Document Detail

Acute lung injury and acute respiratory distress syndrome: experimental and clinical investigations.
Jump to Full Text
MedLine Citation:
PMID:  22783284     Owner:  NLM     Status:  PubMed-not-MEDLINE    
Acute lung injury (ALI) or acute respiratory distress syndrome (ARDS) can be associated with various disorders. Recent investigation has involved clinical studies in collaboration with clinical investigators and pathologists on the pathogenetic mechanisms of ALI or ARDS caused by various disorders. This literature review includes a brief historical retrospective of ALI/ARDS, the neurogenic pulmonary edema due to head injury, the long-term experimental studies and clinical investigations from our laboratory, the detrimental role of NO, the risk factors, and the possible pathogenetic mechanisms as well as therapeutic regimen for ALI/ARDS.
Hsing I Chen
Related Documents :
22783284 - Acute lung injury and acute respiratory distress syndrome: experimental and clinical in...
14649694 - Recurrent salmonella osteomyelitis of both hands in a child with no signs of haemoglobi...
1732404 - Progressive necrotic myelopathy as a paraneoplastic syndrome: report of a case and some...
22098394 - Successful treatment of cutaneous venous malformations in a blue rubber bleb nevus synd...
20196714 - Toxic shock syndrome caused by hospital-acquired methicillin-resistant staphylococcus a...
2668494 - Möbius and möbius-like syndromes (ttv-ofm, omlh).
Publication Detail:
Type:  Journal Article    
Journal Detail:
Title:  Journal of geriatric cardiology : JGC     Volume:  8     ISSN:  1671-5411     ISO Abbreviation:  J Geriatr Cardiol     Publication Date:  2011 Mar 
Date Detail:
Created Date:  2012-07-11     Completed Date:  2012-08-23     Revised Date:  2013-05-30    
Medline Journal Info:
Nlm Unique ID:  101237881     Medline TA:  J Geriatr Cardiol     Country:  China    
Other Details:
Languages:  eng     Pagination:  44-54     Citation Subset:  -    
Institute of Physiological and Anatomical Medicine, Tzu Chi University, Hualien 97004, Taiwan, China.
Export Citation:
APA/MLA Format     Download EndNote     Download BibTex
MeSH Terms

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

Full Text
Journal Information
Journal ID (nlm-ta): J Geriatr Cardiol
Journal ID (iso-abbrev): J Geriatr Cardiol
Journal ID (publisher-id): JGC
ISSN: 1671-5411
Publisher: Science Press
Article Information
Download PDF
Institute of Geriatric Cardiology
Received Day: 6 Month: 1 Year: 2011
Revision Received Day: 12 Month: 3 Year: 2011
Accepted Day: 19 Month: 3 Year: 2011
Print publication date: Month: 3 Year: 2011
Volume: 8 Issue: 1
First Page: 44 Last Page: 54
ID: 3390060
PubMed Id: 22783284
Publisher Id: jgc-08-01-044
DOI: 10.3724/SP.J.1263.2011.00044

Acute lung injury and acute respiratory distress syndrome: experimental and clinical investigations
Hsing I Chen
Institute of Physiological and Anatomical Medicine, Tzu Chi University, Hualien 97004, Taiwan, China
Correspondence: Correspondence to: Hsing I Chen, MD, PhD, Professor, Institute of Physiological and Anatomical Medicine, Tzu Chi University, 701, Sect. 3, Jhongyang Rd., Hualien 97004, Taiwan, China. E-mail:


Acute lung injury (ALI) or acute respiratory distress syndrome (ARDS) is a serious clinical problem with high mortality.[1] In animals and humans, ALI can be induced by various causes such as brain injury,[1][4] enterovirus,[5],[6] Japanese B encephalitis,[7] and coronavirus.[8],[9] The risk factors for ARDS included septicemia, acid aspiration, infection, traumatic injury, fat embolism, ischemia/reperfusion, and other caused.[1],[6],[8],[10][18] Our cardiopulmonary laboratory has carried out experimental studies and clinical investigations on ALI and ARDS since 1973.[1][3],[17],[19],[20] The purposes of this review article are: (1) To describe in brief the historical perspective of ARDS and ALI; (2) To draw attention of an important clinical issue of neurogenic ALI; (3) To present the experimental studies and clinical investigations from our laboratory from 1973 to 2009; (4) To elucidate the functional role of nitric oxide (NO) and other mediators involved in the pathogenesis of ARDS/ALI; (5) To define the risk factors for ARDS and ALI; and (6) To discuss the pathogenetic mechanisms and therapeutic regimen for ARDS/ALI.

Neurogenic pulmonary edema

ALI or pulmonary embolism (PE) has been reported in humans and animals with intracranial disorders such as head trauma, brain tumor, intracranial hypertension or cerebral compression. Early studies in our laboratory demonstrated that acute PE of hemorrhagic and fulminant type occurred accompanying severe hypertension and bradycardia (Cushing responses) in rats following cerebral compression (CC) or intracranial hypertension (ICH). The lung pathology was characterized by intravascular congestion and disruption of pulmonary large and small vessels leading to severe alveolar hemorrhage (alveolar flooding). These changes was prevented by spinal transection, sympathectomy and sympathoadrenergic blocking agents, but was not affected by decerebration, adrenalectomy, vagotomy and atropine. These results suggest that sympathetic nervous system is pivotal in the neurogenic PE. Brain areas above the medulla oblongata and parasympathetic nervous system play little role.[2]

A series of studies was carried out to elucidate the hemodynamic events involved in the neurogenic PE. In anesthetized rats, we measured the aortic and pulmonary blood flow and used techniques of right and left heart bypass. The imbalance in the right and left ventricular output was characterized by a rapid and dramatic decline in aortic flow accompanying a gradual decrease in pulmonary arterial flow. In rats with a right heart bypass, ICH produced severe pulmonary hypertension and PE. In the left heart-bypassed rats, ICH induced systemic hypertension, whereas no significant changes occurred in the lungs.[4] In anesthetized dogs with a total heart bypass preparation, ICH produced constriction of the systemic and pulmonary resistance and capacitance vessels.[21][24] The implications of these findings are: (1) Central sympathetic activation elicits increase in the systemic and pulmonary vascular resistance associated with decreases in vascular capacity in both circulations; (2) The major cause of volume and pressure loading in the pulmonary circulation is acute left ventricular failure resulting in a marked decrease in aortic flow; and (3) Systemic venous constriction causes a shift of blood from the systemic to the pulmonary circulation (Figure 1). A schematic representation summarizes the neural and hemodynamic consequence caused by cerebral compression (Figure 2).

Spectral analysis of the aortic flow and pressure wave was employed to evaluate the hemodynamics of steady and pulsatile components. In anesthetized dogs, ICH caused significant increases in characteristic impedance, pulse wave reflection and total peripheral resistance with decrease in arterial compliance and cardiac output. The ventricular work was elevated.[25] Clinical study in patients with head injury of various severities, analysis of the heart rate variability with frequency analysis revealed increased low frequency percentage, and low to high frequency ratio with decrease in high frequency. The findings indicate augmented sympathetic and attenuated parasympathetic drive. These autonomic functional changes were related to the severity of brain-stem damage.[26] These two studies further support the contention that central sympathetic activation is involved in the Cushing pressor response and consequent hemodynamic and autonomic alterations.

The mediators involved in ALI and pulmonary hypertension

In 1990s, my associates and I were interested in the study of chest disorders. We developed an isolated perfused rat's lung in situ preparation (Figure 3). Previous method involved removing the isolated lungs from the body and placing the organ on a force-displacement transducer to record the changes in lung weight and these procedures were rather complicated and unstable. Our in situ preparation does not require removing the lungs. Instead, the isolated lungs were left in situ. The whole rat was placed in a scale platform to measure the change in body weight (BW). Since the lungs are completely isolated from the body, the changes in BW reflect the lung weight (LW) changes. The preparation can be accomplished in 15 min. We used a digital-analogue converter to transfer the weight change from the scale platform to a recorder. The LW thus could be continuously monitored during the experiment. In this model, we can obtain the lung weight gain, LW/BW ratio, the changes in pulmonary arterial, capillary and venous pressures, the microvascular permeability (capillary filtration coefficient, Kfc), protein concentration in bronchoalveolar lavage (PCBAL), dye leakage, and exhaled nitric oxide (NO). The concentration of nitrate/nitrite, methyl guanidine (an index for hydroxyl radical), proinflammatory cytokines [tumor necrosis factor α (TNFα) and interleukin-1β (IL-1β)] and other factors in the lung perfusate can also be detected. Early animal experimentations investigated the pathogenesis, modulators and mediators involved in the ALI induced by phorphol, air embolism, platelets, hypoxia, ischemia/reperfusion, endotoxin [lipopolysaccharide (LPS)]. The major finding is that cyclooxygenase products of arachidonic acid, thromboxane A2 in particular is involved in the ALI and pulmonary hypertension caused by phorbol, platelets and air embolism.[27],[28] Furthermore, we found that L-arginine and inhaled NO enhanced the lung injury caused by air embolism, while blockade of NO synthase (NOS) with Nω-nitro-L-arginine methyl ester (L-NAME) attenuated the ALI.[28] The result suggests that NO is also involved.

The detrimental role of NO via the iNOS isoform in the ALI/ARDS

During the summers from 2001–2003, we encountered a total of 48 children suffering from hand, foot, and mouth disease.[6] Chest radiography on admission revealed clear lung. However, 21 out of 48 cases developed severe dyspnea, hyperglycemia, leukocytosis, and decreased blood oxygen tension. Arterial pressure (AP) and heart rate (HR) fluctuation ensued. Spectral analysis of the AP and HR variabilities showed elevation in sympathetic activity at the onset of respiratory stress. Thereafter, parasympathetic drive increased with declines in AP and HR. These children died within 4 h after the onset of ARDS. Before death, chest radiography revealed severe lung infiltration. Similar to Japanese B encephalitis, destruction of the medullary depressor area caused initial sympathetic activation. Reverse-transcriptase polymerase chain reaction (RT-PCR) found marked iNOS mRNA expression in the lung parenchyma, suggesting iNOS may also be involved in the pathogenesis of ARDS in patients with enterovirus 71 infection. Furthermore, we have reported ARDS in patients with leptospirosis.[18] In leptospirosis-induced ARDS, histochemical stain demonstrated spirochetes bacteria in the alveolar space. The pathology included alveolar hemorrhage, myocarditis, portal inflammation and interstitial nephritis. Antigen retrieval immunohistochemical stain disclosed iNOS expression in the alveolar type 1 cells, myocardium, hepatocytes and renal tubules. Spectral analysis of AP and HR variabilities indicated decreased sympathetic drive with increased parasympathetic activity. The changes in autonomic functions led to severe hypotension and bradycardia. Biochemical determinations suggested multiple organ damage. The pathogenesis of lung and other organ injury might also involve iNOS and NO production.[18],[29] In subjects with scrub typhus, Orientia tsutsugamushi infection caused alveolar injury. Marked iNOS expression was found in the alveolar macrophages with increase in plasma nitrate/nitrite, suggesting that NO production from the alveolar macrophages accounts for the ALI.[30] The victim from rabies was a woman bitten by a wild dog. In addition to sign of hydrophobia, hypoxia, hypercapnia, hyperglycemia and increased plasma nitrate/nitrite were observed. The woman died of alveolar hemorrhage shortly after admission.[31] Recently, we encountered five cases with long-term malignancy. These subjects displayed signs of respiratory distress following an episode of hypercalcemia. Two cases died of ARDS after the plasma calcium was increased above 6 mmol/L. Search of literatures revealed that Holmes et al.[32] reported a patient who died of ARDS following a hypercalcemia crisis caused by a parathyroid adenoma. We conducted animal experiments in whole rodent and isolated perfused rat's lungs. Our results indicated that hypercalcemia (calcium concentration > 5 mmol/L) caused severe ALI in conscious rats and isolated lungs. Immunohistochemical staining showed iNOS activity in the alveolar macrophages and epithelial cells. Reverse-transcriptase polymerase chain reaction (RT-PCR) found marked increase in iNOS mRNA expression in lung parenchyma. Hypercalcemia also increased nitrate/nitrite, methyl guanidine, proinflammatory cytokines and procalcitonin. Pretreatment with calcitonin or L-N[6] (1-iminoethyl)-lysine (L-Nil, an iNOS inhibitor) attenuated the hypercalcemia-induced changes. We proposed that hypercalcemia produced a sepsis-like syndrome. The ALI caused by hypercalcemia may involve NO and iNOS.[33],[34]

In addition to the aforementioned animal experimentations and clinical observations that NO production through the iNOS may be involved in the lung injury due to various causes, our research team demonstrated that endotoxemia produced in anesthetized rats by intravenous administration of lipopolysaccharide (LPS, endotoxin) provoked systemic hypotension, endothelial damage and ALI accompanied by increased plasma nitrate/nitrite and expression of iNOS mRNA, TNFα and IL-1β. The LPS-induced changes were abolished by nonspecific and specific iNOS inhibitors such as Nω-monomethyl-L-arginine (L-NMMA), L-NAME, aminoguanine and dexamethosone.[35] This study suggested that NO/iNOS, TNFα and IL-1β were involved in the endotoxemia-induced ALI. Generation of NO from the activated neutrophil caused alveolar injury from smoke inhalation.[36] Experiments in many laboratories using specific iNOS inhibitors and/or iNOS-knockout animals have supported the contention that NO/iNOS is responsible for the oxidative stress and endothelial damage in the ARDS/ALI caused by endotoxin, ozone exposure, carrageenan treatment, hypoxia, acute hyperoxia, bleomaycin administration, acid aspiration and other causes.[37][46] Our laboratory further provided evidence to suggest that the NO/iNOS system is involved in the pathogenesis of ALI caused by air embolism,[47] fat embolism,[48][50] ischemia/reperfusion,[51][53] oleic acid[54] and phorbol myristate acetate.[55] In these recent studies, various insults caused increase in nitrate/nitrite in plasma or lung perfusate, upregulation of iNOS mRNA in lung parenchyma accompanied with elevation of proinflammatory cytokines such as TNFα, IL-1β and IL-6. Lin et al.[56] have suggested that an increase in iNOS mRNA triggers the release of proinflammatory cytokines in septic and conscious rats. The inflammatory responses results in multiple organ damage including ALI. Inhibition of iNOS with S-methylisothiourea (SMT) or L-Nil attenuated the inflammatory changes, release of NO and cytokines and prevented the organ dysfunction and ALI.[52]

Risk factors and pathogenetic mechanisms

In animal experiments and clinical investigations, the risk factors causing ALI/ARDS include head injury, intracranial hypertension,[2][4],[57][62] sepsis,[12],[17],[35],[37],[39],[42],[44],[63][66] and infections.[6][8],[10][12],[17],[18],[29][31],[67] Pulmonary embolic disorders such as fat and air embolism are less common causes.[7],[15],[28],[47],[68][70] Ischemia/reperfusion lung injury may develop as a consequence of several pulmonary disorders such as pulmonary artery thromboendarterectomy, thrombolysis after pulmonary embolism and lung transplantation.[13],[51][53],[71][74] Gastric aspiration occurs frequently in surgical patients under anesthesia and other causes such as blunt thoracic trauma, impaired glottis competency, and pregnancy.[73],[75],[76] It is one of the major causes of acute respiratory syndrome (ARDS).[77],[78] Intratracheal instillation of hydrochloric acid (HCI) or gastric particles has been employed as experimental model of acute lung injury (ALI).[16],[79][81] In addition, amphetamine, phorbal myristate acetate, oleic acid have been employed for the induction of ALI.[82][86] Phorbol myristate acetate (PMA, 12-O-tetradecanoyl-phorbol-13-acetate), an ester derivative from croton oil has been used to induce ALI.[65],[83],[86],[87] Experiments in vivo and in vitro have demonstrated that PMA is a strong neutrophil activator.[87][90] Activation and recruitment of neutrophil that lead to release of neutrophil elastase and other mediators may play an initial role in the pathogenesis of ALI.[91],[92] The oleic acid-induced ALI has several clinical implications. First, the blood level of oleic acid was significantly elevated in patients with ARDS.[93],[94] Second, the proportion of oleic acid incorporated into surfactant phospholipids was also increased in patients with ARDS and sepsis.[95],[96] These observations have provided evidence to suggest that serum level of oleic acid as a prediction or prognostic factor for ARDS.[84],[93] Early studies focused on the potential toxic effects of high oxygen fractions on inspired air.[97] Ventilator-induced ALI was attributed to the deleterious effects on capillary stress due to alveolar overdistension. Cyclic opening and closing of atelectatic alveoli during mechanical ventilation might cause lung injury and enhance the injured alveoli. Recent evidence indicated that over distension coupled with repeated collapse and reopening of alveoli initiated an inflammatory cascade of proinflammatory cytokines release.[68],[98][100]

In spite of the risk factors and causes, the pathophysiology of ARDS/ALI has generally considered to be initiated by formation of alveolar edema (even hemorrhage) that is enriched with protein, inflammatory cells or red blood cells. After damage of alveolar-capillary barrier, impairment of gas exchange occurs, with decrease in lung compliance and increases in dispersion of ventilation and perfusion and intrapulmonary shunt. Hypoxia, reduction in arterial oxygen partial pressure to fraction of oxygen in inspired air PaO2/FiO2, hypercapnia ensued despite ventilation with high oxygen.[1],[2],[67],[68],[101],[102] In addition to the potential toxic effects of NO and free radicals, certain chemokines, cytokines, neutrophil elastase, myeloperoxidase and malondialdehyde have been shown to be associated with several types of ARDS/ALI.[50],[54],[55],[91],[103][105] The balance between proinflammatory and anti-inflammatory mediators is regulated by transcriptional factors mainly nuclear factor-ΚB (NF-ΚB).[106] Pulmonary fluid clearance and ion transport are important factors to determine the extent of lung edema. Regulator factors include cystic fibrosis transmembrane conductance regulators, sodium-and potassium−activated adenosine triphophatase (Na+-K+-ATPase), protein kinases, aclenylate cyclase, and cyclic adenosine monophosphate (cAMP).[12],[29],[107],[108]

Possible therapeutic regimen

The treatment of ARDS/ALI is difficult and complex. Several review articles and monographs have addressed the issue of possible therapeutic regimen. The modalities include extracorporeal membrane oxygenation, prone position, mechanical ventilation with appropriate tidal volume and respiratory pressure, fluid and hemodynamic management and permissive hypercapnic acidosis.[68],[100],[109][119]

Other pharmacological treatments are anti-inflammatory and/or antimicrobial agents to control infection and to abrogate sepsis, adequate nutrition, surfactant therapy, inhalation of NO and other vasodilators, glucocorticoids and other nonsteroid anti-inflammatory drugs, agents that accelerate lung water resolution and ion transports.[68],[102],[120][124] Although most animal experimentations on these pharmacological options showed favorable results, the effectiveness and outcomes in clinical studies or trials were conflicting.

Beta agonists to facilitate water removal and ion transport have been shown to be promising. These agents may also stimulate secretion of surfactant and have no serious side effects. There were several reports on the pharmacological and molecular actions of beta agonists, surfactant and vascular endothelial growth factor and related molecules as well as angiotensin-converting enzyme (ACE).[107],[125],[126]

Nonpharmacological and pharmacological therapeutic for ALI and ARDS from recent studies in our laboratory

In addition to the experimental studies and clinical investigations on the pathogenesis of ALI/ARDS, our laboratory has carried out several experimentations on the therapeutic regimen for this serious disorder. In conscious rats, regular exercise training attenuates septic responses such as systemic hypotension, increases in plasma nitrate/nitrite, methyl guanidine, blood urea nitrogen, creatinine, amylase, lipase, asparate aminotransferase, alanine aminotransferase, creatine phosphokinase, lactic dehydrogenase, TNFα, and ILβ. Exercise training also abrogates the cardiac, hepatic and pulmonary injuries caused by endotoxemia.[124] Insulin exerts anti-inflammatory effects on the ALI and associated biochemical changes following intravenous administration of lipopolysaccharide (LPS).[127] Propofol (2,6-diisopropylphenol) has been commonly used for sedation in critically ill patients.[128] This anesthetic has rapid onset, short duration and rapid elimination.[129] Propofol protects the anesthetized rats from ALI caused by endotoxin.[65] In conscious rats, oleic acid results in sepsis-like responses including ALI, inflammatory reactions and increased in neutrophil-derived factors (neutrophil elastase, myeloperoxidase and malondialdehyde), nitrate/nitrite, methyl guanidine, inflammatory cytokines. It depresses the sodium-and potassium-activated ATPase, but upregulates the iNOS mRNA expression. Pretreatment and posttreatment with propofol alleviates or reverses the oleic acid-induced lung pathology and associated biochemical changes.[54] Pentobarbital, an anesthetic agent commonly used in experimental studies and a hypnotic for patients improves the pulmonary and other organ functions following LPS administration. It also increases the survival rate.[15] A later study by Yang et al.[130] further revealed that pentobarbital suppressed the expression of tumor necrosis factorα, which might result from decrease in the activities of nuclear factor-κβ and activator protein 1 and reduction in expression of P38 mitogen-activated protein kinase. In vivo examination of cytotoxic effects of LPS disclosed that LPS caused multiple organ dysfunctions. These changes were attenuated by pentobarbital. Pentobarbital also reduced the cell aptosis caused by deforoxamine-induced hypoxia. Nicotinamide or niacinamide (compound of soluble B complex) abrogates the ALI caused by ischemic/reperfusion or endotoxin by mechanism through inhibition on poly (ADP-ribose) synthase or permerase cytoxic enzyme and subsequent suppression of iNOS, NO, free radicals and proinflammatory cytokines with restoration of adenosine triphosphate ATP.[48],[53]N-acetylcysteine, an antioxidant and cytoprotective agent with scavenging action on reactive oxygen species and inhibitory effects on proinflammatory cytokines ameliorated organ dysfunctions due to sepsis in conscious rats.[131],[132] In a similar endotoxin-induced ALI model, we found that N-acetylcysteine improved the LPS-induced systemic hypotension and leukocytopenia. It also reduced the extent of ALI, as evidenced by reductions in lung weight changes, exhaled NO and lung pathology. In addition, N-acetylcysteine diminished the LPS-induced increases in nitrate/nitrite, TNFα, and ILβ[64] In isolated lungs, N-acetylcysteine attenuated the ALI caused by phorbol myristate acetate.[86] In a recent study, we reported that posttreatment with N-acetylcysteine prevented the ALI caused by fat embolism.[50] Our series of experimental studies provided results in favor of N-acetylcysteine. The conflicting results and practice guidelines from clinical studies in the recommendation of N-acetylcysteine in critically ill patients[133],[134] were commented and analyzed by Molnár.[135] The clinical application of results from animal studies requires further investigations.


ARDS or ALI is a serious clinical problem with high mortality. The risk factors leading to ALI/ARDS include head injury, intracranial disorders, sepsis and infections. Pulmonary embolic disorders such as fat and air embolism are less common causes. Ischemia/reperfusion lung injury may develop as a consequence of several pulmonary disorders such as lung transplantation. Gastric aspiration occurs frequently in several conditions such as anesthesia, trauma and pregnancy. The ventilator-induced ALI has been attributed to the deleterious effects on capillary stress due to alveolar overdistension. In experimental studies, phorbol myristate acetate and oleic acid have been employed to induce ALI.

The pathogenesis of ARDS/ALI is complex. Experimental studies and clinical investigations from our and other laboratories have indicated the detrimental role of nitric NO through inducible NO synthase (iNOS). Activation and recruitment of neutrophils that lead to release of neutrophil elastase, myeloperoxidase, malondialdehyde and pro-inflammatory cytokines may play an initial role in the pathogenesis of ALI/ARDS.

The possible therapeutic regimen for ALI/ARDS include extracorporeal membrane oxygenation, prone position, fluid and hemodynamic management and permissive hypercapnic acidosis etc. Other pharmacological treatments are anti-inflammatory and/or antimicrobial agents, inhalation of NO, glucocorticoids, surfactant therapy and agents that facilitate lung water resolution and ion transports. Adrenergic beta agonists are able to accelerate lung fluid and ion removal and to stimulate surfactant secretion. There are reports on the actions of vascular endothelial growth factor and related molecules as well as angiotensin-converting enzyme.

Our laboratory has reported experimental studies on the effectiveness of several regimen for ALI/ARDS. In conscious rats, regular exercise training alleviates the endotoxin-induced ALI. Propofol and N-acetylcysteine exert protective effect on the ALI causes by endotoxin, oleic acid and phorbol myristate acetate. We have also provided evidence that insulin possesses anti-inflammatory effect. Pentobarbital is capable of reducing the endotoxin-induced ALI and associated changes. In addition, nicotinamide or niacinamide (soluble B complex) abrogates the ALI caused by ischemia/reperfusion or endotoxemia. These nonpharmacological and pharmacological therapeutic strategies require further investigations for clinical application.

Experimental studies and clinical investigations were supported in part by grants from the “National Science Council”. The Grant No. this fiscal year is NSC99-2320-B-320-010-MY3. The author is grateful to Ms. S. Y. Huang for the assistance in typing an editing. I appreciate the long-term coworkers involved this and other studies in my laboratory.

1. Chen HI,Kao SJ,Wang D,et al. Acute respiratory distress syndromeJ Biomed SciYear: 20031058859214576460
2. Chen HI,Sun SC,Chai CY. Pulmonary edema and hemorrhage resulting from cerebral compressionAm J PhysiolYear: 19732242232394510212
3. Chen HI,Chai CY. Pulmonary edema and hemorrhage as a consequence of systemic vasoconstrictionAm J PhysiolYear: 19742271441514367259
4. Chen HI,Liao JF,Kuo L,et al. Centrogenic pulmonary hemorrhagic edema induced by cerebral compression in rats. Mechanism of volume and pressure loading in the pulmonary circulationCirc ResYear: 1980473663737408118
5. Chang LY,Lin TY,Hsu KH,et al. Clinical features and risk factors of pulmonary oedema after enterovirus-71-related hand, foot, and mouth diseaseLancetYear: 19993541682168610568570
6. Kao SJ,Yang FL,Hsu YH,et al. Mechanism of fulminant pulmonary edema caused by enterovirus 71Clin Infect DisYear: 2004381784178815227628
7. Hsu YH,Kao SJ,Lee RP,et al. Acute pulmonary oedema: rare causes and possible mechanismsClin SciYear: 200310425926412605583
8. Lee N,Hui D,Wu A,et al. A major outbreak of severe acute respiratory syndrome in Hong KongN Engl J MedYear: 20033481986199412682352
9. Poutanen SM,Low DE,Henry B,et al. Identification of severe acute respiratory syndrome in CanadaN Engl J MedYear: 20033481995200512671061
10. Ksiazek TG,Erdman D,Goldsmith CS,et al. A novel coronavirus associated with severe acute respiratory syndromeN Engl J MedYear: 20033481953196612690092
11. Drosten C,Günther S,Preiser W,et al. Identification of a novel coronavirus in patients with severe acute respiratory syndromeN Engl J MedYear: 20033481967197612690091
12. Eisenhut M,Wallace H,Barton P,et al. Pulmonary edema in meningococcal septicemia associated with reduced epithelial chloride transportPediatr Crit Care MedYear: 2006711912416446600
13. Kao SJ,Wang D,Yeh DY,et al. Static inflation attenuates ischemia/reperfusion injury in an isolated rat lung in situChestYear: 200412655255815302744
14. Kao SJ,Su CF,Liu DD,et al. Endotoxin-induced acute lung injury and organ dysfunction are attenuated by pentobarbital anaesthesiaClin Exp Pharmacol PhysiolYear: 20073448048717439419
15. Kao SJ,Yeh DY,Chen HI. Clinical and pathological features of fat embolism with acute respiratory distress syndromeClin SciYear: 200711327928517428199
16. Jian MY,Koizumi T,Kubo K. Effects of nitric oxide synthase inhibitor on acid aspiration-induced lung injury in ratsPulm Pharmacol TherYear: 200518333915607125
17. Chen HI,Chang HR,Wu CY,et al. Nitric oxide in the cardiovascular and pulmonary circulation--a brief review of literatures and historical landmarksChin J PhysiolYear: 200750435017608140
18. Chen HI,Kao SJ,Hsu YH. Pathophysiological mechanism of lung injury in patients with leptospirosisPathologyYear: 20073933934417558862
19. Chen HI,Hu CT,Wu CY,et al. Nitric oxide in systemic and pulmonary hypertensionJ Biomed SciYear: 1997424424812386386
20. Chen HI,Su CF,Chai CY. Neural and hemodynamic mechanisms of neurogenic pulmonary edemaProgress Physiol Sci (Beijing)Year: 199930203206
21. Chen HI,Shih WJ,Chen TP. A scintiphotographic study of pulmonary edema and hemorrhage induced by cerebral compression and norepinephrineChin J PhysiolYear: 19762265721028556
22. Chen HI,Lin JD,Liao JF. Participation of regional sympathetic outflows in the centrogenic pulmonary pathologyAm J PhysiolYear: 1981240H109157457614
23. Chen HI,Wang YC,Chai CY. The Cushing responses in the systemic and pulmonary circulation: the role of adrenal glands, bronchial circulation and pulmonary innervationChin J PhysiolYear: 19873029433449323
24. Chen HI,Wang DJ. Systemic and pulmonary hemodynamic responses to intracranial hypertensionAm J PhysiolYear: 1984247H7157216333827
25. Su CF,Hu CT,Chen HI. Effects of intracranial hypertension on steady and pulsatile haemodynamics in dogsClin Exp Pharmacol PhysiolYear: 19992689890210561811
26. Su CF,Kuo TB,Kuo JS,et al. Sympathetic and parasympathetic activities evaluated by heart-rate variability in head injury of various severitiesClin NeurophysiolYear: 20051161273127915978489
27. Wang D,Chou CL,Hsu K,et al. Cyclooxygenase pathway mediates lung injury induced by phorbol and plateletsJ Appl PhysiolYear: 199170241724211909312
28. Wang D,Li MH,Hsu K,et al. Air embolism-induced lung injury in isolated rat lungsJ Appl PhysiolYear: 199272123512421592709
29. Hsu YH,Chen HI. The involvement of nitric oxide and beta-adrenergic pathway signalling in pulmonary oedema and fluid clearancePathologyYear: 20073961261318027275
30. Hsu YH,Chen HI. Pulmonary pathology in patients associated with scrub typhusPathologyYear: 20084026827118428046
31. Hsu YH,Chen HI. Acute respiratory distress syndrome associated with rabiesPathologyYear: 20084064765018752140
32. Holmes F,Harlan J,Felt S,et al. Pulmonary oedema in hypercalcaemic crisisLancetYear: 197413113124130490
33. Hsu YH,Chen HI. Acute respiratory distress syndrome associated with hypercalcemia without parathyroid disordersChin J PhysiolYear: 20085141441819280887
34. Chen HI,Yeh DY,Kao SJ. The detrimental role of inducible nitric oxide synthase in the pulmonary edema caused by hypercalcemia in conscious rats and isolated lungsJ Biomed SciYear: 20081522723817906944
35. Wang D,Wei J,Hsu K,et al. Effects of nitric oxide synthase inhibitors on systemic hypotension, cytokines and inducible nitric oxide synthase expression and lung injury following endotoxin administration in ratsJ Biomed SciYear: 1999628359933740
36. Ischiropoulos H,Mendiguren I,Fisher D,et al. Role of neutrophils and nitric oxide in lung alveolar injury from smoke inhalationAm J Respir Crit Care MedYear: 19941503373418049812
37. Hinder F,Meyer J,Booke M,et al. Endogenous nitric oxide and the pulmonary microvasculature in healthy sheep and during systemic inflammationAm J Respir Crit Care MedYear: 1998157154215499603136
38. Kristof AS,Goldberg P,Laubach V,et al. Role of inducible nitric oxide synthase in endotoxin-induced acute lung injuryAm J Respir Crit Care MedYear: 1998158188318899847282
39. Evgenov OV,Hevroy O,Bremnes KE,et al. Effect of aminoguanidine on lung fluid filtration after endotoxin in awake sheepAm J Respir Crit Care MedYear: 200016246547010934072
40. Inoue H,Aizawa H,Nakano H,et al. Nitric oxide synthase inhibitors attenuate ozone-induced airway inflammation in guinea pigs. Possible role of interleukin-8Am J Respir Crit Care MedYear: 200016124925610619828
41. Cuzzocrea S,Mazzon E,Calabro G,et al. Inducible nitric oxide synthase-knockout mice exhibit resistance to pleurisy and lung injury caused by carrageenanAm J Respir Crit Care MedYear: 20001621859186611069827
42. Wang le F,Patel M,Razavi HM,et al. Role of inducible nitric oxide synthase in pulmonary microvascular protein leak in murine sepsisAm J Respir Crit Care MedYear: 20021651634163912070065
43. Agorreta J,Garayoa M,Montuenga LM,et al. Effects of acute hypoxia and lipopolysaccharide on nitric oxide synthase-2 expression in acute lung injuryAm J Respir Crit Care MedYear: 200316828729612773330
44. Razavi HM,Wang le F,Weicker S,et al. Pulmonary neutrophil infiltration in murine sepsis: role of inducible nitric oxide synthaseAm J Respir Crit Care MedYear: 200417022723315059787
45. Hesse AK,Dörger M,Kupatt C,et al. Proinflammatory role of inducible nitric oxide synthase in acute hyperoxic lung injuryRespir ResYear: 20045112015377396
46. Genovese T,Cuzzocrea S,Di Paola R,et al. Inhibition or knock out of inducible nitric oxide synthase result in resistance to bleomycin-induced lung injuryRespir ResYear: 20056587515955252
47. Liu YC,Kao SJ,Chuang IC,et al. Nitric oxide modulates air embolism-induced lung injury in rats with normotension and hypertensionClin Exp Pharmacol PhysiolYear: 2007341173118017880373
48. Kao SJ,Liu DD,Su CF,et al. Niacinamide abrogates the organ dysfunction and acute lung injury caused by endotoxinJ Cardiovasc PharmacolYear: 20075033334217878764
49. Kao SJ,Chen HI. Nitric oxide mediates acute lung injury caused by fat embolism in isolated rat's lungsJ TraumaYear: 20086446246918301216
50. Liu DD,Kao SJ,Chen HI. N-acetylcysteine attenuates acute lung injury induced by fat embolismCrit Care MedYear: 20083656557118216605
51. Kao SJ,Peng TC,Lee RP,et al. Nitric oxide mediates lung injury induced by ischemia-reperfusion in ratsJ Biomed SciYear: 200310586412566987
52. Su CF,Yang FL,Chen HI. Inhibition of inducible nitric oxide synthase attenuates acute endotoxin-induced lung injury in ratsClin Exp Pharmacol PhysiolYear: 20073433934617324147
53. Su CF,Liu DD,Kao SJ,et al. Nicotinamide abrogates acute lung injury caused by ischaemia/reperfusionEur Respir JYear: 20073019920417504797
54. Chen HI,Hsieh NK,Kao SJ,et al. Protective effects of propofol on acute lung injury induced by oleic acid in conscious ratsCrit Care MedYear: 2008361214122118379248
55. Yang YL,Huang KL,Liou HL,et al. The involvement of nitric oxide, nitric oxide synthase, neutrophil elastase, myeloperoxidase and proinflammatory cytokines in the acute lung injury caused by phorbol myristate acetateJ Biomed SciYear: 20081549950718283562
56. Lin NT,Yang FL,Lee RP,et al. Inducible nitric oxide synthase mediates cytokine release: the time course in conscious and septic ratsLife SciYear: 2006781038104316181643
57. Weissman SJ. Edema and congestion of the lungs from intracranial hemorrhageSurgeryYear: 19396722729
58. Richards P. Pulmonary oedema and intracranial lesionsBr Med JYear: 19632838613982101
59. Ducker TB. Increased intracranial pressure and pulmonary edema. 1. Clinical study of 11 patientsJ NeurosurgYear: 1968281121175638011
60. Ducker TB,Simmons RL. Increased intracranial pressure and pulmonary edema. 2. The hemodynamic response of dogs and monkeys to increased intracranial pressureJ NeurosurgYear: 1968281181234966167
61. Malik AB. Mechanisms of neurogenic pulmonary edemaCirc ResYear: 1985571182988816
62. Jourdan C,Convert J,Rousselle C,et al. Hemodynamic study of acute neurogenic pulmonary edema in childrenPediatrieYear: 1993488058128058442
63. Lee RP,Wang D,Kao SJ,et al. The lung is the major site that produces nitric oxide to induce acute pulmonary oedema in endotoxin shockClin Exp Pharmacol PhysiolYear: 20012831532011251647
64. Kao SJ,Wang D,Lin HI,et al. N-acetylcysteine abrogates acute lung injury induced by endotoxinClin Exp Pharmacol PhysiolYear: 200633334016445696
65. Chu CH,David Liu D,Hsu YH,et al. Propofol exerts protective effects on the acute lung injury induced by endotoxin in ratsPulm Pharmacol TherYear: 20072050351216713316
66. Lee RP,Wang D,Lin NT,et al. Physiological and chemical indicators for early and late stages of sepsis in conscious ratsJ Biomed SciYear: 2002961362112432227
67. Ware LB. Clinical Year in Review III: asthma, lung transplantation, cystic fibrosis, acute respiratory distress syndromeProc Am Thorac SocYear: 2007448949317761964
68. Ware LB,Matthay MA. The acute respiratory distress syndromeN Engl J MedYear: 20003421334134910793167
69. Fabian TC. Unravelling the fat embolism syndromeN Engl J MedYear: 19933299619638361513
70. Goldhaber SZ. Pulmonary embolismLancetYear: 20043631295130515094276
71. Sleiman C,Mal H,Fournier M,et al. Pulmonary reimplantation response in single-lung transplantationEur Respir JYear: 19958597744193
72. Levinson RM,Shure D,Moser KM. Reperfusion pulmonary edema after pulmonary artery thromboendarterectomyAm Rev Respir DisYear: 1986134124112453789523
73. Marik PE. Aspiration pneumonitis and aspiration pneumoniaN Engl J MedYear: 200134466567111228282
74. Ward BJ,Pearse DB. Reperfusion pulmonary edema after thrombolytic therapy of massive pulmonary embolismAm Rev Respir DisYear: 1988138130813113202486
75. Olsson GL,Hallen B,Hambraeus-Jonzon K. Aspiration during anaesthesia: a computer-aided study of 185,358 anaestheticsActa Anaesthesiol ScandYear: 19863084923754372
76. Warner MA,Warner ME,Weber JG. Clinical significance of pulmonary aspiration during the perioperative periodAnesthesiologyYear: 19937856628424572
77. Milberg JA,Davis DR,Steinberg KP,et al. Improved survival of patients with acute respiratory distress syndrome (ARDS): 1983-1993JAMAYear: 19952733063097815658
78. Zilberberg MD,Epstein SK. Acute lung injury in the medical ICU: comorbid conditions, age, etiology, and hospital outcomeAm J Respir Crit Care MedYear: 1998157115911649563734
79. Safdar Z,Yiming M,Grunig G,et al. Inhibition of acid-induced lung injury by hyperosmolar sucrose in ratsAm J Respir Crit Care MedYear: 20051721002100716109982
80. Davidson BA,Knight PR,Wang Z,et al. Surfactant alterations in acute inflammatory lung injury from aspiration of acid and gastric particulatesAm J Physiol Lung Cell Mol PhysiolYear: 2005288L69970815757954
81. Brackenbury AM,Puligandla PS,McCaig LA,et al. Evaluation of exogenous surfactant in HCL-induced lung injuryAm J Respir Crit Care MedYear: 20011631135114211316649
82. Huang KL,Shaw KP,Wang D,et al. Free radicals mediate amphetamine-induced acute pulmonary edema in isolated rat lungLife SciYear: 2002711237124412106589
83. Lin HI,Chu SJ,Wang D,et al. Effects of an endogenous nitric oxide synthase inhibitor on phorbol myristate acetate-induced acute lung injury in ratsClin Exp Pharmacol PhysiolYear: 20033039339812859432
84. Vadász I,Morty RE,Kohstall MG,et al. Oleic acid inhibits alveolar fluid reabsorption: a role in acute respiratory distress syndrome?Am J Respir Crit Care MedYear: 200517146947915542790
85. de Abreu MG,Quelhas AD,Spieth P,et al. Comparative effects of vaporized perfluorohexane and partial liquid ventilation in oleic acid-induced lung injuryAnesthesiologyYear: 200610427828916436847
86. Creamer KM,McCloud LL,Fisher LE,et al. N-acetylcysteine attenuates the acute lung injury caused by phorbol myristate acetate in isolated rat lungsPulm Pharmacol TherYear: 20072072673317071120
87. Creamer KM,McCloud LL,Fisher LE,et al. Pentoxifylline rescue preserves lung function in isolated canine lungs injured with phorbol myristate acetateChestYear: 20011191893190011399720
88. Kuraki T,Ishibashi M,Takayama M,et al. A novel oral neutrophil elastase inhibitor (ONO-6818) inhibits human neutrophil elastase-induced emphysema in ratsAm J Respir Crit Care MedYear: 200216649650012186827
89. Koshika T,Ishizaka A,Nagatomi I,et al. Pretreatment with FK506 improves survival rate and gas exchange in canine model of acute lung injuryAm J Respir Crit Care MedYear: 2001163798411208629
90. Murakami K,Cox RA,Hawkins HK,et al. Cepharanthin, an alkaloid from Stephania cepharantha, inhibits increased pulmonary vascular permeability in an ovine model of sepsisShockYear: 200320465112813368
91. Abraham E. Neutrophils and acute lung injuryCrit Care MedYear: 200331S19519912682440
92. Kinoshita M,Ono S,Mochizuki H. Neutrophils mediate acute lung injury in rabbits: role of neutrophil elastaseEur Surg ResYear: 20003233734611182617
93. Bursten SL,Federighi DA,Parsons P,et al. An increase in serum C18 unsaturated free fatty acids as a predictor of the development of acute respiratory distress syndromeCrit Care MedYear: 199624112911368674324
94. Quinlan GJ,Lamb NJ,Evans TW,et al. Plasma fatty acid changes and increased lipid peroxidation in patients with adult respiratory distress syndromeCrit Care MedYear: 1996242412468605795
95. Schmidt R,Meier U,Yabut-Perez M,et al. Alteration of fatty acid profiles in different pulmonary surfactant phospholipids in acute respiratory distress syndrome and severe pneumoniaAm J Respir Crit Care MedYear: 20011639510011208632
96. Günther A,Schmidt R,Harodt J,et al. Bronchoscopic administration of bovine natural surfactant in ARDS and septic shock: impact on biophysical and biochemical surfactant propertiesEur Respir JYear: 20021979780412030716
97. Pratt PC,Vollmer RT,Shelburne JD,et al. Pulmonary morphology in a multihospital collaborative extracorporeal membrane oxygenation project. I. Light microscopyAm J PatholYear: 197995191214434109
98. Ricard JD,Dreyfuss D,Saumon G. Ventilator-induced lung injuryEur Respir J SupplYear: 2003422s9s12945994
99. Vlahakis NE,Hubmayr RD. Cellular stress failure in ventilator-injured lungsAm J Respir Crit Care MedYear: 20051711328134215695492
100. Bernard GR. Acute respiratory distress syndrome: a historical perspectiveAm J Respir Crit Care MedYear: 200517279880616020801
101. Piantadosi CA,Schwartz DA. The acute respiratory distress syndromeAnn Intern MedYear: 200414146047015381520
102. Matthay MA,Zimmerman GA. Acute lung injury and the acute respiratory distress syndrome: four decades of inquiry into pathogenesis and rational managementAm J Respir Cell Mol BiolYear: 20053331932716172252
103. Lee WL,Downey GP. Leukocyte elastase: physiological functions and role in acute lung injuryAm J Respir Crit Care MedYear: 200116489690411549552
104. Yoshimura K,Nakagawa S,Koyama S,et al. Roles of neutrophil elastase and superoxide anion in leukotriene B4-induced lung injury in rabbitJ Appl PhysiolYear: 19947691968175552
105. Puneet P,Moochhala S,Bhatia M. Chemokines in acute respiratory distress syndromeAm J Physiol Lung Cell Mol PhysiolYear: 2005288L31515591040
106. Fan J,Ye RD,Malik AB. Transcriptional mechanisms of acute lung injuryAm J Physiol Lung Cell Mol PhysiolYear: 2001281L1037105011597894
107. Sartori C,Matthay MA. Alveolar epithelial fluid transport in acute lung injury: new insightsEur Respir JYear: 2002201299131312449188
108. Mutlu GM,Sznajder JI. Mechanisms of pulmonary edema clearanceAm J Physiol Lung Cell Mol PhysiolYear: 2005289L68569516214819
109. Hubmayr RD. Perspective on lung injury and recruitment: a skeptical look at the opening and collapse storyAm J Respir Crit Care MedYear: 20021651647165312070067
110. Angus D,Ishizaka A,Matthay M,et al. Critical care in AJRCCM 2004Am J Respir Crit Care MedYear: 200517153754415753483
111. Mols G,Priebe HJ,Guttmann J. Alveolar recruitment in acute lung injuryBr J AnaesthYear: 20069615616616361299
112. Galiatsou E,Kostanti E,Svarna E,et al. Prone position augments recruitment and prevents alveolar overinflation in acute lung injuryAm J Respir Crit Care MedYear: 200617418719716645177
113. Laffey JG,Honan D,Hopkins N,et al. Hypercapnic acidosis attenuates endotoxin-induced acute lung injuryAm J Respir Crit Care MedYear: 2004169465612958048
114. Broccard AF,Hotchkiss JR,Vannay C,et al. Protective effects of hypercapnic acidosis on ventilator-induced lung injuryAm J Respir Crit Care MedYear: 200116480280611549536
115. Ni Chonghaile M,Higgins B,Laffey JG. Permissive hypercapnia: role in protective lung ventilatory strategiesCurr Opin Crit CareYear: 200511566215659946
116. Lang JD,Figueroa M,Sanders KD,et al. Hypercapnia via reduced rate and tidal volume contributes to lipopolysaccharide-induced lung injuryAm J Respir Crit Care MedYear: 200517114715715477499
117. Feihl F,Eckert P,Brimioulle S,et al. Permissive hypercapnia impairs pulmonary gas exchange in the acute respiratory distress syndromeAm J Respir Crit Care MedYear: 200016220921510903243
118. Calfee CS,Matthay MA. Nonventilatory treatments for acute lung injury and ARDSChestYear: 200713191392017356114
119. Fan E,Needham DM,Stewart TE. Ventilatory management of acute lung injury and acute respiratory distress syndromeJAMAYear: 20052942889289616352797
120. Hite RD,Morris PE. Acute respiratory distress syndrome: pharmacological treatment options in developmentDrugsYear: 20016189790711434447
121. Brower RG,Ware LB,Berthiaume Y,et al. Treatment of ARDSChestYear: 20011201347136711591581
122. Moloney ED,Evans TW. Pathophysiology and pharmacological treatment of pulmonary hypertension in acute respiratory distress syndromeEur Respir JYear: 20032172072712762363
123. Griffiths MJ,Evans TW. Inhaled nitric oxide therapy in adultsN Engl J MedYear: 20053532683269516371634
124. Chen HI,Hsieh SY,Yang FL,et al. Exercise training attenuates septic responses in conscious ratsMed Sci Sports ExercYear: 20073943544217473769
125. Mura M,dos Santos CC,Stewart D,et al. Vascular endothelial growth factor and related molecules in acute lung injuryJ Appl PhysiolYear: 2004971605161715475552
126. Imai Y,Kuba K,Rao S,et al. Angiotensin-converting enzyme 2 protects from severe acute lung failureNatureYear: 200543611211616001071
127. Chen HI,Yeh DY,Liou HL,et al. Insulin attenuates endotoxin-induced acute lung injury in conscious ratsCrit Care MedYear: 20063475876416505662
128. Aitkenhead AR,Pepperman ML,Willatts SM,et al. Comparison of propofol and midazolam for sedation in critically ill patientsLancetYear: 198927047092570958
129. Bryson HM,Fulton BR,Faulds D. Propofol. An update of its use in anaesthesia and conscious sedationDrugsYear: 1995505135598521772
130. Yang FL,Li CH,Hsu BG,et al. The reduction of tumor necrosis factor-alpha release and tissue damage by pentobarbital in the experimental endotoxemia modelShockYear: 20072830931617545946
131. Hsu BG,Yang FL,Lee RP,et al. N-acetylcysteine ameliorates lipopolysaccharide-induced organ damage in conscious ratsJ Biomed SciYear: 20041115216214966365
132. Hsu BG,Lee RP,Yang FL,et al. Post-treatment with N-acetylcysteine ameliorates endotoxin shock-induced organ damage in conscious ratsLife SciYear: 2006792010201616860347
133. Molnár Z,Shearer E,Lowe D. N-Acetylcysteine treatment to prevent the progression of multisystem organ failure: a prospective, randomized, placebo-controlled studyCrit Care MedYear: 1999271100110410397212
134. Berger MM,Chioléro RL. Antioxidant supplementation in sepsis and systemic inflammatory response syndromeCrit Care MedYear: 200735S58459017713413
135. Molnár Z. N-acetylcysteine as the magic bullet: too good to be trueCrit Care MedYear: 20083664564618216629


[Figure ID: jgc-08-01-044-g001]
Figure 1.  Gross inspection of the lungs in rats with and without cerebral compression. (A): The normal configuration of lungs from a control rat without cerebral compression; (B): After cerebral compression, there were edematous and hemorrhagic changes of the lungs. The lungs were enlarged and swollen with marked discoloration.

[Figure ID: jgc-08-01-044-g002]
Figure 2.  Isolated and perfused lung in situ preparation. The system consists of a perfusion pump with heat exchanger and a venous reservoir. The rat is artificially ventilated. Pulmonary arterial pressure (PAP) and venous pressure (PVP) are monitored with transducers. The whole rat is placed on a balance platform to record the body weight change. Since the lung is isolated from the whole body, the change in body weight reflects the lung weight change.

[Figure ID: jgc-08-01-044-g003]
Figure 3.  A schematic representation of the neural and hemo-dynamic mechanisms of neurogenic pulmonary edema caused by cerebral compression. Sympathetic activation from the medullary vasomotor center is the primary culprit leading to edema and hemorrhage in the lung. Hypothalamic “pulmonary edemagenetic center” is not involved. Vagal pathway plays minimal role. Cerebral compression causes sympathetic vasoconstriction of the systemic and pulmonary resistance and capacitance vessels. Resistance change, mainly in the splanchnic beds, results in dramatic decline of left ventricular output. The challenge finally produces passive volume and pressure loading in the pulmonary circulation. Severe pulmonary arterial and venous hypertension induce edema and hemorrhage in the lungs.

Article Categories:
  • Review

Keywords: acute lung injury, acute respiratory distress syndrome, neurogenic pulmonary edema, nitric oxide, free radicals, cytokines.

Previous Document:  Andropause and the development of cardiovascular disease presentation-more than an epi-phenomenon.
Next Document:  Treatment of dyslipidemia in the elderly.