reperfusion might damage endo- thelial cells; however, it has not been tested whether the Leukocyte Infiltration of the Periarterial Space in Allergy Models capillaries in the periarterial space are more prone to this damage than alveolar capillaries and thus induce the periarterial leukocyte influx. In a recent study the role of There are innumerable studies documenting an influx chemokines CXXL9/CXCR3 has been shown, e.g. an of inflammatory cells into this space usually with a paral- anti-CXCL9 therapy combined with a low-dose cyclospo- lel peribronchial influx (fig. 3). Therefore, only a few rin A treatment resulted in much less leukocyte infiltra- papers will be referred to which show specific aspects. tion in the transplanted lung [14]. Some of the allergens involved were: house dust mite [29, In conclusion, the periarterial space seems to be a sen- 30], Aspergillus fumigatus allergen [31], and protease sitive indicator for early transplant rejection, although allergen extract of Penicillium chrysogenum conidia [32]. many details are still not known. The most widely used antigen is ovalbumin (OVA), which Pathobiology 2004;71:287–294 288 Pabst 1 Fig. 1. Schematic drawing of the compartment around the branch of Fig. 3. A After i.p. sensitization with ovalbumin and an intratracheal a pulmonary artery with the unique pattern of capillaries in the instillation of OVA there is an obvious influx of leukocytes into the lung. peribronchial area but the periarterial space is not affected. B Sec- Fig. 2. Edema in the periarterial space in the lung of a rat in a model tions of a rat lung after the instillation of sheep red blood cells into of edema after the application of the platelet-activating factor (PAF). the trachea. There is a predominant influx of immune cells in the (Tissue sample by courtesy of Prof. S. Uhlig, Borstel, Germany). A = periarterial space and only some inflammatory cells in the peribron- branch of the pulmonary artery; Br = bronchial branch. chial area. A = branch of the pulmonary artery; Br = bronchial branch. is mostly injected intraperitoneally for sensitization in dendritic cells (DC) in the OVA model has been repeated- mice or rats, and the animals are later exposed to OVA by ly shown. Nishida et al. [34] documented by microscop- inhalation or tracheal instillation. In all experiments ical and ultrastructural techniques that DC, eosinophils which localized the leukocyte influx, a periarterial infil- and lymphocytes were next to vessels in a chronic OVA tration was documented. Hamada et al. [33] showed an model at 24 h and lymphocytes emigrated via capillaries. age effect in mice: in very young pups no infiltration was When OVA-pulsed DC were instilled into the trachea of seen. However, after combining OVA with residual oil fly rats and these animals challenged for 3 days, a dramatic ash as a typical air pollutant, it induced the development accumulation of mononuclear cells in the periarterial of airway hypersensitivity in neonatal mice. The role of space was seen [35, 36]. The costimulatory molecules Pathobiology 2004;71:287–294 The Periarterial Space in the Lung 289 CD80 and CD86 seem to play a key role in this respect, as Chemokines and their receptors are increasingly be- mice lacking these molecules did not show periarterial infil- coming more interesting. However, little is known of tration after OVA exposure [37]. A dissociation of hyper- these molecules in lung diseases. The chemokine receptor reactivity and eosinophil influx has also been documented 8 (CCR8) had no effect on leukocyte accumulation in the after the transfer of peptide-pulsed DC [38]. Allergen ef- periarterial space in an OVA mouse model [45]. fects can be increased by the concomitant exposition of diesel exhaust particles with different effects on airway hypersensitivity and cellular influx, which was partly focal Lipopolysaccharide (LPS) in Periarterial in the periarterial space [39]. Side stream cigarette smoke Leukocyte Infiltration exposure of mice after birth also influenced eosinophilic inflammation after OVA exposure [40]. The effects of The proinflammatory glycolipid component of the respiratory syncytial virus infection on mite allergen expo- gram-negative bacterial cell wall lipopolysaccharide (LPS) sition were recently studied, demonstrating a preferential is ubiquitously present in many different airborne parti- eosinophilic infiltration of the periarterial space [41]. Po- cles. When mice were repeatedly challenged over 12 tential therapeutic aspects were the focus of two studies us- weeks (twice weekly) by an intratracheal LPS instillation ing the OVA model. Mice without cyclo-oxygenase-1 and the lungs studied at one and 8 weeks after this expo- (COX-1) had an exaggerated cell influx, which was not the sure period, among several other effects a dense periarte- –/– + case in cyclooxygenase-2 mice [42]. The allergen-induced rial infiltration by lymphocytes (mainly CD4 ) was docu- eosinophil influx into the periarterial space was dramatical- mented [46]. Contamination of the bedding material for ly reduced in mice, when recombinant human platelet acti- laboratory animals by bacterial products also induced vating acetylhydroxylase – an inhibitor of platelet-activat- periarterial infiltrations in rats and this might be of major ing factor – was injected. This might be considered as a relevance when experiments between different laborato- therapeutic strategy to reduce the late effects in asthma. ries are compared [47]. In another study in mice, the role Thus, there seems to be common sequelae after aerosol of the Toll-like receptor 4 after sensitization and intrana- exposure with allergens, resulting in periarterial accumu- sal OVA exposure was described. High levels of LPS with lation of leukocytes. The relevance of this general phe- an antigen resulted in a TH1 response, which was in con- nomenon remains to be elucidated. trast to low doses leading to Th2 responses [48]. However, both high and low doses of LPS resulted in periarterial lymphocyte accumulation. In another study LPS reduced The Role of Adhesion Molecules and the sensitization to inhaled antigen by a reduced TH2 Chemokines in the Influx of Leukocytes into development due to DCs and this phenomenon was inde- the Periarterial Space pendent of IL-12 [49]. One reason for the influx of leuko- cytes after LPS might be the well-documented induction It is generally accepted that a variety of microbial stim- of apoptosis of endothelial cells after LPS, which requires uli and cytokines are involved in the expression of adhe- the generation of ceramide [50]. A flavonoid from plants, sion molecules on endothelial cells to recruit leukocytes luteolin, protected against leukocyte periarterial infiltra- into areas of inflammation. Vascular adhesion protein 1 tion after LPS, which was obviously due to a reduced pro- was expressed on the endothelium of large to medium duction of TNF-· and the adhesion molecule ICAM-1 sized pulmonary vessels, but not in alveolar septae in nor- [51]. Another bacterial product, the staphylococcal ente- mal human and mice lungs [43]. In an inflammatory mod- rotoxin B, a well-known superantigen given intranasally el in these experiments, vascular adhesion protein 1 was to mice resulted in a dose-dependent leukocyte infiltra- positive in inflammatory cells in the periarterial space tion of the periarterial space with hardly any peribron- also. In a bleomycin-induced fibrotic lung the endothelial chial influx [52]. adhesion molecules (ICAM-1) could be seen on the venu- In conclusion, bacterial products such as LPS instilled lar and arteriolar endothelia by real time confocal laser in the airspace of mice resulted in a leukocyte influx into luminescence microscope in rats. ICAM-1 was expressed the periarterial space. It remains to be studied how the along the venular and capillary walls [44]. However, capil- information of LPS instillation is conveyed from the air- laries in the periarterial space have not been checked by space to the periarterial capillaries to open the vessel wall this technique, but they might be tested when this lung for leukocytes. compartment is no longer neglected. Pathobiology 2004;71:287–294 290 Pabst Cytokines in Lung Periarterial Leukocyte Influx tions. In pigs the first sign of edema formation was in the periarterial space [Pabst and Binns, unpubl. observa- Intranasal administration of IL-25 resulted in the pro- tions]. In rhesus monkeys a similar compartment could be duction of other cytokines, airway hyper-reactivity, and seen [Plopper, pers. commun.]. Not surprisingly, much epithelial cell hyperplasia, but also a marked infiltrate less is documented for the human lung. In one study on around the branches of the pulmonary arteries (mainly pulmonary arteries in smokers versus nonsmokers a peri- eosinophils with some macrophages and lymphocytes) arterial space was obvious, but it was not filled with infil- –/– [53]. IL-10 mice showed a periarterial infiltration, but trating leukocytes [61]. In another group of patients with no airway hyper-reactivity [54]. In another study on mice, COPD CD8 , leukocytes were seen in the adventitia of a blockade of IL-13 partially blocked airway hypersensi- the branches of pulmonary arteries [62]. In smoking tivity and goblet cell hyperplasia, but not periarterial patients with severe or mild COPD no differences in leu- accumulation of inflammatory cells [55]. kocyte infiltrates were observed in the adventitial layer These data show a rather constant effect of interleukins [63]. These findings resemble a vasculitis. This is in con- on the periarterial leukocyte influx in contrast to a varied trast to data from laboratory animals, in which the wall of effect on typical characteristics of asthma such as airway the pulmonary artery was not infiltrated by inflammatory hyper-reactivity. cells. In conclusion, the periarterial space of the lung seems to be the site of leukocyte infiltration and edema forma- Matrix Metalloproteinases (MMP) and tion in all mammals studied so far. The strain differences Periarterial Cellular Infiltration in mice are difficult to explain at present. In many inflammatory reactions the matrix metallo- proteinases (MMPs) play a critical role, e.g. by affecting The Effect of Genetic Defects on Leukocyte Accumulations in the Periarterial Space the interstitial matrix. In mice lacking MMP-9, compara- ble numbers of eosinophils were found in the bronchoal- veolar lavage and a similar bronchial hyper-responsive- When lymphotoxin was knocked out, there were no –/– ness was documented. However, there was a drastically lung-draining lymph nodes. However, in naı ¨ve LT· reduced leukocyte influx into the periarterial space [56]. mice there was no sign of peribronchial inflammation but In contrast the lack of MMP-2 reduced the influx of leuko- a mild periarterial infiltration, which was much more pro- cytes into the airway lumen despite a periarterial accumu- nounced and consisted mainly of mononuclear cells after lation [57]. The tissue inhibitor of metalloproteinase 1 OVA sensitization [64]. Interestingly, the allergic sensiti- –/– was markedly increased in the periarterial region on day 4 zation was completely absent in splenectomized LT· after bleomycin [58], indicating that the MMPs and tissue mice. In a more recent study, there was an increased per- –/– inhibitors of metalloproteinase also seem to play a role in iarterial leukocyte accumulation in LT· mice with a periarterial cellular infiltrations, e.g. after instilling bleo- reduced IgE level and reduced airway hypersensitivity, mycin into the airway lumen, which might be due to a thus documenting a heterogenous genetic dependence of modulation of matrix turnover. cellular criteria of allergy [65]. With age a spontaneous cumulative airway inflammation developed. In a recent study of mice in which surfactant protein D was knocked Which Species Show a Periarterial Leukocyte out, there was an increased baseline inflammation includ- Infiltration at Different Stages after Allergen ing the periarterial space, probably caused by a disruption Exposure or Lung Infection? of NO signaling within the innate immune system [66]. As in many other models, it is unclear how a defect in the The species studied most often with this accumulation bronchial surface to the air has effects on the periarterial is the mouse. There were obvious strain differences de- space. In a mouse model for lupus erythromatodes (lpr spite comparable age and breeding conditions (BALB-c mice) not only did lymphosplenomegaly and kidney pa- vs. C57Bl/6) [59] [Singh et al., in preparation]. There was thology develop, but also, an ‘angiocentric’, although not less sensitivity for the late airway inflammation in male peribronchial, pattern of cellular infiltration in the lung compared to female BALB/c mice [60]. As will be de- was obvious. The figures seemed to show this infiltration scribed later, the rat shows similar periarterial accumula- as perivenular and not periarterial in one study [67], but Pathobiology 2004;71:287–294 The Periarterial Space in the Lung 291 in a recent study only periarterial [Neumann et al. 2004, in the periarterial space while the peribronchial area in preparation]. There is a growing number of mice in showed only a tendency to lower numbers [72]. which different genes have been knocked out and differ- Thus, there have been a number of recent, very differ- ent lymphoid organs are undeveloped. However, the lung ent therapeutic approaches with promising results in ani- has rarely been studied in such mice. mal models. These data indicate that the lack of draining lymph nodes results in a (probably) secondary accumulation in the periarterial space due to the blocking of lymphatics Conclusions leaving the lung. A relevant biological role of the periarterial space in the lung can be assumed, as it is involved in central patho- Potential Therapeutic Aspects of Periarterial biological phenomena such as edema formation and leu- Leukocyte Accumulations kocyte influx in many heterogenous inflammatory and allergic models in different species. Future research Recently in studies in which very different therapeutic should not overlook this compartment any longer. The approaches were described, effects on periarterial leuko- basic structural and molecular reasons for the preferential cyte accumulations were reported, although it was not edema formation might be due to a unique wall of the clear whether these were the main or secondary effects; periarterial capillaries. It is unclear how an antigen or even in these studies the periarterial space was not the microbial factors which are inhaled or instilled into the focus of the experiments. In a hypersensitivity pneumoni- airspace can modify the production of cytokines or che- tis model in mice, the inhibition of E and P selectin to mokines, which reach the area beyond the bronchial wall. sialyl-Lewis x suppressed the inflammatory response [68]. One idea is that such particular or soluble antigens are Anti-IL-9 treatment in the OVA model in the mouse taken up in the peripheral air space and this stimulus is resulted in a dramatic reduction of periarterial leukocytes transported to the periarterial capillaries modifying the after OVA challenge. There was also no airway hyper- tightness of their wall or upregulating adhesion molecules reactivity in response to metacholin [69]. Lipoxin, a sepa- as a basis for leukocyte efflux. Lymphatics might also play rate class of eicosanoids, inhibited not only airway hyper- a role in this respect. However, this concept does not responsiveness but also the leukocyte influx into the include a convincing argument why leukocytes emigrate periarterial space [70]. Phosphoinositide 3-kinase might and accumulate in this compartment. This review might be a relevant contributor in the pathogenesis of asthma. stimulate future experiments and stop the long neglect of The fusion protein of a dominant negative form of the this compartment. regulatory subunit P85· blocked the leukocyte accumula- tion in the periarterial space in parallel to other criteria of asthma [71]. In a recently published study simvastatin, a Acknowledgments drug widely used as a serum cholesterol-lowering drug, The author’s experiments have been supported by the Deutsche had an anti-inflammatory effect in the mouse OVA mod- Forschungsgemeinschaft (SFB 587/B1). The meticulous correction of el. The influx of leukocytes was significantly reduced only the English by Sheila Fryk is greatly acknowledged. 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Journal

Pathobiology – Karger

Published: Dec 1, 2004

Keywords: Lung; Compartments; Periarterial space; Edema; Inflammation

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