**5. Pathogenesis**

The exact mechanism of late pulmonary complication of SM exposure are not fully defined (14).Although the pathogenesis of COPD has completely determined and is mainly dependent on chronic inflammation and oxidative stress following activation of airway inflammatory cells, but there are few studies about the inflammatory basis of mustard lung (8,9,15).The pathological studies have shown that mustard lung is a neutrophilic / lymphocytic disorder (16,17).Also bronchiolar disease with varying degrees of inflammation as the main pathological finding, was demonstrated in a recent pathologic study in patients with sulfur mustard injury (18 ). According to the previous pathological studies, it seems that activation of inflammatory cells and generation of reactive oxygen species resulting in oxidative stress be involved (16, 17). It has been shown that decreased glutathione and increased serum malondialdehyde levels in mustard lung patients can be an indicator of oxidative-antioxidative system imbalance (16). The previous animal model studies have mentioned that the activation of inflammatory cells are involved in the pathogenesis of SM lung injury (19, 20).It is well documented that oxidative antioxidative imbalance may result in oxidative stress and triggering inflammatory process (21).

Despite the accepted role of inflammatory cytokines in acute pulmonary complications of SM, there are limited studies on the level of cytokines in the long term complications of SM

cross" (it was a symbol means "skin damaging agent" during world war I) (11,12) .It is a colorless to yellowish- brown oily liquid at room temperature that converts to a gas with

SM is absorbed by different ways: inhalation, through the skin, eyes, and gasterointestinal tract due to consumption of contaminated food (3 ).In large amount exposure, it can cause damages in rapid proliferating tissues particularly bone marrow (3 ).SM can cause different

Following the SM exposure, acute and late (long term) complications may occur. The long term complications of SM exposure are much serious than acute effects .Generally the long term effects of SM exposure occur several years after a mild contact and are totally different from continuous longtime exposure (mainly occupational exposure) (12, 13).Several studies in Iran demonstrated that the most common late complication are respiratory problems, including chronic obstructive pulmonary disease (COPD), chronic bronchitis, bronchiolitis obliterans, bronchiectasis, airway hyperreactivity, and lung fibrosis (3-6).Ophthalmologic and cutenous problems are also seen in this period. Unfortunately, the respiratory problems usually exacerbate over time (12).A unique form of COPD known as" Mustard lung" is

The exact mechanism of late pulmonary complication of SM exposure are not fully defined (14).Although the pathogenesis of COPD has completely determined and is mainly dependent on chronic inflammation and oxidative stress following activation of airway inflammatory cells, but there are few studies about the inflammatory basis of mustard lung (8,9,15).The pathological studies have shown that mustard lung is a neutrophilic / lymphocytic disorder (16,17).Also bronchiolar disease with varying degrees of inflammation as the main pathological finding, was demonstrated in a recent pathologic study in patients with sulfur mustard injury (18 ). According to the previous pathological studies, it seems that activation of inflammatory cells and generation of reactive oxygen species resulting in oxidative stress be involved (16, 17). It has been shown that decreased glutathione and increased serum malondialdehyde levels in mustard lung patients can be an indicator of oxidative-antioxidative system imbalance (16). The previous animal model studies have mentioned that the activation of inflammatory cells are involved in the pathogenesis of SM lung injury (19, 20).It is well documented that oxidative antioxidative imbalance may result

Despite the accepted role of inflammatory cytokines in acute pulmonary complications of SM, there are limited studies on the level of cytokines in the long term complications of SM

weapon system delivery (3,11).It has the odor of mustard, garlic, or onion (3 ).

Fig. 1. Molecular structure of sulfur mustard

frequently seen as a long term complication (7).

in oxidative stress and triggering inflammatory process (21).

**4. Classification** 

**5. Pathogenesis** 

biochemical reactions and alterations in DNA structure ( 1).

injury .Our recent studies (8,9) on 50 stable mustard lung patients with all stages according to GOLD (Global Initiative for Chronic Obstructive Lung Disease) classification (Fig.2) (22),showed that despite the exclusion of smoking, cardiovascular diseases, infections, and other important inflammatory conditions, serum level of highly sensitive c reactive protein (hs-CRP) and interleukin 6 (IL-6), as inflammatory markers, are elevated in mustard lung patients in comparison of normal controls and are directly related to severity of COPD according to spirometry findings (Fig.3,4)(8,9). It is clearly documented that IL-6 has an important part in reduced forced expiratory volume in one second (FEV1), impaired functional capacity, and worsening the underlying inflammatory condition by release of acute phase proteins (23,24).Also the previous studies in COPD patients have shown that the serum hs-CRP is related to severity of airflow obstruction (25,26).

Fig. 2. The frequency of GOLD stages in mustard lung patients (9)

Fig. 3. The correlation of FEV1 and hs-CRP in mustard lung patients (8)

COPD Due to Sulfur Mustard (Mustard Lung) 235

These findings provide evidence of the possibility of an inflammatory basis for the late pulmonary complications of sulfur mustard exposure and is in accordance with previous studies in other COPD patients which pointed out that, even during the stable phase of

The most common compliant of mustard lung patients is chronic cough (12).A study showed that a triad of cough, expectoration and dyspnea was found in more than 80% of

On physical examination, crackles, wheezing, and rhonchi depending to the state of the patient, can be seen (12, 29).The attacks of COPD exacerbation with increasing the severity of dyspnea, cough, and discoloration of sputum, is a common clinical presentation (12, 30). The late pulmonary complications of SM injury may occur in patients who had not developed acute symptoms (12).A study on patients who did not have acute symptoms showed that 38%

Our previous studies on exercise tolerance of mustard lung patients have shown that the mean exercise capacity of these patients measured by 6 minute walk distance test (6MWD) has been decreased in comparison of normal population (8,9 ).Also the evaluation of quality of life in mustard lung patients showed significant impairment in this assessment by saint George respiratory questionnaire (SGRQ) (8,9,32).Additionally ,in our study the BODE (body mass index, obstruction, dyspnea, and exercise capacity) index had significant

Spirometry is a common diagnostic way for staging the severity of pulmonary impairment. Like to COPD due to other causes, generally an obstructive pattern is present in patients. A study showed that FEV1 is decreased at a rate of 50 ml/year in mustard lung patients (11, 33). In body plethysmography, total lung capacity (TLC) and residual volume (RV) are markedly increased and Diffusing Capacity of the Lung for Carbon Monoxide (DLCO)

Since the majority of mustard lung patients have normal or near normal chest x-ray (CXR) , some authors believe that CXR is not a reliable diagnostic imaging modality in these patients (12,35). Increased bronchovascular markings, and hyperinflation, pulmonary

Chest HRCT has became a imaging modality of choice in SM patients (12).Air trapping and

airway abnormal wall thickening are the most common HRCT finding (12,37).

COPD, serum levels of inflammatory markers, including IL-6, may be raised (8,9)

of these patients had air trapping on high resolution CT (HRCT) of chest (31).

correlation with the serum level of inflammatory markers (8,9).

**6. Clinical manifestations** 

**7. Diagnostic evaluation Pulmonary function tests** 

remains normal (11, 34).

hypertension can be seen in CXR (12, 36).

**Chest x-ray** 

**HRCT** 

Iranian veterans 3 years after the exposure (1,28).

Fig. 4. The correlation of FEV1 and IL-6 in mustard lung patients (9)

Furthermore, the BODE (body mass index, obstruction, dyspnea, and exercise capacity) index, that is more reliable parameter of COPD morbidity and mortality, was significantly correlated with the serum IL-6 level (Fig 5) (9).

Fig. 5. The correlation of BODE index and serum IL-6 (9)

Additionally increased levels of IL-8 in the bronchoalveolar lavage fluid of patients with sulfur mustard poisoning and late pulmonary complications have been demonstrated (15) Despite these studies, few studies reported that inflammatory mediators probably do not have any major role in the pathogenesis and persistence of pulmonary complications of sulfur mustard exposure (27).

These findings provide evidence of the possibility of an inflammatory basis for the late pulmonary complications of sulfur mustard exposure and is in accordance with previous studies in other COPD patients which pointed out that, even during the stable phase of COPD, serum levels of inflammatory markers, including IL-6, may be raised (8,9)
