Pulmonary fibrosis: cellular and molecular events

Connective tissue remodeling of the interstitium is an important feature of chronic lung diseases encompassing interstitial inflammatory changes and subsequent pulmonary fibrosis. The early inflammatory phase is usually associated with the release of several cytokines and chemokines by activated resident cells and infiltrating cells which, in turn, help further recruit inflammatory mononuclear cells. Cytokines and growth factors secreted by inflammatory cells and by interstitial cells (fibroblasts and myofibroblasts) play an important role in the fibrogenic phase of pulmonary fibrosis by inducing matrix synthesis. In addition, matrix-degrading enzymes and their inhibitors also contribute to extracellular matrix (ECM) remodeling in pulmonary fibrosis. This review addresses the pathophysiology of wound healing and different phases of pulmonary fibrosis.     

Arterial and interstitial remodelling processes in non-specific interstitial pneumonia: systemic sclerosis versus idiopathic

Aims:  To compare septal and vascular matrix remodelling, vascular occlusion, pulmonary function tests and survival between two groups: one with idiopathic non-specific interstitial pneumonia (NSIP) and one with NSIP associated with systemic sclerosis (SSc).
Methods and results:  Pulmonary biopsy specimens were examined from 40 patients, 22 with NSIP and 18 with NSIP associated with SSc.
The content of septal collagen and elastic fibres, as well as the elastic fibres in the vascular interstitium, were higher in the SSc group ( P  = 0.01, P  = 0.001 and P  < 0.0001, respectively). Among pulmonary function tests, the diffusing capacity for carbon monoxide/alveolar volume was affected to a greater extent in the SSc group (59% of the predicted value in SSc and 97% in the idiopathic group). There were no differences in collagen content of the vascular interstitium, arterial occlusion, or survival between the two groups.
Conclusions:  Although the fibrotic process is more intense in the SSc group, it does not affect the prognosis of these patients. Because the elastotic process is higher in the SSc group, this might suggest that autoimmune inflammatory mechanisms affecting the elastic fibre system play a greater role in the pathogenesis and pulmonary remodelling process of SSc NSIP than in idiopathic NSIP.     

Human T cells stimulate fibroblast-mediated degradation of extracellular matrix in vitro

Several chronic diseases are characterized by inflammation, T cell recruitment and tissue remodelling. We hypothesized that activated T cells may stimulate remodelling of extracellular matrix (ECM) in vitro. Total T cells (CD3+) as well as CD4+ and CD8+ subsets were isolated from peripheral blood and stimulated, after which conditioned media (CM) were obtained. CM was added to human lung fibroblasts in three-dimensional collagen gels and the area of gels was measured daily. Hydroxyproline was determined as a measure of collagen degradation in the gels. Matrix metalloproteinase (MMP) activity in the culture media was analysed by gelatine zymography. Cytokine secretion of stimulated CD4+ and CD8+ T cells was analysed. CD3+ CM augmented collagen gel contraction in a time- and dose-dependent manner (P < 0.0001). CD4+ T cell CM was more potent than CD8+ T cell CM (P < 0.001). CD3+ CM and CD4+ T cell CM, but not CD8+ T cell CM, stimulated fibroblast-mediated collagen degradation and MMP-9 activity. A broad-spectrum MMP-inhibitor added to the culture system inhibited both gel contraction and MMP activity. Activated CD4+ T cells secreted significantly more tumour necrosis factor (TNF) and interleukin (IL)-6 compared to CD8+ T cells. CD3+ CM from patients with chronic obstructive pulmonary disease stimulated fibroblast-mediated collagen gel contraction to the same magnitude as CD3+ CM from healthy controls. In conclusion, activated CD4+ T cells can stimulate fibroblast-mediated degradation of ECM in vitro. This could be a mechanism by which activated T cells stimulate degradation of lung tissue leading to pulmonary emphysema.     

Extracellular matrix powder protects against bleomycin-induced pulmonary fibrosis

Pulmonary fibrosis refers to a group of lung diseases characterized by inflammation, fibroblast proliferation, and excessive collagen deposition. Although the mechanisms underlying pulmonary fibrosis are poorly understood, current evidence suggests that epithelial injury contributes to the development of fibrosis. Regenerative medicine approaches using extracellular matrix (ECM) scaffolds have been shown to promote site-specific tissue remodeling. This led to the hypothesis that particulate ECM would promote normal tissue repair and attenuate bleomycin-induced pulmonary fibrosis. C57BL/6 mice were treated intratracheally with bleomycin or saline with or without a particulate form of ECM scaffold from porcine urinary bladder matrix (UBM-ECM) or enzymatically digested UBM-ECM. Mice were sacrificed 5 and 14 days after exposure. Compared to control mice, bleomycin-exposed mice had similar increases in inflammation in the bronchoalveolar lavage fluid regardless of UBM-ECM treatment. However, 14 days after exposure, lung histology and collagen levels revealed that mice treated with bleomycin and the particulate or digested UBM-ECM had negligible fibrosis, whereas mice given only bleomycin had marked fibrosis. Administration of the particulate UBM-ECM 24 h after bleomycin exposure also significantly protected against pulmonary injury. In vitro epithelial cell migration and wound healing assays revealed that particulate UBM-ECM promoted epithelial cell chemotaxis and migration. This suggests that promotion of epithelial wound repair may be one mechanism in which UBM-ECM limits pulmonary fibrosis.     

Extracellular matrix mechanics in lung parenchymal diseases

In this review, we examine how the extracellular matrix (ECM) of the lung contributes to the overall mechanical properties of the parenchyma, and how these properties change in disease. The connective tissues of the lung are composed of cells and ECM, which includes a variety of biological macromolecules and water. The macromolecules that are most important in determining the mechanical properties of the ECM are collagen, elastin, and proteoglycans. We first discuss the various components of the ECM and how their architectural organization gives rise to the mechanical properties of the parenchyma. Next, we examine how mechanical forces can affect the physiological functioning of the lung parenchyma. Collagen plays an especially important role in determining the homeostasis and cellular responses to injury because it is the most important load-bearing component of the parenchyma. We then demonstrate how the concept of percolation can be used to link microscopic pathologic alterations in the parenchyma to clinically measurable lung function during the progression of emphysema and fibrosis. Finally, we speculate about the possibility of using targeted tissue engineering to optimize treatment of these two major lung diseases.     

Cigarette smoke-induced pulmonary inflammation, but not airway remodelling, is attenuated in chemokine receptor 5-deficient mice

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is characterized by a chronic inflammatory response of the airways and lungs to noxious particles and gases, mostly cigarette smoke (CS). Pathological changes characteristic of COPD include airway wall thickening, peribronchial fibrosis, peribronchial lymphoid follicles and destruction of lung parenchyma (emphysema). The recruitment of inflammatory cells into the lung in response to CS is thought to play an important role in the development of COPD. OBJECTIVE: Our aim was to study the contribution of chemokine receptor 5 (CCR5) to the pathogenesis of COPD and specifically whether the development of airway remodelling is a direct result of airway inflammation or rather occurs through an independent mechanism. METHODS: In this study, C57BL/6 wild-type mice and CCR5-deficient mice were subjected to sub-acute (4 weeks) and chronic (24 weeks) CS exposure. RESULTS: Both sub-acute and chronic CS exposure significantly increased CCR5 mRNA expression and protein levels of CCR5 ligands [macrophage inflammatory protein-1alpha (MIP-1alpha), MIP-1beta and regulated upon activation, normal T expressed and secreted (RANTES)], and induced the recruitment of neutrophils, macrophages, dendritic cells, and lymphocytes to the bronchoalveolar lavage (BAL) of wild-type mice. Chronic CS exposure also increased the number and extent of peribronchial lymphoid follicles. In CCR5 knockout (KO) mice, these CS-induced increases in CCR5 ligands, inflammatory cells in BAL and peribronchial lymphoid follicles were all significantly attenuated compared with wild-type animals. Importantly, chronic CS exposure induced airspace enlargement in wild-type mice, while CCR5 KO mice were partially protected against the development of emphysema. However, CCR5 deficiency did not affect CS-induced airway wall remodelling, because chronic CS exposure induced a similar increase in airway wall thickness, smooth muscle mass and peribronchial deposition of collagen and fibronectin in both wild-type and CCR5 KO mice. CONCLUSION: Our data suggest that CCR5 contributes to pulmonary inflammation and to the development of emphysema in response to CS. CCR5 is, however, not implicated in CS-induced airway wall remodelling, suggesting that the mechanisms that lead to airway inflammation are distinct to those responsible for airway remodelling.     

Expression profile of extracellular matrix and its regulatory proteins during the process of interstitial fibrosis after anti-glomerular basement membrane antibody-induced glomerular sclerosis in Sprague-Dawley rats

Anti-glomerular basement membrane (GBM) nephritis in Sprague-Dawley (SD) rats was characterized by development of marked glomerular sclerosis and tubulointerstitial fibrosis. To elucidate sequential change of the glomerular sclerosis and tubulointerstitial fibrosis, accumulation and mRNA expression of extracellular matrix (ECM) components and transforming growth factor (TGF)-beta were examined in the glomerulus and cortex during the disease course by histology, immunostaining and ribonuclease protection assay. Mild proliferative and degenerative lesions appeared in the glomeruli by day 15 after anti-GBM antibody binding to GBM and progressed to glomerular sclerotic lesion thereafter. Conversely, interstitial change was first recognized by infiltration of mononuclear cells after day 20, followed by marked accumulation of ECM and tubular degeneration. The interstitial fibrosis was induced without apparent binding of anti-GBM antibody to tubular basement membrane. Accumulation of fibronectin, collagen type I and type IV was noted in the interstitium by immunofluorescence microscopy in association with enhanced expression of mRNA for these ECM components and their regulatory molecules such as matrix metalloproteinase (MMP2), tissue inhibitor of metalloproteinase (TIMP)-1 and TGF-beta1 both in glomeruli and cortex. The glomerular expression of these mRNA increased apparently by day 15 and reached a plateau or a peak at day 20. The expression of the same mRNA increased gradually from day 15 to day 29 in the cortex. These observations show that interstitial fibrosis follows glomerular sclerosis after anti-GBM antibody injection in SD rats, suggesting that at least a part of the mechanism for ECM accumulation in the glomerulus and interstitium is essentially the same in terms of composition of ECM and expression of its regulatory molecules.     

Potential role for bone marrow-derived fibrocytes in the orbital fibroblast heterogeneity associated with thyroid-associated ophthalmopathy

Fibroblast heterogeneity has been recognized for decades, but the basis for multiple phenotypes among these cells has been investigated only recently. More than 15 years ago, Bucalla and his colleagues described for the first time a population of fibroblast‐like cells among circulating mononuclear blood cells. Subsequently these mesenchymal cells, termed fibrocytes, have been characterized and found to participate in normal and pathological tissue remodelling. In this review, I have attempted to present the evidence generated thus far suggesting that fibrocytes are participants in autoimmune diseases where tissues are injured and undergo remodelling. Aspects of their phenotype suggest that they are well suited to help orchestrate immune responses through mononuclear cell recruitment and their ability to produce inflammatory mediators and extracellular matrix molecules. These attributes also raise the possibility that they might be useful targets against which therapeutic agents might be aimed.     

An extracellular matrix infrastructure provides support for murine secondary palatal shelf remodelling

A cricial part of secondary palate morphogenesis is the movement of the palatal shelves from an initial vertical position on either side of the tongue to a final horizontal one above it to achieve palate closure. The immunocytochemical localization of extracellular matrix (ECM) molecules in the palatal shelf during this remodelling and reorientation revealed the existence of an ECM infrastructure within the mesenchyme. The major components of this infrastructure were collagen III, fibronectin, and hyaluronate (HA). With remodelling, HA's domain within the mesenchyme was expanded, whereas those of fibronectin and collagen III became more circumscribed. The expansion of an HA-rich matrix within the mesenchyme is thought to be crucial for palatal reorientation. The results of this study suggest that, as this expansion occurs, it is modulated by collagen and fibronectin components of the ECM infrastructure. Prior to shelf remodelling, this infrastructure may be anchored by a specialized region of the midoral epithelial-mesenchymal interface and the subjacent mesenchyme which is characterized by the unique distribution of collagen III, fibronectin, and tenascin. The midoral palatal epithelium also may play a role in directing shelf expansion. This epithelial region undergoes changes in cell packing and epithelial cell layering that correlate with shelf remodelling. These changes occur concomitantly with changes in the expression of collagen III, collagen IV, and laminin within the underlying basement membrane. The localization and patterning of tenascin within the developing palate suggests that it not only contributes to the postulated anchoring structure of the midoral epithelial-mesenchymal region, but also plays a role in the determining the fate of the medial edge epithelial cells during the final stage of palate closure.© Willey-Liss, Inc.     

Synovial remodeling process induced by type V collagen immunization in rabbits

The pathogenesis of diffuse connective tissue diseases is still unknown despite studies of the autoimmunity aspects related to extracellular matrix elements, mainly the collagens. Articulations are frequently affected by the synovitis process in these diseases. The objective of the present study was to verify the morphologic aspects of the synovial membrane of rabbits immunized with type V collagen, which has some particular characteristics 75 days after the first antigen inoculation and when compared to control animals. The synovial membrane of the animals sacrificed after 75 days of immunization presented an intense remodeling phenomenon along the connective tissue screen and interlobular septa of the adipose-muscle tissue screen compartment. The remodeling process determined type I and III collagen fiber depositions in the vascular and connective tissue compartments of the synovial membrane. The nutrient vessels of the adipose-muscle compartment showed a similar remodeling process, which resulted in small vessel occlusion. Few residual inflammatory foci consisting of monocytes and eosinophils were observed. Thus, our experimental model reproduces morphologic changes in different tissues, characterized by an extracellular matrix remodeling process similar to those observed in many diffuse connective tissue diseases such as systemic lupus erytematosus and scleroderma. Therefore, this model could be useful in understanding the pathogenesis and the treatment of these diseases.     

An extracellular matrix infrastructure provides support for murine secondary palatal shelf remodelling.

A crucial part of secondary palate morphogenesis is the movement of the palatal shelves from an initial vertical position on either side of the tongue to a final horizontal one above it to achieve palate closure. The immunocytochemical localization of extracellular matrix (ECM) molecules in the palatal shelf during this remodelling and reorientation revealed the existence of an ECM infrastructure within the mesenchyme. The major components of this infrastructure were collagen III, fibronectin, and hyaluronate (HA). With remodelling, HA's domain within the mesenchyme was expanded, whereas those of fibronectin and collagen III became more circumscribed. The expansion of an HA-rich matrix within the mesenchyme is thought to be crucial for palatal reorientation. The results of this study suggest that, as this expansion occurs, it is modulated by collagen and fibronectin components of the ECM infrastructure. Prior to shelf remodelling, this infrastructure may be anchored by a specialized region of the midoral epithelial-mesenchymal interface and the subjacent mesenchyme which is characterized by the unique distribution of collagen III, fibronectin, and tenascin. The midoral palatal epithelium also may play a role in directing shelf expansion. This epithelial region undergoes changes in cell packing and epithelial cell layering that correlate with shelf remodelling. These changes occur concomitantly with changes in the expression of collagen III, collagen IV, and laminin within the underlying basement membrane. The localization and patterning of tenascin within the developing palate suggests that it not only contributes to the postulated anchoring structure of the midoral epithelial-mesenchymal region, but also plays a role in the determining the fate of the medial edge epithelial cells during the final stage of palate closure.     

慢性阻塞性肺疾病药物治疗研究

慢性阻塞性肺疾病（COPD）是一种最常见的慢性气道疾病，其起病较为缓慢、病程较长、病情迁延难愈，在早期没有自觉症状。伴随着病情的不断发展，可出现终身不愈的慢性咳嗽，并在气道、肺血管、肺实质内出现炎症应激反应，也会并发慢性呼吸衰竭、自发性气胸、慢性肺源性心脏病等疾病，严重影响患者正常工作与生活质量。目前，临床针对COPD的治疗仍以药物为主，药物治疗的目标在于改善临床症状、提高生活质量，延缓或减弱肺功能减退，预防和治疗并发症，提高存活率，避免或减少用药副作用。因此，寻求合适的药物治疗方案来满足COPD患者的临床治疗需求对于改善患者预后具有十分重要意义。本文通过对COPD致病机制、药物治疗方案作一综述，旨在为临床治疗该疾病提供参考依据。     

The distribution of matrix metalloproteinases and tissue inhibitors of metalloproteinases in the lungs of congenital diaphragmatic hernia patients and age-matched controls

AIMS: In congenital diaphragmatic hernia (CDH), the pathogenesis of abnormal pulmonary morphology is still incompletely understood. Matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) are known to play an important role in the turnover of the extracellular matrix (ECM) during development and in remodelling of tissue. The aim of this study was to investigate differences in the expression of MMPs and TIMPs between CDH lungs and controls, against the background of the abnormal pulmonary vasculature in CDH. METHODS: We studied 12 lungs of term CDH patients who died < 24 h after birth and 11 normal age-matched control lungs, by immunohistochemistry with antibodies against human MMP-1, -2, -9, TIMP-1 and -2. RESULTS: There was a clear increase in the number of MMP-1-reactive capillaries and fibroblasts in CDH lungs compared with controls. In contrast, TIMP-2 reactivity in these structures was decreased in CDH lungs. The arterial endothelium and medial smooth muscle expressed MMP-2, -9 and TIMP-2 in both CDH and control lungs. In small arteries (< 100 microm in diameter), the positive surface area of MMP-2, -9 and TIMP-2 was significantly larger in CDH lungs than in controls. There was no difference in the distribution and expression of TIMP-1 between CDH lungs and normal controls. CONCLUSION: The differences in staining pattern of MMPs and TIMPs between normal and CDH lungs suggest that these enzymes might play a role in the abnormal remodelling of the interstitium and the pulmonary arteries in CDH lungs. This could contribute to our understanding of the abnormal lung morphology and the occurrence of pulmonary hypertension, which forms one of the major obstacles to the successful treatment of these patients.     

Extracellular matrix and lung inflammation

Lung injury triggers an acute inflammatory response characterized by increased expression and deposition of extracellular matrix (ECM) components such as fibronectin and collagen. Although the function of newly deposited matrices in injured lungs is unknown, their ability to affect the migration, proliferation, differentiation, and activation state of cells in vitro suggests an important role in the initiation and maintenance of the inflammatory response in vivo. Interactions between immune and nonimmune cells with the lung ECM are mediated via cell surface receptors of the integrin family which link the ECM with intracellular molecules involved in signal transduction. Activation of integrin-mediated intracellular signals may promote inflammation by facilitating leukocyte recruitment and cytokine expression. *** DIRECT SUPPORT *** A02GS030 00009     

Crocidolite-induced pulmonary fibrosis in mice. Cytokinetic and biochemical studies.

The responses of pulmonary alveolar and bronchial cells to asbestos exposure were studied by relating the cytokinetic changes of injury and repair to the inflammatory process and subsequent fibroblastic activity. The lesions were induced by intratracheal instillation of 1 mg crocidolite asbestos in mice, which were killed up to 20 weeks thereafter; 3H-thymidine was injected 1 hour before death. A rapid inflammatory response with elevated polymorphonuclear leukocytes and lysosomal enzyme release was largely over by 2 weeks, but the increase in alveolar macrophages was maintained. Focal necrosis of bronchial epithelial cells was repaired by cell regeneration, whereby new epithelial cells overgrew luminal exudates to incorporate long asbestos fibers into the peribronchial interstitium, where macrophagic granulomas formed. Increased collagen levels were largely due to stimulation of peribronchial fibroblasts. A lesser reaction of epithelial damage, Type 2 cell proliferation, and fibroblast stimulation also occurred in the alveolar walls. The results suggest that macrophage-fibroblast interactions associated with enhanced fibrosis occur readily in the peribronchial interstitium following injury and repair of epithelial cells by long asbestos fibers.     

Vitamin A deficiency alters pulmonary parenchymal collagen and tissue mechanics

The mechanical properties of the pulmonary parenchyma are strongly influenced by the collagen and elastic fibers that course through the alveolar interstitium and interconnect the bronchovascular bundles. Vitamin A deficiency (VAD) produces effacement and remodeling of the alveolar architecture, resulting in alternating areas of alveolar dilatation and collapse. To better understand the mechanical consequences and reversibility of this remodeling process, we have examined how the remodeling of collagen and elastic fibers correlates with the mechanical properties of the lung parenchyma in VAD rats. An oscillatory impulse was applied at different levels of stress on the fiber network and the tissue damping (G), elastance (H), hysteresivity (G/H, eta) were analyzed. At a supra-physiological functional residual capacity, the lung parenchyma of VAD rats exhibited a lower G and H than Vitamin A sufficient (VAS) rats, which was accompanied by a significant decrease in the quantity of parenchymal collagen and collagen fibers. Retinoic acid (RA) administration restored the parenchymal collagen and mechanical properties.     

How Much Do We Know about Atopic Asthma： Where Are We Now？

Asthma is a common disease in the worldwide and it affects over 3.5 million adults and children in the UK. Asthma is a chronic disease characterized by airway hyperresponsiveness, airway inflammation, airway remodelling and reversible airway obstruction. Inflammatory cells, cytokines, chemokines, adhesion molecules, and mediators are involved in pathogenesis of asthma. Chronic airway inflammation and remodelling are the major characters in asthma, which result in decreased pulmonary function. The precise processes are far understood at moment. Although corticosteroid therapy plus other exiting drugs （bronchodilators and oral leukotriene receptor antagonists） influences many different inflammatory and structural cell types and continues to be as the ＂gold standard＂ of therapy in asthma, many thousands have chronic, severe diseases and suffer daily symptoms which make their lives a misery. There remains a clear need for novel approaches to therapy, which will be informed by a clearer understanding of disease pathogenesis, particularly in the target organ where airway inflammation and remodelling, the hallmarks of asthma occur. Cellular ＆ Molecular Immunology.     

The involvement of matrix metalloproteinase-9 in airway inflammation of patients with acute asthma

BACKGROUND: Bronchial asthma is an inflammatory disease of the airway characterized by airway remodelling, and is due at least in part to an excess of extracellular matrix (ECM) deposition in the airway wall, which leads to subepithelial collagen deposition. Matrix metalloproteinase-9 (MMP-9) is the major proteolytic enzyme that induces bronchial remodelling in asthma. MMP-9 is also important in the migration of inflammatory cells through basement membrane components. OBJECTIVES: We evaluated whether airway inflammatory cells correlated with levels of MMP-9 in acute asthma and we examined the time course of sputum levels of MMP-9 activity in patients with spontaneous asthma exacerbation. METHODS: We performed zymographic analysis and checked levels of MMP-9 by means of enzyme immunoassay. MMP-9 levels were also evaluated during a spontaneous attack of asthma. RESULTS: Pro-MMP-9 activities and concentrations of MMP-9 in asthmatic patients significantly exceeded those of control subjects (P < 0.01). The activities of pro-MMP-9 were significantly higher in acute asthmatic patients than in stable asthmatic patients (P < 0.01). The elevated MMP-9 activities significantly decreased after 7 and 28 days of therapy. In acute asthmatic patients, the levels of sputum MMP-9 significantly correlated with the total macrophage + neutrophil + eosinophil cell numbers. CONCLUSION: These data suggest that airway inflammation after asthma exacerbation correlates with the overproduction of MMP-9, which then leads to airway remodelling.     

ECM hydrogel coating mitigates the chronic inflammatory response to polypropylene mesh

Polypropylene has been used as a surgical mesh material for several decades. This non-degradable synthetic polymer provides mechanical strength, a predictable host response, and its use has resulted in reduced recurrence rates for ventral hernia and pelvic organ prolapse. However, polypropylene and similar synthetic materials are associated with a chronic local tissue inflammatory response and dense fibrous tissue deposition. These outcomes have prompted variations in mesh design to minimize the surface area interface and increase integration with host tissue. In contrast, biologic scaffold materials composed of extracellular matrix (ECM) are rapidly degraded in-vivo and are associated with constructive tissue remodeling and minimal fibrosis. The objective of the present study was to assess the effects of an ECM hydrogel coating on the long-term host tissue response to polypropylene mesh in a rodent model of abdominal muscle injury. At 14 days post implantation, the ECM coated polypropylene mesh devices showed a decreased inflammatory response as characterized by the number and distribution of M1 macrophages (CD86+/CD68+) around mesh fibers when compared to the uncoated mesh devices. At 180 days the ECM coated polypropylene showed decreased density of collagen and amount of mature type I collagen deposited between mesh fibers when compared to the uncoated mesh devices. This study confirms and extends previous findings that an ECM coating mitigates the chronic inflammatory response and associated scar tissue deposition characteristic of polypropylene.     

Atelectasis induced by thoracotomy causes lung injury during mechanical ventilation in endotoxemic rats

Atelectasis can impair arterial oxygenation and decrease lung compliance. However, the effects of atelectasis on endotoxemic lungs during ventilation have not been well studied. We hypothesized that ventilation at low volumes below functional residual capacity (FRC) would accentuate lung injury in lipopolysaccharide (LPS)-pretreated rats. LPS-pretreated rats were ventilated with room air at 85 breaths/min for 2 hr at a tidal volume of 10 mL/kg with or without thoracotomy. Positive end-expiratory pressure (PEEP) was applied to restore FRC in the thoracotomy group. While LPS or thoracotomy alone did not cause significant injury, the combination of endotoxemia and thoracotomy caused significant hypoxemia and hypercapnia. The injury was observed along with a marked accumulation of inflammatory cells in the interstitium of the lungs, predominantly comprising neutrophils and mononuclear cells. Immunohistochemistry showed increased inducible nitric oxide synthase (iNOS) expression in mononuclear cells accumulated in the interstitium in the injury group. Pretreatment with PEEP or an iNOS inhibitor (1400 W) attenuated hypoxemia, hypercapnia, and the accumulation of inflammatory cells in the lung. In conclusion, the data suggest that atelectasis induced by thoracotomy causes lung injury during mechanical ventilation in endotoxemic rats through iNOS expression.