**6. COPD and MMPs**

*vitro* by MMP-1, -2 and -9 [22]. These data indicate a dual role for MMPs in the biphasic modulation of inflammatory-mediator activity. MMPs are involved in both the activation and

Moreover, several studies have indicated that MMPs can either directly or indirectly affect the activity interferon-γ [23], vascular endothelial growth factor [24], epidermal growth factors [25], fibroblast growth factors [26] and transforming growth factor (TGF)-β. As shown using TGF-β-deficient mice, this cytokine functions to restrain mononuclear inflammation [27-29]. In both cells and tissue-explant models, MMP-3 [30], MMP-9 [31] and MMP-14 [32] have been

Lopez-Boado et al. reported a 25-fold induction of MMP-7 in lung epithelial cells following infection with *Escherichia coli* [33] and *Pseudomonas aeruginosa*, [34] which could explain the upregulation of this enzyme in the airway of cystic fibrosis patients who are commonly infected with these bacteria. It has also been shown that proinflammatory cytokines, such as IL-1β and TNF-α, upregulate the expression of MMP-9 in human airway epithelial cells

Lung inflammation is deeply associated with the process of pulmonary fibrosis. MMP-9 was observed in alveolar macrophages from idiopathic pulmonary fibrosis patients [36] and in the bronchoalveolar lavage (BAL) fluid from patients with bleomycin-induced pulmonary fibrosis [37, 38]. An mRNA study also supported that the activation of MMP-2 and MMP-9, both gelatinases, is involved in pulmonary fibrosis [39]. The function of other MMPs, such as collagenases or stromelysins, in pulmonary fibrosis is still unclear, despite their importance in ECM deposition. Edwards and colleagues reported that mast cells harvested from the tissues of patients with interstitial lung diseases demonstrated the expression of MMP-1. MMP-1 has thus been reported to be important for controlling fibrogenesis in humans [40]. Although the existence of MMP-1 is unclear in rodents [41], other collagenases, such as MMP-13, have been detected [42]. Similarly, collagenase activity has been observed after bleomycin administration [37]. An immunohistochemical analysis demonstrated that MMP-13 expression was present after bleomycin administration [43]. However, other researchers have reported that the MMP-9 (gelatinase B), MMP-3 (stromelysin-1) and interstitial collagenase gene expression did not

As mentioned previously, doxycycline inhibits MMP activity. We demonstrated that the early administration of doxycycline inhibited early inflammation and resulted in an inhibition of the development of pulmonary fibrosis through the inhibition of early inflammation [45]. However, doxycycline did not affect established pulmonary fibrosis. A MMPs inhibitor,

inactivation of these inflammatory molecules.

64 Lung Inflammation

following a one-day treatment [35].

**4. Pulmonary fibrosis and MMPs**

significantly change after bleomycin administration [44].

**5. Therapeutic trials for pulmonary fibrosis**

shown or suggested to activate a proportion of the total TGF-β.

Both alveolar and bronchial inflammation have been shown to be present in human COPD. Hence, chronic inflammation contributes to the development of COPD through the destruction of alveoli and the induction of MMPs. Recently, the role of MMPs has been given increasing attention as a possible mechanism underlying the development of pulmonary emphysema. Additionally, the inflammatory cells invading the lung during the course of COPD are also a major source of different MMPs. It has been shown that neutrophils and macrophages are the predominant inflammatory cells in the lungs of COPD patients [47, 48].

Lipopolysaccharide (LPS) is a strong proinflammatory compound present in the cell wall of gram-negative bacteria. Acute LPS instillation induces apoptotic cell death in bronchial epithelial cells at early time points, and neutrophil apoptosis in the lungs at later time points [49, 50], and this is associated with the production of MMPs, mainly gelatinase [51]. LPS leads to the recruitment of neutrophils and macrophage activation with concomitant airspace enlargement [52, 53]. Although humans tolerate bacterial pneumonia without any residual emphysema, the chronic instillation of LPS was found to induce COPD-like changes. Bacterial endotoxin was demonstrated to be present in high concentrations in tobacco (approximately 20 µg/cigarette), and bioactive LPS could be detected in both mainstream and sidestream cigarette smoke (approximately 0.12-0.2 µg/cigarette) [54, 55]. Repetitive LPS instillation for 12 weeks led to COPD-like changes [56]. This mouse model mimicked several important pathological changes that are observed in COPD patients. These mice demonstrated goblet cell metaplasia in the larger airways, thickening of the airway walls and irreversible alveolar enlargements [57]. It is well known that LPS induces TNFα. TNF-α overexpression in mice has been reported to have diverse effects, including the induction of pulmonary emphysema and pulmonary fibrosis. At first, the overexpression of TNF-α in the lungs of mice was thought to lead to pulmonary fibrosis [58, 59]. In contrast, TNF-α overexpressing mice bred in Denver demonstrated pulmonary emphysema [60]. Chronic inflammation, a reduced elastic recoil, a huge lung size and an activation of MMPs (mainly MMP-2 and MMP-9) were all observed in these mice, along with a progression of pulmonary hypertension [61]. In addition, this mouse model was insensitive to fibrogene‐ sis factor, bleomycin and TGF-β [62]. Many evidence have demonstrated that TNF-α plays a critical role in smoking-related emphysema [63]. Taking these findings into considera‐ tion, TNF-α is considered to play a crucical role in the development of COPD and MMPs, mainly MMP-2 and MMP-9 is associated with the COPD pathogenesis.

and also found protein expression and enzymatic activity in the lung samples of patients with emphysema. However, there was no MMP-1 detected in the lungs of normal control subjects [81]. Additionally, Ohnishi and colleagues documented a more than three-fold increase in the level of MMP-2 protein and activation in lung samples from emphysematous patients compared to subjects in the control group [82]. Another study reported an increase in the MMP-9 protein level in 40% of COPD patients compared to healthy subjects. The location of the MMP-9 expression was confirmed by an immunohistochemical analysis to be in the bronchial epithelium and submucosal areas [87]. Furthermore, an extracellular MMP inducer, called basigin, a member of the immunoglobulin G (IgG) superfamily, were increased in smokers' BAL fluid samples [88]. The extracellular MMP inducer was prominent in the bronchial glands, bronchial epithelium and alveolar macrophages. An increase in the level of MMP-9 has also been reported in the sputum of patients with chronic bronchitis compared to

The Role of MMPs in the Progression of Chronic Lung Inflammatory Diseases

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67

MMP-9 and MMP-12 play key roles in the development of COPD in mice. However, studies in patients suggest that the spectrum of MMPs in human disease may differ significantly from these models. Studies of MMP activity demonstrate divergent results at different stages of disease evolution, and lead to controversy about which MMPs are critical in pulmonary disease in humans. Taking the data from both clinical and animal studies into consideration, MMP-9 is the most compelling molecule related to the development of COPD. In contrast, MMP-12 is essential for the cigarette smoke-induced pathology in the mouse, but may not be equally

MMP inhibition could be a promising candidate therapy for COPD. In fact, a MMP inhibitor, GM6001, has been reported to block the emphysematous changes associated with methyl‐ prednisolone-induced emphysema in rats [90]. However, past experiences, including our own study, have shown that a broad spectrum MMP inhibitor would be of limited benefit [91-93]. In fact, our preliminary study using CGS27023A, an MMP inhibitor, or doxycycline, did not improve the COPD in mice with TNF-α overexpression (unpublished data). Nonselective MMP inhibitors, such as marimastat, have major side effects. Isoenzyme-selective inhibitors or inhaled delivery may be needed. A dual MMP9–MMP12 inhibitor (AZ11557272) was shown to prevent emphysema, small airway fibrosis and inflammation in guinea pigs that were exposed to cigarette smoke over a six‑month period [94], but its clinical development has now been stopped for some unknown reason. MMP-9 is potentially a good target for patients with emphysema, but progress in the development of drugs targeting MMP-9 has been disappoint‐ ing, because it has proved to be difficult to discover safe and selective MMP-9 inhibitors [93].

A more sophisticated approach is therefore required in the future.

control subjects [89].

critical in human disease.

**7. Therapeutic trials for COPD**

Several transgenic mouse strains with targeted expression of cytokines show COPD-like lesions, such as airspace enlargement, thickening of the airway walls and subepithelial fibrosis without any exposure to a specific agent [64, 65]. An overexpression of IL-13 in the murine lung caused an asthma-like eosinophil- and lymphocyte-rich inflammation, goblet cell hyperplasia, airway fibrosis and alveolar enlargement [66, 67]. The induced overexpression of interferon (IFN)-γ in the lungs of mice caused a phenotype mimicking human COPD [68]. In these models, the overexpression of these inflammatory cytokines was associated with an increased expression of MMPs (mainly gelatinase) and cysteine proteases, including cathe‐ psins. Similarly, macrophage colony stimulating factor (M-CSF)-deficient mice, surfactant protein D (SP-D)-deficient mice and integrin αvβ6-deficient mice also develop air space enlargement [69-71]. The macrophages of SP-D-deficient mice have increased oxidant pro‐ duction, which activates nuclear factor (NF)-κB and subsequently leads to MMP expression [72]. NF-kB is also well known to be a transcription factor involved in the induction of TNFα. Inflammation and MMPs activation (mainly gelatinase) contribute to the development of COPD.

Another mechanism for COPD involves macrophage elastase (MMP-12). MMP-12 is nearly undetectable in healthy macrophages, while MMP-12 is expressed in the alveolar macrophages of human cigarette smokers. Of note, MMP-12 knockout mice did not develop emphysema in response to long-term cigarette smoke exposure [73, 74]. MMP-12 knockout mice also failed to recruit macrophages into their lungs in response to cigarette smoke. Neutrophil elastasedeficient mice were significantly protected from the development of pulmonary emphysema after cigarette smoke exposure [75]. Mice that constitutively overexpress human MMP-1 develop spontaneous air space enlargement, showing that MMP-1 can drive pulmonary destruction [76]. Since that report, numerous transgenic mouse models have been developed, in which emphysema-like changes are induced. The absence of MMP inhibitors can also result in abnormal pulmonary matrix turnover, as TIMP-3 deficient mice spontaneously develop air space enlargement at two weeks of age [77].

The functional importance of MMP activity in these models was confirmed by crossing emphysema-developing mice with MMP-knockout mice. For example, in the IL-13 overex‐ pression model, a deficiency of MMP-9 or MMP-12 results in reduced pathological changes and less respiratory failure [78]. Similarly, crossing integrin αvβ6-deficient mice with MMP-12 deficient mice prevents the development of age-related emphysema [79].

MMPs seem to be strongly related to the development of COPD [80]. In a clinical study, there were increases in the pulmonary expression of MMP -1 [81], MMP-2 [82], MMP-8 [83], MMP -9 [84], MMP-12 [85] and MMP-14[82] in COPD patients. For example, Finlay and colleagues detected collagenase activity in BAL fluid samples from 100% of emphysematous patients but in only 10% of smoking controls; and MMP-9 was present in 60% of patients compared to 20% in the control group [84]. Segura-Valdez and colleagues showed a significant upregulation of MMPs -1, -2, -8, and -9 in the BAL fluid samples obtained from COPD patients [86]. In another study, Imai and colleagues reported the detection of MMP-1 mRNA by *in situ* hybridization, and also found protein expression and enzymatic activity in the lung samples of patients with emphysema. However, there was no MMP-1 detected in the lungs of normal control subjects [81]. Additionally, Ohnishi and colleagues documented a more than three-fold increase in the level of MMP-2 protein and activation in lung samples from emphysematous patients compared to subjects in the control group [82]. Another study reported an increase in the MMP-9 protein level in 40% of COPD patients compared to healthy subjects. The location of the MMP-9 expression was confirmed by an immunohistochemical analysis to be in the bronchial epithelium and submucosal areas [87]. Furthermore, an extracellular MMP inducer, called basigin, a member of the immunoglobulin G (IgG) superfamily, were increased in smokers' BAL fluid samples [88]. The extracellular MMP inducer was prominent in the bronchial glands, bronchial epithelium and alveolar macrophages. An increase in the level of MMP-9 has also been reported in the sputum of patients with chronic bronchitis compared to control subjects [89].

MMP-9 and MMP-12 play key roles in the development of COPD in mice. However, studies in patients suggest that the spectrum of MMPs in human disease may differ significantly from these models. Studies of MMP activity demonstrate divergent results at different stages of disease evolution, and lead to controversy about which MMPs are critical in pulmonary disease in humans. Taking the data from both clinical and animal studies into consideration, MMP-9 is the most compelling molecule related to the development of COPD. In contrast, MMP-12 is essential for the cigarette smoke-induced pathology in the mouse, but may not be equally critical in human disease.

## **7. Therapeutic trials for COPD**

tion, TNF-α is considered to play a crucical role in the development of COPD and MMPs,

Several transgenic mouse strains with targeted expression of cytokines show COPD-like lesions, such as airspace enlargement, thickening of the airway walls and subepithelial fibrosis without any exposure to a specific agent [64, 65]. An overexpression of IL-13 in the murine lung caused an asthma-like eosinophil- and lymphocyte-rich inflammation, goblet cell hyperplasia, airway fibrosis and alveolar enlargement [66, 67]. The induced overexpression of interferon (IFN)-γ in the lungs of mice caused a phenotype mimicking human COPD [68]. In these models, the overexpression of these inflammatory cytokines was associated with an increased expression of MMPs (mainly gelatinase) and cysteine proteases, including cathe‐ psins. Similarly, macrophage colony stimulating factor (M-CSF)-deficient mice, surfactant protein D (SP-D)-deficient mice and integrin αvβ6-deficient mice also develop air space enlargement [69-71]. The macrophages of SP-D-deficient mice have increased oxidant pro‐ duction, which activates nuclear factor (NF)-κB and subsequently leads to MMP expression [72]. NF-kB is also well known to be a transcription factor involved in the induction of TNFα. Inflammation and MMPs activation (mainly gelatinase) contribute to the development of

Another mechanism for COPD involves macrophage elastase (MMP-12). MMP-12 is nearly undetectable in healthy macrophages, while MMP-12 is expressed in the alveolar macrophages of human cigarette smokers. Of note, MMP-12 knockout mice did not develop emphysema in response to long-term cigarette smoke exposure [73, 74]. MMP-12 knockout mice also failed to recruit macrophages into their lungs in response to cigarette smoke. Neutrophil elastasedeficient mice were significantly protected from the development of pulmonary emphysema after cigarette smoke exposure [75]. Mice that constitutively overexpress human MMP-1 develop spontaneous air space enlargement, showing that MMP-1 can drive pulmonary destruction [76]. Since that report, numerous transgenic mouse models have been developed, in which emphysema-like changes are induced. The absence of MMP inhibitors can also result in abnormal pulmonary matrix turnover, as TIMP-3 deficient mice spontaneously develop air

The functional importance of MMP activity in these models was confirmed by crossing emphysema-developing mice with MMP-knockout mice. For example, in the IL-13 overex‐ pression model, a deficiency of MMP-9 or MMP-12 results in reduced pathological changes and less respiratory failure [78]. Similarly, crossing integrin αvβ6-deficient mice with MMP-12-

MMPs seem to be strongly related to the development of COPD [80]. In a clinical study, there were increases in the pulmonary expression of MMP -1 [81], MMP-2 [82], MMP-8 [83], MMP -9 [84], MMP-12 [85] and MMP-14[82] in COPD patients. For example, Finlay and colleagues detected collagenase activity in BAL fluid samples from 100% of emphysematous patients but in only 10% of smoking controls; and MMP-9 was present in 60% of patients compared to 20% in the control group [84]. Segura-Valdez and colleagues showed a significant upregulation of MMPs -1, -2, -8, and -9 in the BAL fluid samples obtained from COPD patients [86]. In another study, Imai and colleagues reported the detection of MMP-1 mRNA by *in situ* hybridization,

deficient mice prevents the development of age-related emphysema [79].

mainly MMP-2 and MMP-9 is associated with the COPD pathogenesis.

COPD.

66 Lung Inflammation

space enlargement at two weeks of age [77].

MMP inhibition could be a promising candidate therapy for COPD. In fact, a MMP inhibitor, GM6001, has been reported to block the emphysematous changes associated with methyl‐ prednisolone-induced emphysema in rats [90]. However, past experiences, including our own study, have shown that a broad spectrum MMP inhibitor would be of limited benefit [91-93]. In fact, our preliminary study using CGS27023A, an MMP inhibitor, or doxycycline, did not improve the COPD in mice with TNF-α overexpression (unpublished data). Nonselective MMP inhibitors, such as marimastat, have major side effects. Isoenzyme-selective inhibitors or inhaled delivery may be needed. A dual MMP9–MMP12 inhibitor (AZ11557272) was shown to prevent emphysema, small airway fibrosis and inflammation in guinea pigs that were exposed to cigarette smoke over a six‑month period [94], but its clinical development has now been stopped for some unknown reason. MMP-9 is potentially a good target for patients with emphysema, but progress in the development of drugs targeting MMP-9 has been disappoint‐ ing, because it has proved to be difficult to discover safe and selective MMP-9 inhibitors [93]. A more sophisticated approach is therefore required in the future.

#### **8. Conclusion**

There is a controversy concerning the role of MMPs in the development of chronic inflamma‐ tory lung diseases. There were two possible but conflicting roles of MMPs: promoting the deposition of the ECM by facilitating fibroblast migration, or degenerating the ECM. MMPs play important roles in the degradation of the ECM and recovery from lung damage. Similar to inflammation, MMPs activation was observed in both pulmonary fibrosis and COPD. The role of MMPs in inflammatory lung diseases is therefore complex. The different MMPs show variations in terms of their effecting depending on different condition. In addition, MMP inhibitors appear to work in different ways. More precise and specific studies of both the proteins themselves and their specific inhibitors will be needed in the future. Moreover, there are discrepancies between mice and humans. Novel therapeutic agents targeting MMPs for use against chronic inflammation are currently under development, and more will likely be developed as more is learned about the MMPs and their functions. This information is summarized in Figure 2.

immunoglobulin G (IgG)

lipopolysaccharide (LPS)

nuclear factor (NF)

**Author details**

Masaki Fujita\*

**References**

surfactant protein D (SP-D)

tumor-necrosis factor (TNF)

TNF-converting enzyme (TACE) transforming growth factor (TGF)

matrix metalloproteinases (MMPs) membrane-type MMPs (MT-MMPs)

macrophage colony stimulating factor (M-CSF)

tissue inhibitors of metalloproteinases (TIMPs)

Address all correspondence to: mfujita@fukuoka-u.ac.jp

Springer: New York; 2010

nology 2006;4: 617-629

1994;49: 602-609.

views Immunology 2010;10: 712-723

Department of Respiratory Medicine, Fukuoka University Hospital, Fukuoka, Japan

[1] Clark IM Edit. Matrix metalloproteinase protocols, second edition. Humana Press/

The Role of MMPs in the Progression of Chronic Lung Inflammatory Diseases

http://dx.doi.org/10.5772/57391

69

[2] William C. Parks, Carole L. Wilson & Yolanda S. López-Boado. Matrix metalloprotei‐ nases as modulators of inflammation and innate immunity. Nature Reviews Immu‐

[3] Lydia Sorokin. The impact of the extracellular matrix on inflammation.Nature Re‐

[4] O'Connor CM, FitzGerald MX. Matrix metalloproteases and lung disease. Thorax

interleukin (IL) interferon (IFN)

**Figure 2.** A schematic drawing of the relationship between MMPs and lung injury.

#### **Abbreviations**

a disintegrin and metalloproteinase (ADAMs) bronchoalveolar lavage (BAL) chronic obstructive pulmonary disease (COPD) extracellular matrix (ECM) IL-1-converting enzyme (ICE)

immunoglobulin G (IgG) interleukin (IL) interferon (IFN) lipopolysaccharide (LPS) macrophage colony stimulating factor (M-CSF) matrix metalloproteinases (MMPs) membrane-type MMPs (MT-MMPs) nuclear factor (NF) surfactant protein D (SP-D) tissue inhibitors of metalloproteinases (TIMPs) tumor-necrosis factor (TNF) TNF-converting enzyme (TACE) transforming growth factor (TGF)

## **Author details**

Masaki Fujita\*

**8. Conclusion**

68 Lung Inflammation

summarized in Figure 2.

**Abbreviations**

bronchoalveolar lavage (BAL)

extracellular matrix (ECM) IL-1-converting enzyme (ICE)

**Figure 2.** A schematic drawing of the relationship between MMPs and lung injury.

a disintegrin and metalloproteinase (ADAMs)

chronic obstructive pulmonary disease (COPD)

There is a controversy concerning the role of MMPs in the development of chronic inflamma‐ tory lung diseases. There were two possible but conflicting roles of MMPs: promoting the deposition of the ECM by facilitating fibroblast migration, or degenerating the ECM. MMPs play important roles in the degradation of the ECM and recovery from lung damage. Similar to inflammation, MMPs activation was observed in both pulmonary fibrosis and COPD. The role of MMPs in inflammatory lung diseases is therefore complex. The different MMPs show variations in terms of their effecting depending on different condition. In addition, MMP inhibitors appear to work in different ways. More precise and specific studies of both the proteins themselves and their specific inhibitors will be needed in the future. Moreover, there are discrepancies between mice and humans. Novel therapeutic agents targeting MMPs for use against chronic inflammation are currently under development, and more will likely be developed as more is learned about the MMPs and their functions. This information is

Address all correspondence to: mfujita@fukuoka-u.ac.jp

Department of Respiratory Medicine, Fukuoka University Hospital, Fukuoka, Japan

#### **References**


[5] Van Wart HE, Birkedal-Hansen H. The cysteine switch: a principle of regulation of metalloproteinase activity with potential applicability to the entire matrix metallo‐ proteinase gene family. Proc Natl Acad Sci USA 1990;87: 5578–5582.

[18] English WR, Puente XS, Freije JM, Knauper V, Amour A, Merryweather A, Lopez-Otin C, Murphy G. Membrane type 4 matrix metalloproteinase (MMP17) has tumor necrosis factor-α convertase activity but does not activate pro-MMP2. J Biol Chem

The Role of MMPs in the Progression of Chronic Lung Inflammatory Diseases

http://dx.doi.org/10.5772/57391

71

[19] Visse R, Nagase H. Matrix metalloproteinases and tissue inhibitors of metalloprotei‐

[20] Fantuzzi G, Ku G, Harding MW, Livingston DJ, Sipe JD, Kuida K, Flavell RA, Dinar‐ ello CA. Response to local inflammation of IL-1β-converting enzyme-deficient mice. J

[21] Schönbeck U, Mach F, Libby P. Generation of biologically active IL-1β by matrix met‐ alloproteinases: a novel caspase-1-independent pathway of IL-1β processing. J Im‐

[22] Ito A, Mukaiyama A, Itoh Y, Nagase H, Thogersen IB, Enghild JJ, Sasaguri Y, Mori Y. Degradation of interleukin 1β by matrix metalloproteinases. J Biol Chem 1996; 271:

[23] Nelissen I, Martens E, Van den Steen PE, Proost P, Ronsse I, Opdenakker G. Gelati‐ nase B/matrix metalloproteinase-9 cleaves interferon-β and is a target for immuno‐

[24] Bergers G, Brekken R, McMahon G, Vu TH, Itoh T, Tamaki K, Tanzawa K, Thorpe P, Itohara S, Werb Z, Hanahan D. Matrix metalloproteinase-9 triggers the angiogenic

[25] Suzuki M, Raab G, Moses MA, Fernandez CA, Klagsbrun M. Matrix metalloprotei‐ nase-3 releases active heparin-binding EGF-like growth factor by cleavage at a specif‐

[26] Levi E, Fridman R, Miao HQ, Ma YS, Yayon A, Vlodavsky I. Matrix metalloprotei‐ nase 2 releases active soluble ectodomain of fibroblast growth factor receptor 1. Proc

[27] Shull MM, Ormsby I, Kier AB, Pawlowski S, Diebold RJ, Yin M, Allen R, Sidman C, Proetzel G, Calvin D, Annunziata N, Doetschman T. Targeted disruption of the mouse transforming growth factor-β 1 gene results in multifocal inflammatory dis‐

[28] Kulkarni AB, Karlsson S. Transforming growth factor-β 1 knockout mice. A mutation in one cytokine gene causes a dramatic inflammatory disease. Am J Pathol 1993;143:

[29] Munger JS, Huang X, Kawakatsu H, Griffiths MJ, Dalton SL, Wu J, Pittet JF, Kamin‐ ski N, Garat C, Matthay MA, Rifkin DB, Sheppard D. The integrin αvβ6 binds and activates latent TGFβ1: a mechanism for regulating pulmonary inflammation and fib‐

switch during carcinogenesis. Nature Cell Biol 2000; 2: 737–744.

ic juxtamembrane site. J Biol Chem 1997; 272:31730–31737.

nases: structure, function, and biochemistry. Circ Res 2003; 92: 827–839.

2000;275: 14046–14055.

Immunol 1997;158: 1818–1824.

munol 1998;161: 3340–3346.

therapy. Brain 2003;126:1371–1381.

Natl Acad Sci USA 1996;93:7069–7074.

ease. Nature 1992;359: 693–699.

rosis. Cell 1999;96: 319–328.

3–9.

14657–14660.


[18] English WR, Puente XS, Freije JM, Knauper V, Amour A, Merryweather A, Lopez-Otin C, Murphy G. Membrane type 4 matrix metalloproteinase (MMP17) has tumor necrosis factor-α convertase activity but does not activate pro-MMP2. J Biol Chem 2000;275: 14046–14055.

[5] Van Wart HE, Birkedal-Hansen H. The cysteine switch: a principle of regulation of metalloproteinase activity with potential applicability to the entire matrix metallo‐

[6] Brew K, Dinakarpandian D, Nagase H. Tissue inhibitors of metalloproteinases: evo‐

[7] MacPherson LJ, Bayburt EK, Capparelli MP, et al. Discovery of CGS 27023A, a nonpeptidic, potent, and orally active stromelysin inhibitor that blocks cartilage degrada‐

[8] Coussens LM, Fingleton B, Matrisian LM. Matrix metalloproteinase inhibitors and

[9] Broker LE, Giaccone G. The role of new agents in the treatment of non-small cell lung

[10] Hoekstra R, Eskens FA, Verweij J. Matrix metalloproteinase inhibitors: current devel‐

[11] Whelan, CJ. Metalloprotease inhibitors as anti-inflammatory agents: an evolving tar‐

[12] Morrison CJ, Butler GS, Rodriguez D, Overall CM. Matrix metalloproteinase proteo‐ mics: substrates, targets, and therapy. Curr Opin Cell Biol 2009;21: 645–653.

[13] Cauwe B, Van den Steen PE, Opdenakker G. The biochemical, biological, and patho‐ logical kaleidoscope of cell surface substrates processed by matrix metalloproteinas‐

[14] Struyf S, Proost P, Van Damme J. Regulation of the immune response by the interac‐

[15] ack RA, Rauch CT, Kozlosky CJ, Peschon JJ, Slack JL, Wolfson MF, Castner BJ, Stock‐ ing KL, Reddy P, Srinivasan S, Nelson N, Boiani N, Schooley KA, Gerhart M, Davis R, Fitzner JN, Johnson RS, Paxton RJ, March CJ, Cerretti DP. A metalloproteinase dis‐ integrin that releases tumour-necrosis factor-α from cells. Nature 1997;385:729–733.

[16] Moss ML, Jin SL, Milla ME, Bickett DM, Burkhart W, Carter HL, Chen WJ, Clay WC, Didsbury JR, Hassler D, Hoffman CR, Kost TA, Lambert MH, Leesnitzer MA, McCauley P, McGeehan G, Mitchell J, Moyer M, Pahel G, Rocque W, Overton LK, Schoenen F, Seaton T, Su JL, Warner J, Willarad D, Becherer JD. Cloning of a disinte‐ grin metalloproteinase that processes precursor tumour-necrosis factor-α. Nature

[17] Mohan MJ, Seaton T, Mitchell J, Howe A, Blackburn K, Burkhart W, Moyer M, Patel I, Waitt GM, Becherer JD, Moss ML, Milla ME. The tumor necrosis factor-α convert‐ ing enzyme (TACE): a unique metalloproteinase with highly defined substrate selec‐

proteinase gene family. Proc Natl Acad Sci USA 1990;87: 5578–5582.

tion in rabbits. J Med Chem 1997;40: 2525-2532.

cancer. Eur J Cancer 2002;38: 2347-2361

70 Lung Inflammation

get? Curr Opin Investig Drugs 2004;5: 511-516

es. Crit Rev Biochem Mol Biol 2007;42: 113–185.

1997;385:733–736.

tivity. Biochemistry 2002;41:9462–9469.

cancer: trials and tribulations. Science 2002;295: 2387-2392

opments and future perspectives. Oncologist 2001;6: 415-427

tion of chemokines and proteases. Adv Immunol 2003;81: 1–44.

lution, structure and function. Biochim Biophys Acta 2000;1477: 267–283.


[30] Maeda S, Dean DD, Gomez R, Schwartz Z, Boyan BD. The first stage of transforming growth factor β1 activation is release of the large latent complex from the extracellu‐ lar matrix of growth plate chondrocytes by matrix vesicle stromelysin-1 (MMP-3). Calcif Tissue Int 2002;70: 54–65.

two diverging murine counterparts of human interstitial collagenase (MMP-1) ex‐

The Role of MMPs in the Progression of Chronic Lung Inflammatory Diseases

http://dx.doi.org/10.5772/57391

73

pressed at sites of embryo implantation. J Biol Chem 2001;276: 10253-10262.

the underlying bone-resorbing compartment. J Cell Sci 1993;106: 1071-1082.

2008; 21: 401-408.

1355-1360.

590-596.

502-509.

Agents Chemother 2006;50: 739-743.

Cell Mol Biol 2001;24: 569-576.

Am J Respir Cell Mol Biol 2002;27: 122-124.

[42] Delaisse JM, Eeckhout Y, Neff L, Francois-Gillet C, Henriet P, Su Y, Vaes G, Baron R. (Pro)collagenase (matrix metalloproteinase-1) is present in rodent osteoclasts and in

[43] Ouchi H, Fujita M, Ikegame S, Ye Q, Inoshima I, Harada E, Kuwano K, Nakanishi Y. The role of collagenases in experimental pulmonary fibrosis. Pulm. Pharmacol. Ther.

[44] Swiderski R, Dencoff J, Floerchinger C, Shapiro S, Hunninghake G. Differential ex‐ pression of extracellular matrix remodeling genes in a murine model of bleomycin-

[45] Fujita M, Ye Q, Ouchi H, Harada E, Inoshima I, Kuwano K, Nakanishi Y. Doxycy‐ cline attenuated pulmonary fibrosis induced by bleomycin in mice. Antimicrob

[46] Cook DN, Brass DM, Schwartz DA. A matrix for new ideas in pulmonary fibrosis.

[47] Lim S, Roche N, Oliver BG, Mattos W, Barnes PJ, Chung KF. Balance of matrix metal‐ lo-protease-9 and tissue inhibitor of metalloprotease-1 from alveolar macrophages in cigarette smokers. Regulation by interleukin-10. Am J Respir Crit Care Med 2000;162:

[48] Dahlen B, Shute J, Howarth P. Immunohistochemical localisation of the matrix metal‐ loproteinases MMP-3 and MMP-9 within the airways in asthma. Thorax 1999;54:

[49] Vernooy JH, Dentener MA, van Suylen RJ, Buurman WA, Wouters EF. Intratracheal instillation of lipopolysaccharide in mice induces apoptosis in bronchial epithelial cells: no role for tumor necrosis factor-alpha and infiltrating neutrophils. Am J Respir

[50] Rowe SJ, Allen L, Ridger VC, Hellewell PG, Whyte MK. Caspase-1-deficient mice have delayed neutrophil apoptosis and a prolonged inflammatory response to lipo‐

[51] Fujita M, Harada E, Ikegame S, Ye Q, Ouchi H, Inoshima I, Kuwano K, Nakanishi Y. Doxycycline attenuated lung injury by its biological effect apart from its antimicrobi‐

[52] Wittels EH, Coalson JJ, Welch MH, Guenter CA. Pulmonary intravascular leukocyte sequestration. A potential mechanism of lung injury. Am Rev Respir Dis 1974;109:

polysaccharide-induced acute lung injury. J Immunol 2002;169: 6401-6407.

al function. Pulm Pharmacol Ther 2007;20: 669-675.

induced pulmonary fibrosis. Am J Pathol 1998;152: 821-828.


two diverging murine counterparts of human interstitial collagenase (MMP-1) ex‐ pressed at sites of embryo implantation. J Biol Chem 2001;276: 10253-10262.

[42] Delaisse JM, Eeckhout Y, Neff L, Francois-Gillet C, Henriet P, Su Y, Vaes G, Baron R. (Pro)collagenase (matrix metalloproteinase-1) is present in rodent osteoclasts and in the underlying bone-resorbing compartment. J Cell Sci 1993;106: 1071-1082.

[30] Maeda S, Dean DD, Gomez R, Schwartz Z, Boyan BD. The first stage of transforming growth factor β1 activation is release of the large latent complex from the extracellu‐ lar matrix of growth plate chondrocytes by matrix vesicle stromelysin-1 (MMP-3).

[31] Yu Q, Stamenkovic I. Cell surface-localized matrix metalloproteinase-9 proteolytical‐ ly activates TGF-β and promotes tumor invasion and angiogenesis. Genes Dev

[32] Karsdal MA, Larsen L, Engsig MT, Lou H, Ferreras M, Lochter A, Delaissé JM, Foged NT. Matrix metalloproteinase-dependent activation of latent transforming growth factor-β controls the conversion of osteoblasts into osteocytes by blocking osteoblast

[33] López-Boado YS, Wilson CL, Hooper LV, Gordon JI, Hultgren SJ, Parks WC. Bacteri‐ al exposure induces and activates matrilysin in mucosal epithelial cells. J Cell Biol

[34] Lopez-Boado YS, Wilson CL, Parks WC. Regulation of matrilysin expression in air‐ way epithelial cells by Pseudomonas aeruginosa flagellin. J Biol Chem 2001;276:

[35] Yao PM, Delclaux C, d'Ortho MP, Maitre B, Harf A, Lafuma C. Cell-matrix interac‐ tions modulate 92-kD gelatinase expression by human bronchial epithelial cells. Am J

[36] Lemjabbar H, Gosset P, Lechapt-Zalcman E, Franco-Montoya ML, Wallaert B, Harf A, Lafuma C. Overexpression of alveolar macrophage gelatinase B (MMP-9) in pa‐ tients with idiopathic pulmonary fibrosis. Effect of steroid and immunosuppressive

[37] Bakowska J, Adamson IY. Collagenase and gelatinase activities in bronchoalveolar lavage fluids during bleomycin-induced lung injury. J Pathol 1998;185: 319-323. [38] Corbel M, Caulet-Maugendre S, Germain N, Molet S, Lagente V, Boichot E. Inhibi‐ tion of bleomycin-induced pulmonary fibrosis in mice by the matrix metalloprotei‐

[39] Fukuda Y, Ishizaki M, Kudoh S, Kitaichi M Yamanaka N. Localization of matrix met‐ alloproteinases-1, -2, and -9 and tissue inhibitor of metalloproteinase-2 in interstitial

[40] Edwards ST, Cruz AC, Donnelly S, Dazin PF, Schulman ES, Jones KD, Wolters PJ, Hoopes C, Dolganov GM, Fang KC. c-Kit immunophenotyping and metalloprotei‐ nase expression profiles of mast cells in interstitial lung diseases. J Pathol 2005;206:

[41] Balbin M, Fueyo A, Knauper V, Lopez JM, Alvarez J, Sanchez LM, Quesada V, Bor‐ dallo J, Murphy G, Lopez-Otin C. Identification and enzymatic characterization of

Calcif Tissue Int 2002;70: 54–65.

apoptosis. J Biol Chem 2002;277: 44061–44067.

Respir Cell Mol Biol 1998;18: 813-822.

treatment. Am J Respir Cell Mol Biol 1999;20: 903-913.

nase inhibitor batimastat. J Pathol 2001;193: 538-545.

lung diseases. Lab Invest 1998;78: 687-698.

2000;14: 163–176.

72 Lung Inflammation

2000;148: 1305-1315.

41417-41423.

279-290.


[53] Corteling R, Wyss D, Trifilieff A. In vivo models of lung neutrophil activation. Com‐ parison of mice and hamsters. BMC Pharmacol 2002;2: 1.

[66] Zhu Z, Homer RJ, Wang Z, Chen Q, Geba GP, Wang J, Zhang Y, Elias JA. Pulmonary expression of interleukin-13 causes inflammation, mucus hypersecretion, subepithe‐ lial fibrosis, physiologic abnormalities, and eotaxin production. J Clin Invest

The Role of MMPs in the Progression of Chronic Lung Inflammatory Diseases

http://dx.doi.org/10.5772/57391

75

[67] Zheng T, Zhu Z, Wang Z, Homer RJ, Ma B, Riese RJ. Inducible targeting of IL-13 to the adult lung causes matrix metalloproteinase- and cathepsin-dependent emphyse‐

[68] Wang Z, Zheng T, Zhu Z, Homer RJ, Riese RJ, Chapman HA Jr, Shapiro SD, Elias JA. Interferon gamma induction of pulmonary emphysema in the adult murine lung. J

[69] Wert SE, Yoshida M, LeVine AM, Ikegami M, Jones T, Ross GF, Fisher JH, Korfhagen TR, Whitsett JA. Increased metalloproteinase activity, oxidant production, and em‐ physema in surfactant protein D gene-inactivated mice. Proc Natl Acad Sci USA

[70] Shibata Y, Zsengeller Z, Otake K, Palaniyar N, Trapnell BC. Alveolar macrophage deficiency in osteopetrotic mice deficient in macrophage colony-stimulating factor is spontaneously corrected with age and associated with matrix metalloproteinase ex‐

[71] Morris DG, Huang X, Kaminski N, Wang Y, Shapiro SD, Dolganov G, Glick A, Shep‐ pard D. Loss of integrin alpha(v)beta6- mediated TGF-beta activation causes

[72] Yoshida M, Korfhagen TR, Whitsett JA. Surfactant protein D regulates NF-kappa B and matrix metalloproteinase production in alveolar macrophages via oxidant-sensi‐

[73] Shipley JM, Wesselschmidt RL, Kobayashi DK, Ley TJ, Shapiro SD. Metalloelastase is required for macrophage-mediated proteolysis and matrix invasion in mice. Proc

[74] Hautamaki RD, Kobayashi DK, Senior RM, Shapiro SD. Requirement for macro‐ phage elastase for cigarette smoke-induced emphysema in mice. Science 1997;277:

[75] Shapiro SD, Goldstein NM, Houghton AM, Kobayashi DK, Kelley D, Belaaouaj A. Neutrophil elastase contributes to cigarette smoke-induced emphysema in mice. Am

[76] D'Armiento J, Dalal SS, Okada Y, Berg RA, Chada K. Collagenase expression in the lungs of transgenic mice causes pulmonary emphysema. Cell 1992;71: 955–961. [77] Leco KJ, Waterhouse P, Sanchez OH, Gowing KL, Poole AR, Wakeham A, Mak TW, Khokha R. Spontaneous air space enlargement in the lungs of mice lacking tissue in‐

hibitor of metalloproteinases-3 (TIMP-3). J Clin Invest 2001;108: 817–829.

1999;103: 779-788.

2000;97: 5972–5977.

2002–2004.

ma. J Clin Invest 2000;106: 1081-1093.

pression and emphysema. Blood 2001;98: 2845–2852.

tive pathways. J Immunol 2001;166: 7514-7519.

Natl Acad Sci USA 1996; 93: 3942-3946.

J Pathol 2003;163: 2329-2335.

MMP12-dependent emphysema. Nature 2003;422: 169–173.

Exp Med 2000;192: 1587-1600.


[66] Zhu Z, Homer RJ, Wang Z, Chen Q, Geba GP, Wang J, Zhang Y, Elias JA. Pulmonary expression of interleukin-13 causes inflammation, mucus hypersecretion, subepithe‐ lial fibrosis, physiologic abnormalities, and eotaxin production. J Clin Invest 1999;103: 779-788.

[53] Corteling R, Wyss D, Trifilieff A. In vivo models of lung neutrophil activation. Com‐

[54] Hasday J, Dubin W, Fitzgerald T, Bascom R. Cigarettes are a rich source of bacterial

[55] Hasday JD, Bascom R, Costa JJ, Fitzgerald T, Dubin W. Bacterial endotoxin is an ac‐

[56] Vernooy JH, Dentener MA, van Suylen RJ, Buurman WA, Wouters EF. Longterm in‐ tratracheal lipopolysaccharide exposure in mice results in chronic lung inflammation

[57] Brusselle GG, Bracke KR, Maes T, D'hulst AI, Moerloose KB, Joos GF, Pauwels RA.

[58] Miyazaki Y, Araki K, Vesin C, Garcia I, Kapanci Y, Whitsett JA, Piguet PF, Vassalli P. Expression of a tumor necrosis factor-alpha transgene in murine lung causes lym‐ phocytic and fibrosing alveolitis. A mouse model of progressive pulmonary fibrosis.

[59] Piguet PF, Collart MA, Grau GE, Kapanci Y, Vassalli P. Tumor necrosis factor/ cachectin plays a key role in bleomycin-induced pneumopathy and fibrosis. J Exp

[60] Fujita M, Shannon JM, Irvin CG, Fagan KA, Cool C, Augustin A, Mason RJ. Overex‐ pression of tumor necrosis factor-a produces an increase in lung volumes and pul‐ monary hypertension. Am. J. Physiol. Lung Cell Mol. Physiol. 2001;280: L39-L49.

[61] Fujita M, Mason RJ, Cool C, Shannon JM, Hara N, Fagan KA. Pulmonary hyperten‐ sion in TNF-alpha-overexpressing mice is associated with decreased VEGF gene ex‐

[62] Fujita M, Shannon JM, Morikawa O, Gauldie J, Hara N, Mason RJ. Overexpression of tumor necrosis factor-alpha diminishes pulmonary fibrosis induced by bleomycin or

[63] Churg A, Wang RD, Tai H, Wang X, Xie C, Wright JL. Macrophage metalloelastase mediates acute cigarette smoke-induced inflammation via tumor necrosis factor-{al‐

[64] Tang W, Geba GP, Zheng T, Ray P, Homer RJ,Kuhn C 3rd, Flavell RA, Elias JA. Tar‐ geted expression of IL-11 in the murine airway causes lymphocytic inflammation, bronchial remodeling, and airways obstruction. J Clin Invest 1996;98: 2845-2853.

[65] Kuhn C, 3rd, Homer RJ, Zhu Z, Ward N, Flavell RA, Geba GP, Elias JA. Airway hy‐ perresponsiveness and airway obstruction in transgenic mice. Morphologic corre‐ lates in mice overexpressing interleukin (IL)-11 and IL-6 in the lung. Am J Respir Cell

transforming growth factor-beta. Am J Respir Cell Mol Biol 2003;29: 669-676.

pha} release. Am J Respir Crit Care Med 2003;167: 1083-1089..

and persistent pathology. Am J Respir Cell Mol Biol 2002;26: 152-159.

Murine models of COPD. Pulm Pharmacol Ther. 2006;19:155-65.

parison of mice and hamsters. BMC Pharmacol 2002;2: 1.

tive component of cigarette smoke. Chest 1999;115: 829-835.

endotoxin. Chest 1996;109: 63S-64S.

74 Lung Inflammation

J Clin Invest. 1995; 96: 250-259.

pression. J Appl Physiol 2002;93: 2162-2170.

Med 1989;170: 655-663.

Mol Biol 2000;22: 289-295.


[78] Lanone S, Zheng T, Zhu Z, Liu W, Lee CG, Ma B, Chen Q, Homer RJ, Wang J, Rabach LA, Rabach ME, Shipley JM, Shapiro SD, Senior RM, Elias JA. Overlapping and en‐ zyme-specific contributions of matrix metalloproteinases-9 and -12 in IL-13-induced inflammation and remodeling. J Clin Invest 2002;110: 463–474.

[90] Choe KH, Taraseviciene-Stewart L, Scerbavicius R, Gera L, Tuder RM, Voelkel NF. Methylprednisolone causes matrix metalloproteinase-dependent emphysema in

The Role of MMPs in the Progression of Chronic Lung Inflammatory Diseases

http://dx.doi.org/10.5772/57391

77

[91] Daheshia M. Therapeutic Inhibition of Matrix Metalloproteinases for the Treatment of Chronic Obstructive Pulmonary Disease (COPD) Curr Med Res Opin 2005;21:

[93] Barnes PJ. New anti-inflammatory targets for chronic obstructive pulmonary disease.

[94] Churg A, Wang R, Wang X, Onnervik PO, Thim K, Wright JL. Effect of an MMP-9/ MMP-12 inhibitor on smoke-induced emphysema and airway remodelling in guinea

[92] Barnes PJ. New treatments for COPD. Nat Rev Drug Discov 2002;1: 437-446.

adult rats. Am. J. Respir. Crit. Care Med., 2003;167:1516-1521.

Nat Rev Drug Discov. 2013;12: 543-559.

pigs. Thorax 2007; 62: 706–713.

587-594.


[78] Lanone S, Zheng T, Zhu Z, Liu W, Lee CG, Ma B, Chen Q, Homer RJ, Wang J, Rabach LA, Rabach ME, Shipley JM, Shapiro SD, Senior RM, Elias JA. Overlapping and en‐ zyme-specific contributions of matrix metalloproteinases-9 and -12 in IL-13-induced

[79] Balbín M, Fueyo A, Knäuper V, López JM, Alvarez J, Sánchez LM, Quesada V, Bor‐ dallo J, Murphy G, López-Otín C. Identification and enzymatic characterization of two diverging murine counterparts of human interstitial collagenase (MMP-1) ex‐

[81] Imai K, Dalal SS, Chen ES, Downey R, Schulman LL, Ginsburg M, D'Armiento J. Hu‐ man collagenase (matrix metalloproteinase-1) expression in the lungs of patients

[82] Ohnishi K, Takagi M, Kurokawa Y, Satomi S, Konttinen YT. Matrix metalloprotei‐ nase-mediated extracellular matrix protein degradation in human pulmonary em‐

[83] Betsuyaku T, Nishimura M, Takeyabu K, Tanino M, Venge P, Xu S, Kawakami Y. Neutrophil granule proteins in bronchoalveolar lavage fluid from subjects with sub‐

[84] Finlay GA, Russell KJ, McMahon KJ, D'arcy EM, Masterson JB, FitzGerald MX, O'Connor CM. Elevated levels of matrix metalloproteinases in bronchoalveolar lav‐

[85] Shapiro SD. Elastolytic metalloproteinases produced by human mononuclear phago‐ cytes. Potential roles in destructive lung disease. Am J Respir Crit Care Med

[86] Segura-Valdez L, Pardo A, Gaxiola M, Uhal BD, Becerril C, Selman M. Upregulation of gelatin ases A and B, collagenases 1 and 2, and increased parenchymal cell death

[87] Han Z, Junxu, Zhong N. Expression of matrix metalloproteinases MMP-9 within the

[88] Betsuyaku T, Tanino M, Nagai K, Nasuhara Y, Nishimura M, Senior RM. Extracellu‐ lar matrix metalloproteinase inducer is increased in smokers' bronchoalveolar lavage

[89] Vignola AM, Riccobono L, Mirabella A, Profita M, Chanez P, Bellia V, Mautino G, D'accardi P, Bousquet J, Bonsignore G. Sputum metallo-proteinase-9/tissue inhibitor of metalloproteinase-1 ratio correlates with airflow obstruction in asthma and chron‐

pressed at sites of embryo implantation. J Biol Chem 2001;276: 10253–10262.

inflammation and remodeling. J Clin Invest 2002;110: 463–474.

[80] Shapiro SD. Proteolysis in the lung. Eur Respir J Suppl 2003;44: 30s-32s.

with emphysema. Am J Respir Crit Care Med 2001;163: 786-791

clin ical emphysema. Am J Respir Crit Care Med 1999;159: 1985-1991

age fluid of emphysema tous patients. Thorax 1997;52: 502-506.

physema. Lab Invest 1998;78: 1077-1087.

1994;150: S160-164

76 Lung Inflammation

in COPD. Chest 2000;117: 684-694

airways in asthma. Respir Med 2003;97: 563-567.

fluid. Am J Respir Crit Care Med 2003;168: 222-227.

ic bronchitis. Am J Respir Crit Care Med 1998;158: 1945-1950


**Chapter 4**

**Nature and Consequences of the Systemic Inflammatory**

Lung inflammation is the basis for the majority of acute and chronic lung conditions. Acute lung injury (ALI) caused by either communicable (such as infection) or non-communicable (such as acid aspiration) diseases are characterized by a rapidly induced inflammatory response in the lung. There are numerous causes for ALI, as the lung is exposed to external factors either via the airways (infectious agents and environmental pollutants) or via the blood stream (sepsis, endotoxin, fat) and, when severe, can lead to acute respiratory distress syndrome (ARDS), a spectrum of lung diseases characterized by a severe inflammatory process in the lung parenchyma causing diffuse alveolar damage and respiratory failure [1, 2]. This acute inflammatory response in the lung is strongly associated with a systemic inflammatory response that may lead to multiple organ dysfunction and is associated with high mortality [3]. Similarly, chronic inflammatory lung conditions such as chronic obstructive pulmonary disease (COPD), asthma, bronchiectasis and interstitial lung diseases, especially those associated with collagen vascular disease, have in recent years also been shown to be accom‐ panied by a systemic inflammatory response, albeit different in nature [4-14]. In addition, the systemic response induced by chronic lung inflammation is also associated with downstream adverse effects on different organ systems. This chapter will focus on defining the nature and features of this systemic response as a consequence of lung inflammation and will focus

**2. Lung conditions associated with a systemic inflammatory response**

Numerous lung conditions, especially inflammatory lung conditions, are known to be associated with a systemic inflammatory response. Although the associations and consequen‐

> © 2014 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

**Response Induced by Lung Inflammation**

Kunihiko Hiraiwa and Stephan F. van Eeden

Additional information is available at the end of the chapter

predominantly on chronic inflammatory lung conditions.

http://dx.doi.org/10.5772/57392

**1. Introduction**
